The use of IVIg in fetal and neonatal alloimmune thrombocytopenia— Principles and mechanisms

  • Hanna Wabnitz
    Affiliations
    Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S 1A8, Canada

    Keenan Research Centre, Department of Laboratory Medicine, St. Michael’s Hospital, Toronto, ON, M5B 1W8, Canada

    Toronto Platelet Immunobiology Group (TPIG), Toronto, ON, M5B 1T8, Canada
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  • Ramsha Khan
    Affiliations
    Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S 1A8, Canada

    Keenan Research Centre, Department of Laboratory Medicine, St. Michael’s Hospital, Toronto, ON, M5B 1W8, Canada

    Toronto Platelet Immunobiology Group (TPIG), Toronto, ON, M5B 1T8, Canada

    Canadian Blood Services, Centre for Innovation, Ottawa, ON, K1G 4J5, Canada
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  • Alan H. Lazarus
    Correspondence
    Corresponding author at: 219 Victoria Street, Room 422, Keenan Research Centre, St. Michael’s Hospital, Toronto, ON, M5B 1T8, Canada.
    Affiliations
    Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S 1A8, Canada

    Keenan Research Centre, Department of Laboratory Medicine, St. Michael’s Hospital, Toronto, ON, M5B 1W8, Canada

    Toronto Platelet Immunobiology Group (TPIG), Toronto, ON, M5B 1T8, Canada

    Canadian Blood Services, Centre for Innovation, Ottawa, ON, K1G 4J5, Canada

    Department of Medicine, St. Michael’s Hospital, University of Toronto, Toronto, ON, M5S 1A8, Canada
    Search for articles by this author
Published:December 31, 2019DOI:https://doi.org/10.1016/j.transci.2019.102710

      Abstract

      Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare neonatal disorder that is caused by alloimmunization against platelet antigens during pregnancy. Although rare, affecting only 1 in 1000 live births, it can cause intracranial hemorrhage and other bleeding complications that can lead to miscarriage, stillbirth and life-long neurological complications. One of the gold-standard therapies for at risk pregnancies is the administration of IVIg. Although IVIg has been used in a variety of different disorders for over 40 years, its exact mechanism of action is still unknown. In FNAIT, the majority of its therapeutic effect is thought the be mediated through the neonatal Fc receptor, however other mechanisms cannot be excluded. Due to safety, supply and other concerns that are associated with IVIg use, alternative therapies that could replace IVIg are additionally being investigated. This includes the possibility of a prophylaxis regimen for FNAIT, similarly to what has been successfully used in hemolytic disease of the fetus and newborn for over 50 years.

      Keywords

      1. Introduction

      Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a severe, but rare disorder that affects about 1 in 1000 newborns [
      • Baker J.M.
      • Shehata N.
      • Bussel J.
      • Murphy M.F.
      • Greinacher A.
      • Bakchoul T.
      • et al.
      Postnatal intervention for the treatment of FNAIT: a systematic review.
      ]. It is characterized by the destruction of fetal platelets by maternal antibodies directed against paternally inherited platelet antigens [
      • Winkelhorst D.
      • Oepkes D.
      Foetal and neonatal alloimmune thrombocytopenia.
      ]. The major causative antigen in Caucasians is the human platelet antigen 1a (HPA-1a), but more than 30 additional implicated antigens including HPA-5b, HPA-15, HPA-3a and HPA-2a or 2b have been identified so far [
      • Winkelhorst D.
      • Oepkes D.
      Foetal and neonatal alloimmune thrombocytopenia.
      ,
      • Arnold D.M.
      • Smith J.W.
      • Kelton J.G.
      Diagnosis and management of neonatal alloimmune thrombocytopenia.
      ]. The most feared complication is intracranial hemorrhage (ICH) as it carries significant morbidity and mortality and usually occurs during the late stages of pregnancy [
      • Baker J.M.
      • Shehata N.
      • Bussel J.
      • Murphy M.F.
      • Greinacher A.
      • Bakchoul T.
      • et al.
      Postnatal intervention for the treatment of FNAIT: a systematic review.
      ,
      • Bertrand G.
      • Kaplan C.
      How do we treat fetal and neonatal alloimmune thrombocytopenia?.
      ]. Up to 20 % of FNAIT neonates [
      • Baker J.M.
      • Shehata N.
      • Bussel J.
      • Murphy M.F.
      • Greinacher A.
      • Bakchoul T.
      • et al.
      Postnatal intervention for the treatment of FNAIT: a systematic review.
      ] are affected by ICH and about 30 % of cases are fatal [
      • Lieberman L.
      • Greinacher A.
      • Murphy M.F.
      • Bussel J.
      • Bakchoul T.
      • Corke S.
      • et al.
      Fetal and neonatal alloimmune thrombocytopenia: recommendations for evidence-based practice, an international approach.
      ]. Non-fatal cases can be affected by life-long sequela including seizures, intellectual disability or cortical blindness [
      • Arnold D.M.
      • Smith J.W.
      • Kelton J.G.
      Diagnosis and management of neonatal alloimmune thrombocytopenia.
      ,
      • Winkelhorst D.
      • Kamphuis M.M.
      • Steggerda S.J.
      • Rijken M.
      • Oepkes D.
      • Lopriore E.
      • et al.
      Perinatal outcome and long-term neurodevelopment after intracranial haemorrhage due to fetal and neonatal alloimmune thrombocytopenia.
      ].

      2. Current treatment options

      Due to the lack of a population-based screening program as it is performed in hemolytic disease of the fetus and newborn (HDFN), the red blood cell counterpart to FNAIT, diagnosis is mostly made after birth through the observation of neonatal thrombocytopenia [
      • Serrarens-Janssen V.M.
      • Semmekrot B.A.
      • Novotny V.M.
      • Porcelijn L.
      • Lotgering F.K.
      • Delemarre F.M.
      • et al.
      Fetal/neonatal allo-immune thrombocytopenia (FNAIT): past, present, and future.
      ] and bleeding complications [
      • Winkelhorst D.
      • Oepkes D.
      • Lopriore E.
      Fetal and neonatal alloimmune thrombocytopenia: evidence based antenatal and postnatal management strategies.
      ]. This means that treatment is generally only available for women who had a previous pregnancy which was complicated by FNAIT or who have a sister who’s pregnancy was affected [
      • Winkelhorst D.
      • Oepkes D.
      Foetal and neonatal alloimmune thrombocytopenia.
      ]. Consequently, treatment tends to be individualized to the patient [
      • Arnold D.M.
      • Smith J.W.
      • Kelton J.G.
      Diagnosis and management of neonatal alloimmune thrombocytopenia.
      ,
      • Winkelhorst D.
      • Murphy M.F.
      • Greinacher A.
      • Shehata N.
      • Bakchoul T.
      • Massey E.
      • et al.
      Antenatal management in fetal and neonatal alloimmune thrombocytopenia: a systematic review.
      ] and is best performed at a center specializing in neonatal care in FNAIT [
      • Winkelhorst D.
      • Oepkes D.
      Foetal and neonatal alloimmune thrombocytopenia.
      ]. Overall, medical intervention has been aimed at two outcomes – treating a FNAIT-affected newborn and preventing ICH in subsequent pregnancies [
      • Winkelhorst D.
      • Oepkes D.
      • Lopriore E.
      Fetal and neonatal alloimmune thrombocytopenia: evidence based antenatal and postnatal management strategies.
      ].

      2.1 Antenatal treatment

      There are currently no clinical parameters that are considered to be directly linked to disease severity with the exception of the occurrence of ICH in a previous pregnancy [
      • Winkelhorst D.
      • Oepkes D.
      Foetal and neonatal alloimmune thrombocytopenia.
      ]. The true recurrence rate for ICH in a subsequent pregnancy is unknown but estimated to be high [
      • Radder C.M.
      • Brand A.
      • Kanhai H.H.H.
      Will it ever be possible to balance the risk of intracranial haemorrhage in fetal or neonatal alloimmune thrombocytopenia against the risk of treatment strategies to prevent it?.
      ]. Consequently, the main goal of antenatal treatment is to prevent severe bleeding and ICH rather than thrombocytopenia [
      • Winkelhorst D.
      • Oepkes D.
      • Lopriore E.
      Fetal and neonatal alloimmune thrombocytopenia: evidence based antenatal and postnatal management strategies.
      ].
      Initially, antenatal treatment consisted of ultrasound-guided fetal blood sampling (FBS) and intrauterine platelet transfusions (IUPT) [
      • Serrarens-Janssen V.M.
      • Semmekrot B.A.
      • Novotny V.M.
      • Porcelijn L.
      • Lotgering F.K.
      • Delemarre F.M.
      • et al.
      Fetal/neonatal allo-immune thrombocytopenia (FNAIT): past, present, and future.
      ]. While the technique allows fetal platelet monitoring [
      • Winkelhorst D.
      • Oepkes D.
      Foetal and neonatal alloimmune thrombocytopenia.
      ], it requires continuous cordocentesis which, in a thrombocytopenic fetus can lead to fetal death [
      • Serrarens-Janssen V.M.
      • Semmekrot B.A.
      • Novotny V.M.
      • Porcelijn L.
      • Lotgering F.K.
      • Delemarre F.M.
      • et al.
      Fetal/neonatal allo-immune thrombocytopenia (FNAIT): past, present, and future.
      ,
      • Radder C.M.
      • Brand A.
      • Kanhai H.H.H.
      Will it ever be possible to balance the risk of intracranial haemorrhage in fetal or neonatal alloimmune thrombocytopenia against the risk of treatment strategies to prevent it?.
      ]. Additionally, the transfused platelets have a short half-life [
      • Kamphuis M.M.
      • Oepkes D.
      Fetal and neonatal alloimmune thrombocytopenia: prenatal interventions.
      ]. Due to complications, FBS and IUPT have been nearly completely replaced as the treatment for FNAIT with only a few centers still using it as a diagnostic tool [
      • van den Akker E.S.
      • Oepkes D.
      • Lopriore E.
      • Brand A.
      • Kanhai H.H.
      Noninvasive antenatal management of fetal and neonatal alloimmune thrombocytopenia: safe and effective.
      ].
      Nowadays, intravenous immunoglobulin (IVIg) is the first line of treatment. Since its introduction for FNAIT in 1988 by Bussel et al. [
      • Bussel J.B.
      • Berkowitz R.L.
      • McFarland J.G.
      • Lynch L.
      • Chitkara U.
      Antenatal treatment of neonatal alloimmune thrombocytopenia.
      ], IVIg has been shown to be highly effective in preventing ICH with a 98.7 % success rate [
      • Winkelhorst D.
      • Murphy M.F.
      • Greinacher A.
      • Shehata N.
      • Bakchoul T.
      • Massey E.
      • et al.
      Antenatal management in fetal and neonatal alloimmune thrombocytopenia: a systematic review.
      ], however it should be noted that it is used “off-label” and its effectiveness has therefore never been tested in a placebo-controlled randomized trial [
      • Lieberman L.
      • Greinacher A.
      • Murphy M.F.
      • Bussel J.
      • Bakchoul T.
      • Corke S.
      • et al.
      Fetal and neonatal alloimmune thrombocytopenia: recommendations for evidence-based practice, an international approach.
      ]. Despite its routine administration, the gestational age at which to start treatment as well as the IVIg dose still vary greatly between centers [
      • Winkelhorst D.
      • Oepkes D.
      Foetal and neonatal alloimmune thrombocytopenia.
      ]. Most commonly an empirical dose of 1 g/kg per week is used in adaptation from the dose used to treat immune thrombocytopenia (ITP) in pregnancy [
      • Winkelhorst D.
      • Oepkes D.
      • Lopriore E.
      Fetal and neonatal alloimmune thrombocytopenia: evidence based antenatal and postnatal management strategies.
      ]. No conclusive randomized controlled trial has investigated whether the dose of IVIg as well as the treatment start date has an effect on outcome [
      • Lieberman L.
      • Greinacher A.
      • Murphy M.F.
      • Bussel J.
      • Bakchoul T.
      • Corke S.
      • et al.
      Fetal and neonatal alloimmune thrombocytopenia: recommendations for evidence-based practice, an international approach.
      ]. Mothers are usually stratified into two groups based on the occurrence or non-occurrence of ICH in a previous pregnancy [
      • Winkelhorst D.
      • Oepkes D.
      • Lopriore E.
      Fetal and neonatal alloimmune thrombocytopenia: evidence based antenatal and postnatal management strategies.
      ]. For the high-risk group (i.e. previous pregnancy affected by ICH) different studies suggest 1 g/kg or even 2 g/kg of IVIg per week [
      • Winkelhorst D.
      • Murphy M.F.
      • Greinacher A.
      • Shehata N.
      • Bakchoul T.
      • Massey E.
      • et al.
      Antenatal management in fetal and neonatal alloimmune thrombocytopenia: a systematic review.
      ], while the low-risk group (previous pregnancy not affected by ICH) has been considered to be appropriately managed with 0.5 g/kg [
      • Winkelhorst D.
      • Oepkes D.
      • Lopriore E.
      Fetal and neonatal alloimmune thrombocytopenia: evidence based antenatal and postnatal management strategies.
      ]. Although the trial comparing 0.5 g/kg of IVIg with the standard dose of 1 g/kg recorded no incidence of ICH, it was ended prematurely due poor recruitment and therefore lacked the statistical power to compare the effectiveness of the lower dose versus the standard 1 g/kg dose [
      • Paridaans N.P.
      • Kamphuis M.M.
      • Taune Wikman A.
      • Tiblad E.
      • Van den Akker E.S.
      • Lopriore E.
      • et al.
      Low-dose versus standard-dose intravenous immunoglobulin to prevent fetal intracranial hemorrhage in fetal and neonatal alloimmune thrombocytopenia: a randomized trial.
      ]. The gestational age at which treatment is being initiated also varies greatly between centers. In Europe 28 weeks is commonly used as a start date, whereas in the US treatment tends to start at 20 or 24 weeks [
      • Winkelhorst D.
      • Oepkes D.
      Foetal and neonatal alloimmune thrombocytopenia.
      ]. A recent guideline recommendation by the International Collaboration for Transfusion Medicine Guidelines (ICTMG) proposes even earlier start dates. Here, treatment is suggested to commence at 12–16 weeks gestation for the high-risk group and at 20–22 weeks gestation for the low-risk group [
      • Lieberman L.
      • Greinacher A.
      • Murphy M.F.
      • Bussel J.
      • Bakchoul T.
      • Corke S.
      • et al.
      Fetal and neonatal alloimmune thrombocytopenia: recommendations for evidence-based practice, an international approach.
      ].
      In some centers, corticosteroids are added to the IVIg treatment regimen. This intervention was also initiated by Bussel et al., however the addition of dexamethasone caused significant side effects [
      • Bussel J.B.
      • Berkowitz R.L.
      • McFarland J.G.
      • Lynch L.
      • Chitkara U.
      Antenatal treatment of neonatal alloimmune thrombocytopenia.
      ]. Dexamethasone has since been mostly replaced by prednisone at a dose of 0.5 g/kg per day [
      • Lieberman L.
      • Greinacher A.
      • Murphy M.F.
      • Bussel J.
      • Bakchoul T.
      • Corke S.
      • et al.
      Fetal and neonatal alloimmune thrombocytopenia: recommendations for evidence-based practice, an international approach.
      ] although the benefits remain unclear. A recent systematic review concluded that the majority of studies did not show a significant difference in platelet count, ICH or mortality when comparing standard IVIg treatment to IVIg plus steroids [
      • Winkelhorst D.
      • Murphy M.F.
      • Greinacher A.
      • Shehata N.
      • Bakchoul T.
      • Massey E.
      • et al.
      Antenatal management in fetal and neonatal alloimmune thrombocytopenia: a systematic review.
      ].

      2.2 Postnatal treatment

      The main goal of postnatal treatment is to prevent hemorrhaging [
      • Winkelhorst D.
      • Oepkes D.
      • Lopriore E.
      Fetal and neonatal alloimmune thrombocytopenia: evidence based antenatal and postnatal management strategies.
      ] in the newborn through platelet transfusions until the FNAIT resolves within 1–16 weeks after birth [
      • Kamphuis M.M.
      • Oepkes D.
      Fetal and neonatal alloimmune thrombocytopenia: prenatal interventions.
      ]. Similar to antenatal treatment, there is considerable variability in the guidelines concerning postnatal treatment and they tend to be based on a general consensus rather than direct evidence [
      • Crighton G.L.
      • Scarborough R.
      • McQuilten Z.K.
      • Phillips L.E.
      • Savoia H.F.
      • Williams B.
      • et al.
      Contemporary management of neonatal alloimmune thrombocytopenia: good outcomes in the intravenous immunoglobulin era: results from the Australian neonatal alloimmune thrombocytopenia registry.
      ]. Bertrand and Kaplan have recommended that newborns with a platelet count below 30 × 109/L should receive immediate platelet transfusions, while newborns with a count above 30 × 109/L generally don’t require any treatment [
      • Bertrand G.
      • Kaplan C.
      How do we treat fetal and neonatal alloimmune thrombocytopenia?.
      ], unless they were born prematurely or are sick [
      • Lieberman L.
      • Greinacher A.
      • Murphy M.F.
      • Bussel J.
      • Bakchoul T.
      • Corke S.
      • et al.
      Fetal and neonatal alloimmune thrombocytopenia: recommendations for evidence-based practice, an international approach.
      ]. Ideally, the transfused platelets should be negative for the antigen, i.e. HPA-matched transfusions [
      • Winkelhorst D.
      • Oepkes D.
      • Lopriore E.
      Fetal and neonatal alloimmune thrombocytopenia: evidence based antenatal and postnatal management strategies.
      ]. However, unless the FNAIT was identified antenatally, the causative alloantibody will be unknown until laboratory testing is completed which would delay the platelet transfusion [
      • Serrarens-Janssen V.M.
      • Semmekrot B.A.
      • Novotny V.M.
      • Porcelijn L.
      • Lotgering F.K.
      • Delemarre F.M.
      • et al.
      Fetal/neonatal allo-immune thrombocytopenia (FNAIT): past, present, and future.
      ]. In these cases, Winkelhorst and Oepkes have suggested that HPA-1bb/5aa platelets should be transfused as they are antigen-negative in 90 % of cases [
      • Winkelhorst D.
      • Oepkes D.
      Foetal and neonatal alloimmune thrombocytopenia.
      ]. If both options are unavailable, Lieberman et al. suggested that random platelet transfusions should be given [
      • Lieberman L.
      • Greinacher A.
      • Murphy M.F.
      • Bussel J.
      • Bakchoul T.
      • Corke S.
      • et al.
      Fetal and neonatal alloimmune thrombocytopenia: recommendations for evidence-based practice, an international approach.
      ]. They have been shown by Kiefel and colleagues to increase platelet counts sufficiently to prevent hemorrhaging until matched platelet transfusions become available [
      • Kiefel V.
      • Bassler D.
      • Kroll H.
      • Paes B.
      • Giers G.
      • Ditomasso J.
      • et al.
      Antigen-positive platelet transfusion in neonatal alloimmune thrombocytopenia (NAIT).
      ]. These recommendations were recently corroborated by a systematic review published on behalf of ICTMG [
      • Baker J.M.
      • Shehata N.
      • Bussel J.
      • Murphy M.F.
      • Greinacher A.
      • Bakchoul T.
      • et al.
      Postnatal intervention for the treatment of FNAIT: a systematic review.
      ].
      Contrary to its role antenatally, it has been concluded that IVIg should not be given as the sole treatment postnatally, as its induced rise in platelet count takes longer than the rise induced by platelet transfusions alone [
      • te Pas A.B.
      • Lopriore E.
      • van den Akker E.S.
      • Oepkes D.
      • Kanhai H.H.
      • Brand A.
      • et al.
      Postnatal management of fetal and neonatal alloimmune thrombocytopenia: the role of matched platelet transfusion and IVIG.
      ]. Additionally, combining IVIg treatment with platelet transfusions doesn’t appear to be beneficial and has not been recommended [
      • Lieberman L.
      • Greinacher A.
      • Murphy M.F.
      • Bussel J.
      • Bakchoul T.
      • Corke S.
      • et al.
      Fetal and neonatal alloimmune thrombocytopenia: recommendations for evidence-based practice, an international approach.
      ].

      3. IVIg

      IVIg is a blood product that is purified from the plasma of thousands of healthy donors [
      • Galeotti C.
      • Kaveri S.V.
      • Bayry J.
      IVIG-mediated effector functions in autoimmune and inflammatory diseases.
      ]. It is mainly composed of the IgG isotype, but impurities of IgA and IgM can also be present [
      • Galeotti C.
      • Kaveri S.V.
      • Bayry J.
      IVIG-mediated effector functions in autoimmune and inflammatory diseases.
      ]. Initially, IVIg preparations were used as a replacement therapy for primary immunodeficiency disorders [
      • Pyne D.
      • Ehrenstein M.
      • Morris V.
      The therapeutic uses of intravenous immunoglobulins in autoimmune rheumatic diseases.
      ]. In 1981, Imbach et al. additionally showed that IVIg was effective in patients with refractory ITP [
      • Imbach P.
      • Barandun S.
      • Baumgartner C.
      • Hirt A.
      • Hofer F.
      • Wagner H.P.
      High-dose intravenous gammaglobulin therapy of refractory, in particular idiopathic thrombocytopenia in childhood.
      ], indicating that its effects might be benefitial in a wider range of diseases. Nowadays, the US Food and Drug Administration (FDA) has approved the use of IVIg in primary immunodeficiency disorders, ITP, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, Kawasaki syndrome and B-cell chronic lymphocytic leukemia [
      • De Ranieri D.
      • Fenny N.S.
      Intravenous immunoglobulin in the treatment of primary immunodeficiency diseases.
      ]. In Europe, IVIg is additionally licenced by the European Medicines Agency for the treatment of Guillain Barré syndrome [
      • Committee for Medicinal Products for Human Use (CHMP)
      Guideline on core SmPC for human normal immunoglobulin for intravenous administration (IVIg).
      ]. However, IVIg is actually used in a much wider range of diseases including FNAIT, infections, haematological disorders, rheumatological conditions as well as neurological and dermatological diseases [
      • De Ranieri D.
      • Fenny N.S.
      Intravenous immunoglobulin in the treatment of primary immunodeficiency diseases.
      ], even though its effectiveness has not been concusively established [
      • Pierce L.R.
      • Jain N.
      Risks associated with the use of intravenous immunoglobulin.
      ]. It is estimated that the majority of IVIg in the US is being used for these “off-label” treatments [
      • Pierce L.R.
      • Jain N.
      Risks associated with the use of intravenous immunoglobulin.
      ].

      3.1 Problems associated with IVIg

      As a blood product, IVIg has the potential to transmit infectious diseases and cases involving the transmission of hepatitis C virus have been reported before 1995 [
      • Chaigne B.
      • Mouthon L.
      Mechanisms of action of intravenous immunoglobulin.
      ]. Since then, manufacturers have introduced a stringent production process, starting with the screening and testing of donors, as well as the introduction of viral inactivation steps and nanofiltration [
      • Pierce L.R.
      • Jain N.
      Risks associated with the use of intravenous immunoglobulin.
      ].
      Overall, IVIg treatment is considered to be safe and well tolerated with only mild side effects in most patients [
      • Galeotti C.
      • Kaveri S.V.
      • Bayry J.
      IVIG-mediated effector functions in autoimmune and inflammatory diseases.
      ,
      • Zuercher A.W.
      • Spirig R.
      • Baz Morelli A.
      • Käsermann F.
      IVIG in autoimmune disease — potential next generation biologics.
      ,
      • Schwab I.
      • Nimmerjahn F.
      Intravenous immunoglobulin therapy: how does IgG modulate the immune system?.
      ], however adverse effects are underreported in pregnant women at risk of FNAIT [
      • Rossi K.Q.
      • Lehman K.J.
      • O’Shaughnessy R.W.
      Effects of antepartum therapy for fetal alloimmune thrombocytopenia on maternal lifestyle.
      ]. These include flu-like symptoms such as headache, chills, fever, nausea or fatigue [
      • Rossi K.Q.
      • Lehman K.J.
      • O’Shaughnessy R.W.
      Effects of antepartum therapy for fetal alloimmune thrombocytopenia on maternal lifestyle.
      ] and are thought to be caused by the high levels of infused IVIg [
      • Galeotti C.
      • Kaveri S.V.
      • Bayry J.
      IVIG-mediated effector functions in autoimmune and inflammatory diseases.
      ]. Reducing the rate of IVIg infusion as well as premedicating patients with hydrocortisone [
      • Pyne D.
      • Ehrenstein M.
      • Morris V.
      The therapeutic uses of intravenous immunoglobulins in autoimmune rheumatic diseases.
      ] or diphenhydramine and acetaminophen [
      • De Ranieri D.
      • Fenny N.S.
      Intravenous immunoglobulin in the treatment of primary immunodeficiency diseases.
      ] generally decreases the incidence and severity of these side effects. Additionally, there are a few serious, but rare complications. IgE-mediated anaphylaxis has been observed in a small percentage of IgA-deficient patients, even though anti-IgA antibodies are present in only about one-third of them [
      • Pierce L.R.
      • Jain N.
      Risks associated with the use of intravenous immunoglobulin.
      ]. Another rare side effect is acute renal failure which occurs much more commonly in patients with pre-existing renal impairment [
      • Pyne D.
      • Ehrenstein M.
      • Morris V.
      The therapeutic uses of intravenous immunoglobulins in autoimmune rheumatic diseases.
      ,
      • Katz U.
      • Achiron A.
      • Sherer Y.
      • Shoenfeld Y.
      Safety of intravenous immunoglobulin (IVIG) therapy.
      ]. All IVIg products now include a boxed warning for renal failure by the FDA advising against the use of sucrose-containing IVIg products and recommending the usage of the lowest IVIg dose and infusion rate possible [
      • Limited B.P.L.
      Package insert GAMMAPLEX®.
      ]. Lastly, aseptic meningitis is another rare complication which mostly affects patients that are receiving high doses of IVIg [
      • Pierce L.R.
      • Jain N.
      Risks associated with the use of intravenous immunoglobulin.
      ].
      It should be noted that IVIg products differ slightly in their immunoglobulin composition [
      • Zuercher A.W.
      • Spirig R.
      • Baz Morelli A.
      • Käsermann F.
      IVIG in autoimmune disease — potential next generation biologics.
      ] and that each product is therefore considered to be unique by the FDA [
      • Pierce L.R.
      • Jain N.
      Risks associated with the use of intravenous immunoglobulin.
      ]. So far, formal comparisons between different products have not been conducted and the extensive “off-label” use of IVIg means that studies are usually of limited size and statistically only able to detect the incidence of side effects which is greater than 6 % [
      • Pierce L.R.
      • Jain N.
      Risks associated with the use of intravenous immunoglobulin.
      ].

      3.2 Proposed mechanisms of action of IVIg

      The effectiveness of IVIg in various diseases suggests that its therapeutic potential may not necessarily be due to a single mechanism of action but rather multiple mutually non-exclusive mechanisms that have been described experimentally and clinically [
      • Galeotti C.
      • Kaveri S.V.
      • Bayry J.
      IVIG-mediated effector functions in autoimmune and inflammatory diseases.
      ]. Furthermore, the potential of specific mechanisms within the different diseases varies significantly, from simple IgG replacement in primary immunodeficiency disorders to immune modulation in autoimmune and inflammatory conditions [
      • De Ranieri D.
      • Fenny N.S.
      Intravenous immunoglobulin in the treatment of primary immunodeficiency diseases.
      ]. While the major theoretical mechanisms of action are outlined here, a detailed description and their role within the various diseases is beyond the scope of this review and can be found elsewhere [
      • Galeotti C.
      • Kaveri S.V.
      • Bayry J.
      IVIG-mediated effector functions in autoimmune and inflammatory diseases.
      ,
      • Schwab I.
      • Nimmerjahn F.
      Intravenous immunoglobulin therapy: how does IgG modulate the immune system?.
      ,
      • Lazarus A.H.
      Mechanisms of action and immunomodulation by IVIg.
      ]. Overall, IgG molecules can be thought of as consisting of two functional domains or regions that mediate its effect; the antigen binding F(ab’)2 portion and the Fc portion which interacts with components of the innate immune system.

      3.2.1 F(ab’)2-dependent mechanisms of action

      The mechanism by which IVIg is considered to be effective in primary immunodeficiency disorders is immune substitution. Due to its purification from thousands of donors, IVIg in its composition is very similar to human sera and contains a variety of antibodies directed against bacterial and viral pathogens [
      • Chaigne B.
      • Mouthon L.
      Mechanisms of action of intravenous immunoglobulin.
      ]. In patients with primary immunodeficiency disorders, these antibodies can protect against infections by neutralising the pathogen or targeting its destruction by the innate immune system [
      • De Ranieri D.
      • Fenny N.S.
      Intravenous immunoglobulin in the treatment of primary immunodeficiency diseases.
      ,
      • Chaigne B.
      • Mouthon L.
      Mechanisms of action of intravenous immunoglobulin.
      ]. Consequently, the polyclonality of IVIg is likely advantageous as it allows a greater substitution of the immune response [
      • Chaigne B.
      • Mouthon L.
      Mechanisms of action of intravenous immunoglobulin.
      ].
      Similarly, IVIg also contains antibodies against auto-antibodies, known as anti-idiotypic antibodies [
      • Galeotti C.
      • Kaveri S.V.
      • Bayry J.
      IVIG-mediated effector functions in autoimmune and inflammatory diseases.
      ,
      • Crow A.R.
      • Song S.
      • Siragam V.
      • Lazarus A.H.
      Mechanisms of action of intravenous immunoglobulin in the treatment of immune thrombocytopenia.
      ]. These anti-idiotypic antibodies have been thought to mediate their therapeutic effect through neutralisation which is suggested to lead to a drop in pathogenic antibody titer [
      • Kaveri S.V.
      Intravenous immunoglobulin: exploiting the potential of natural antibodies.
      ]. Although a large number of anti-ideotypic antibodies against autoantibodies to DNA, platelets, endothelial cells or phospholipids have been observed [
      • Chaigne B.
      • Mouthon L.
      Mechanisms of action of intravenous immunoglobulin.
      ,
      • Bayary J.
      • Dasgupta S.
      • Misra N.
      • Ephrem A.
      • Duong Van Huyen J.-P.
      • Delignat S.
      • et al.
      Intravenous immunoglobulin in autoimmune disorders: an insight into the immunoregulatory mechanisms.
      ], their effectiveness has been questioned in multiple animal models [
      • Lazarus A.H.
      Mechanisms of action and immunomodulation by IVIg.
      ,
      • Crow A.R.
      • Song S.
      • Semple J.W.
      • Freedman J.
      • Lazarus A.H.
      IVIg inhibits reticuloendothelial system function and ameliorates murine passive-immune thrombocytopenia independent of anti-idiotype reactivity.
      ].
      Additionally, IVIg has been shown to bind anaphylatoxins C3a and C5a which are part of the complement cascade [
      • Galeotti C.
      • Kaveri S.V.
      • Bayry J.
      IVIG-mediated effector functions in autoimmune and inflammatory diseases.
      ,
      • Chaigne B.
      • Mouthon L.
      Mechanisms of action of intravenous immunoglobulin.
      ]. This could theoretically prevent the recruitment of innate immune cells [
      • Baerenwaldt A.
      • Biburger M.
      • Nimmerjahn F.
      Mechanisms of action of intravenous immunoglobulins.
      ] and complement-mediated tissue damage [
      • Crow A.R.
      • Song S.
      • Siragam V.
      • Lazarus A.H.
      Mechanisms of action of intravenous immunoglobulin in the treatment of immune thrombocytopenia.
      ].

      3.2.2 Fc-dependent mechanisms of action

      3.2.2.1 Mononuclear phagocytic system (MPS) blockade

      One of the earliest documented mechanisms of action of IVIg is its interference with the MPS. In 1982, Fehr et al. showed that IVIg delayed the clearance of opsonized red blood cells in ITP patients while elevating platelet counts [
      • Fehr J.
      • Hofmann V.
      • Kappeler U.
      Transient reversal of thrombocytopenia in idiopathic thrombocytopenic purpura by high-dose intravenous gamma globulin.
      ]. Salama and colleagues further confirmed that opsonization of red blood cells by IVIg inhibited the MPS which prevented the destruction of platelets and consequently explained the rise in platelet levels in IVIg-treated ITP patients [
      • Salama A.
      • Mueller-Eckhardt C.
      • Kiefel V.
      Effect of intravenous immunoglobulin in immune thrombocytopenia: competitive inhibition of reticuloendothelial system function by sequestration of autologous red blood cells?.
      ]. Numerous studies since then have supported the importance of MPS blockade as a therapeutic effector mechanism of IVIg [
      • Siragam V.
      • Brinc D.
      • Crow A.R.
      • Song S.
      • Freedman J.
      • Lazarus A.H.
      Can antibodies with specificity for soluble antigens mimic the therapeutic effects of intravenous IgG in the treatment of autoimmune disease?.
      ,
      • Crow A.R.
      • Lazarus A.H.
      The mechanisms of action of intravenous immunoglobulin and polyclonal anti-d immunoglobulin in the amelioration of immune thrombocytopenic purpura: what do we really know?.
      ,
      • Crow A.R.
      • Song S.
      • Suppa S.J.
      • Ma S.
      • Reilly M.P.
      • Andre P.
      • et al.
      Amelioration of murine immune thrombocytopenia by CD44 antibodies: a potential therapy for ITP?.
      ,
      • Teeling J.L.
      • Jansen-Hendriks T.
      • Kuijpers T.W.
      • de Haas M.
      • van de Winkel J.G.
      • Hack C.E.
      • et al.
      Therapeutic efficacy of intravenous immunoglobulin preparations depends on the immunoglobulin G dimers: studies in experimental immune thrombocytopenia.
      ].

      3.2.2.2 Inhibitory receptor FcγRIIB

      Another major hypothesis proposes that the immunomodulatory function of IVIg is mediated by the upregulation of the inhibitory receptor FcγRIIB [
      • Nagelkerke S.Q.
      • Kuijpers T.W.
      Immunomodulation by IVIg and the role of Fc-gamma receptors: classic mechanisms of action after all?.
      ], which is present on haematopoietic cells [
      • Crow A.R.
      • Song S.
      • Freedman J.
      • Helgason C.D.
      • Humphries R.K.
      • Siminovitch K.A.
      • et al.
      IVIg-mediated amelioration of murine ITP via FcγRIIB is independent of SHIP1, SHP-1, and Btk activity.
      ]. Indeed, experiments using FcγRIIB knock-out mice have shown that IVIg treatment does not ameliorate ITP or arthritis in these animals [
      • Siragam V.
      • Brinc D.
      • Crow A.R.
      • Song S.
      • Freedman J.
      • Lazarus A.H.
      Can antibodies with specificity for soluble antigens mimic the therapeutic effects of intravenous IgG in the treatment of autoimmune disease?.
      ,
      • Crow A.R.
      • Song S.
      • Freedman J.
      • Helgason C.D.
      • Humphries R.K.
      • Siminovitch K.A.
      • et al.
      IVIg-mediated amelioration of murine ITP via FcγRIIB is independent of SHIP1, SHP-1, and Btk activity.
      ,
      • Samuelsson A.
      • Towers T.L.
      • Ravetch J.V.
      Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor.
      ]. Wild-type mice on the other hand showed a 60 % increase in their FcγRIIB-expression levels on macrophages [
      • Samuelsson A.
      • Towers T.L.
      • Ravetch J.V.
      Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor.
      ]. These results were further supported by a human study showing that upregulation of FcγRIIB on B-cells was associated with IVIg treatment in chronic inflammatory demyelinating polyneuropathy patients [
      • Tackenberg B.
      • Jelcic I.
      • Baerenwaldt A.
      • Oertel W.H.
      • Sommer N.
      • Nimmerjahn F.
      • et al.
      Impaired inhibitory Fc gamma receptor IIB expression on B cells in chronic inflammatory demyelinating polyneuropathy.
      ]. It is still unclear though how IVIg leads to the upregulation of FcγRIIB. Additionally, it is likely that the findings from murine studies may not translate to humans as the FcγR expression differs significantly between mice and humans [
      • Nagelkerke S.Q.
      • Kuijpers T.W.
      Immunomodulation by IVIg and the role of Fc-gamma receptors: classic mechanisms of action after all?.
      ].

      3.2.2.3 Dendritic cells

      Dendritic cells have been suggested as a promising target for immunomodulation due to their key role in the initiation of adaptive immune responses. It has been shown that IVIg can prevent the differentiation and maturation of dendritic cells [
      • Galeotti C.
      • Kaveri S.V.
      • Bayry J.
      IVIG-mediated effector functions in autoimmune and inflammatory diseases.
      ,
      • Chaigne B.
      • Mouthon L.
      Mechanisms of action of intravenous immunoglobulin.
      ] as well as alter their cytokine production away from the pro-inflammatory IL-12 towards the anti-inflammatory IL-10 [
      • Crow A.R.
      • Song S.
      • Siragam V.
      • Lazarus A.H.
      Mechanisms of action of intravenous immunoglobulin in the treatment of immune thrombocytopenia.
      ,
      • Bayary J.
      • Dasgupta S.
      • Misra N.
      • Ephrem A.
      • Duong Van Huyen J.-P.
      • Delignat S.
      • et al.
      Intravenous immunoglobulin in autoimmune disorders: an insight into the immunoregulatory mechanisms.
      ]. This anti-inflammatory function of dendritic cells was further supported by Siragam and colleagues who showed that IVIg-primed dendritic cells were able to ameliorate ITP in a murine model [
      • Siragam V.
      • Crow A.R.
      • Brinc D.
      • Song S.
      • Freedman J.
      • Lazarus A.H.
      Intravenous immunoglobulin ameliorates ITP via activating Fcγ receptors on dendritic cells.
      ]. This effect was likely mediated by the binding of immune complexes to activating Fc receptors on dendritic cells and has been confirmed in other disease models [
      • Crow A.R.
      • Brinc D.
      • Lazarus A.H.
      New insight into the mechanism of action of IVIg: the role of dendritic cells.
      ].

      3.2.2.4 Neonatal Fc receptor (FcRn)

      IVIg can interact with FcRn, the neonatal Fc receptor, which is present on endothelial cells. It acts as a protective receptor prolonging the half-life of serum IgG to 2–3 weeks by preventing its catabolism [
      • Galeotti C.
      • Kaveri S.V.
      • Bayry J.
      IVIG-mediated effector functions in autoimmune and inflammatory diseases.
      ,
      • Chaigne B.
      • Mouthon L.
      Mechanisms of action of intravenous immunoglobulin.
      ,
      • Schwab I.
      • Nimmerjahn F.
      Intravenous immunoglobulin therapy: how does IgG modulate the immune system?.
      ]. Saturation of the receptor with IVIg is thought to block the binding of autoantibodies thereby shortening their half-life and increasing their clearance from the circulation [
      • Siragam V.
      • Brinc D.
      • Crow A.R.
      • Song S.
      • Freedman J.
      • Lazarus A.H.
      Can antibodies with specificity for soluble antigens mimic the therapeutic effects of intravenous IgG in the treatment of autoimmune disease?.
      ,
      • Ben Mkaddem S.
      • Benhamou M.
      • Monteiro R.C.
      Understanding Fc receptor involvement in inflammatory diseases: from mechanisms to new therapeutic tools.
      ]. This would explain why much larger concentrations (2 g/kg) of IVIg are required for its immunomodulatory function compared to the low doses (400−600 mg) that are sufficient in primary immunodefiency disorders [
      • De Ranieri D.
      • Fenny N.S.
      Intravenous immunoglobulin in the treatment of primary immunodeficiency diseases.
      ]. On the other hand, recent work in a murine model of ITP has shown that FcRn was not required for the amelioration of the disease [
      • Crow A.R.
      • Suppa S.J.
      • Chen X.
      • Mott P.J.
      • Lazarus A.H.
      The neonatal Fc receptor (FcRn) is not required for IVIg or anti-CD44 monoclonal antibody–mediated amelioration of murine immune thrombocytopenia.
      ]. Consequently, its importance in mediating the anti-inflammatory effects of IVIg is unclear and requires further study [
      • Schwab I.
      • Nimmerjahn F.
      Intravenous immunoglobulin therapy: how does IgG modulate the immune system?.
      ].

      3.2.2.5 Cytokines

      IVIg has been found to alter cytokine levels in a variety of autoimmune diseases. These include IL-1, TNF-α, TNF-β, and IFN-γ in Kawasaki disease [
      • Ballow M.
      The IgG molecule as a biological immune response modifier: mechanisms of action of intravenous immune serum globulin in autoimmune and inflammatory disorders.
      ], IL-10 in ITP [
      • Cooper N.
      • Heddle N.M.
      • Haas M.
      • Reid M.E.
      • Lesser M.L.
      • Fleit H.B.
      • et al.
      Intravenous (IV) anti-D and IV immunoglobulin achieve acute platelet increases by different mechanisms: modulation of cytokine and platelet responses to IV anti-D by FcgammaRIIa and FcgammaRIIIa polymorphisms.
      ] and IL-33 in murine autoimmune models [
      • Anthony R.M.
      • Kobayashi T.
      • Wermeling F.
      • Ravetch J.V.
      Intravenous gammaglobulin suppresses inflammation through a novel TH2 pathway.
      ] among others. However, differences in cytokine analysis have to be taken into consideration when evaluating the effect of IVIg on cytokine levels, as well as the contribution of other IVIg mechanisms that could alter cytokine secretion [
      • Lazarus A.H.
      Mechanisms of action and immunomodulation by IVIg.
      ].

      3.2.2.6 Complement

      The complement cascade can also be inhibited by IVIg through a Fc-dependent mechanism. Binding of the complement effectors C3b and C4b to IVIg stops the formation of the C5b-C9 membrane attack complex and subsequently prevents complement-mediated cell death and tissue damage [
      • Galeotti C.
      • Kaveri S.V.
      • Bayry J.
      IVIG-mediated effector functions in autoimmune and inflammatory diseases.
      ,
      • Chaigne B.
      • Mouthon L.
      Mechanisms of action of intravenous immunoglobulin.
      ,
      • Crow A.R.
      • Song S.
      • Siragam V.
      • Lazarus A.H.
      Mechanisms of action of intravenous immunoglobulin in the treatment of immune thrombocytopenia.
      ]. This mechanism of action seems to be effective in dermatomyositis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy and myasthenia gravis [
      • Dalakas M.C.
      • Illa I.
      • Dambrosia J.M.
      • Soueidan S.A.
      • Stein D.P.
      • Otero C.
      • et al.
      A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis.
      ,
      • Basta M.
      • Illa I.
      • Dalakas M.C.
      Increased in vitro uptake of the complement C3b in the serum of patients with Guillain-Barre syndrome, myasthenia gravis and dermatomyositis.
      ,
      • Dalakas M.C.
      Intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: present status and practical therapeutic guidelines.
      ].

      4. Mechanisms of IVIg relevant to FNAIT

      The exact mechanism of action responsible for the therapeutic effect of IVIg in FNAIT is unclear, however it is possible that multiple mechanisms are involved. Although these mechanisms have been supported by different studies, many of the details remain unclear. Additional research is required to fully elucidate the role of FcRn in IVIg-ameliorated FNAIT and provide insight on its significance in comparison to other mechanisms that may also be contributing to its therapeutic activity.

      4.1 The role of FcRn

      FcRn is expressed throughout an individual’s lifetime, albeit expression levels do change developmentally and temporally [
      • Pyzik M.
      • Rath T.
      • Lencer W.I.
      • Baker K.
      • Blumberg R.S.
      FcRn: the architect behind the immune and nonimmune functions of IgG and albumin.
      ,
      • Baker K.
      • Qiao S.W.
      • Kuo T.
      • Kobayashi K.
      • Yoshida M.
      • Lencer W.I.
      • et al.
      Immune and non-immune functions of the (not so) neonatal Fc receptor, FcRn.
      ]. It is a heterodimer composed of the MHC class I-like α heavy chain and the β2 microglobulin (β2m) light chain [
      • Simister N.E.
      • Mostov K.E.
      An Fc receptor structurally related to MHC class I antigens.
      ,
      • Roopenian D.C.
      • Akilesh S.
      FcRn: the neonatal Fc receptor comes of age.
      ] and is expressed by selected cell types including the vascular endothelium (such as at the blood-brain interface), most epithelial cells (such as in the placenta, lung, liver, skin, kidneys, eyes and intestine) and the hematopoietic cells (such as monocytes, macrophages, dendritic cells, neutrophils and B cells) [
      • Pyzik M.
      • Rath T.
      • Lencer W.I.
      • Baker K.
      • Blumberg R.S.
      FcRn: the architect behind the immune and nonimmune functions of IgG and albumin.
      ,
      • Baker K.
      • Qiao S.W.
      • Kuo T.
      • Kobayashi K.
      • Yoshida M.
      • Lencer W.I.
      • et al.
      Immune and non-immune functions of the (not so) neonatal Fc receptor, FcRn.
      ,
      • Roopenian D.C.
      • Akilesh S.
      FcRn: the neonatal Fc receptor comes of age.
      ,
      • Wilcox C.R.
      • Holder B.
      • Jones C.E.
      Factors affecting the FcRn-mediated transplacental transfer of antibodies and implications for vaccination in pregnancy.
      ,
      • Sesarman A.
      • Vidarsson G.
      • Sitaru C.
      The neonatal Fc receptor as therapeutic target in IgG-mediated autoimmune diseases.
      ,
      • Yu Z.
      • Lennon V.A.
      Mechanism of intravenous immune globulin therapy in antibody-mediated autoimmune diseases.
      ].
      FcRn is well known for its ability to interact with IgG antibodies and albumin [
      • Pyzik M.
      • Rath T.
      • Lencer W.I.
      • Baker K.
      • Blumberg R.S.
      FcRn: the architect behind the immune and nonimmune functions of IgG and albumin.
      ,
      • Baker K.
      • Qiao S.W.
      • Kuo T.
      • Kobayashi K.
      • Yoshida M.
      • Lencer W.I.
      • et al.
      Immune and non-immune functions of the (not so) neonatal Fc receptor, FcRn.
      ,
      • Roopenian D.C.
      • Akilesh S.
      FcRn: the neonatal Fc receptor comes of age.
      ,
      • Wilcox C.R.
      • Holder B.
      • Jones C.E.
      Factors affecting the FcRn-mediated transplacental transfer of antibodies and implications for vaccination in pregnancy.
      ]. It has been implicated in a myriad of functions, such as bidirectional transcytosis of IgG and IgG immune complexes [
      • Pyzik M.
      • Rath T.
      • Lencer W.I.
      • Baker K.
      • Blumberg R.S.
      FcRn: the architect behind the immune and nonimmune functions of IgG and albumin.
      ,
      • Roopenian D.C.
      • Akilesh S.
      FcRn: the neonatal Fc receptor comes of age.
      ,
      • Wilcox C.R.
      • Holder B.
      • Jones C.E.
      Factors affecting the FcRn-mediated transplacental transfer of antibodies and implications for vaccination in pregnancy.
      ,
      • Sesarman A.
      • Vidarsson G.
      • Sitaru C.
      The neonatal Fc receptor as therapeutic target in IgG-mediated autoimmune diseases.
      ,
      • Kuo T.T.
      • Aveson V.G.
      Neonatal Fc receptor and IgG-based therapeutics.
      ], anti-tumor surveillance [
      • Wilcox C.R.
      • Holder B.
      • Jones C.E.
      Factors affecting the FcRn-mediated transplacental transfer of antibodies and implications for vaccination in pregnancy.
      ], membrane recycling [
      • Kuo T.T.
      • Aveson V.G.
      Neonatal Fc receptor and IgG-based therapeutics.
      ], anaphylactic sensitization [
      • Baker K.
      • Qiao S.W.
      • Kuo T.
      • Kobayashi K.
      • Yoshida M.
      • Lencer W.I.
      • et al.
      Immune and non-immune functions of the (not so) neonatal Fc receptor, FcRn.
      ], enhancing IgG-mediated phagocytosis [
      • Wilcox C.R.
      • Holder B.
      • Jones C.E.
      Factors affecting the FcRn-mediated transplacental transfer of antibodies and implications for vaccination in pregnancy.
      ], and facilitating antigen presentation [
      • Baker K.
      • Qiao S.W.
      • Kuo T.
      • Kobayashi K.
      • Yoshida M.
      • Lencer W.I.
      • et al.
      Immune and non-immune functions of the (not so) neonatal Fc receptor, FcRn.
      ,
      • Wilcox C.R.
      • Holder B.
      • Jones C.E.
      Factors affecting the FcRn-mediated transplacental transfer of antibodies and implications for vaccination in pregnancy.
      ,
      • Kuo T.T.
      • Aveson V.G.
      Neonatal Fc receptor and IgG-based therapeutics.
      ]. However, in adults it is primarily known for its ability to prevent the catabolism of its ligands (IgG and albumin) and mediate their antenatal placental transfer from a mother to her fetus. Both of these major functions can potentially be affected by IVIg as part of its therapeutic mechanism of action in FNAIT.

      4.1.1 IgG catabolism

      FcRn is known to selectively bind IgG and albumin and protect them from degradation [
      • Sesarman A.
      • Vidarsson G.
      • Sitaru C.
      The neonatal Fc receptor as therapeutic target in IgG-mediated autoimmune diseases.
      ]. The binding sites for the two ligands are different from each other and their binding is neither cooperative nor competitive [
      • Baker K.
      • Qiao S.W.
      • Kuo T.
      • Kobayashi K.
      • Yoshida M.
      • Lencer W.I.
      • et al.
      Immune and non-immune functions of the (not so) neonatal Fc receptor, FcRn.
      ]. FcRn mediated recycling of albumin and IgG maintains their homeostatic level and extends their half-life in comparison to other serum proteins [
      • Pyzik M.
      • Rath T.
      • Lencer W.I.
      • Baker K.
      • Blumberg R.S.
      FcRn: the architect behind the immune and nonimmune functions of IgG and albumin.
      ,
      • Baker K.
      • Qiao S.W.
      • Kuo T.
      • Kobayashi K.
      • Yoshida M.
      • Lencer W.I.
      • et al.
      Immune and non-immune functions of the (not so) neonatal Fc receptor, FcRn.
      ,
      • Roopenian D.C.
      • Akilesh S.
      FcRn: the neonatal Fc receptor comes of age.
      ,
      • Wilcox C.R.
      • Holder B.
      • Jones C.E.
      Factors affecting the FcRn-mediated transplacental transfer of antibodies and implications for vaccination in pregnancy.
      ,
      • Sesarman A.
      • Vidarsson G.
      • Sitaru C.
      The neonatal Fc receptor as therapeutic target in IgG-mediated autoimmune diseases.
      ,
      • Kuo T.T.
      • Aveson V.G.
      Neonatal Fc receptor and IgG-based therapeutics.
      ]. The binding occurs with relatively high affinity in an acidic environment (pH 6.0) but not significantly at neutral pH (7.4) [
      • Pyzik M.
      • Rath T.
      • Lencer W.I.
      • Baker K.
      • Blumberg R.S.
      FcRn: the architect behind the immune and nonimmune functions of IgG and albumin.
      ,
      • Roopenian D.C.
      • Akilesh S.
      FcRn: the neonatal Fc receptor comes of age.
      ,
      • Sesarman A.
      • Vidarsson G.
      • Sitaru C.
      The neonatal Fc receptor as therapeutic target in IgG-mediated autoimmune diseases.
      ]. It has been proposed that IgG and albumin are protected by FcRn via the following mechanism; uptake of IgG and albumin likely occurs through non-specific pinocytosis in neutral pH environments. The acidity of the resulting endosome then facilitates the binding of IgG and albumin in the endosome to FcRn and safely shuttles them back to the cell surface where they are released into the extracellular environment (pH 7.4) while other serum proteins are degraded in the lysosome [
      • Pyzik M.
      • Rath T.
      • Lencer W.I.
      • Baker K.
      • Blumberg R.S.
      FcRn: the architect behind the immune and nonimmune functions of IgG and albumin.
      ,
      • Yu Z.
      • Lennon V.A.
      Mechanism of intravenous immune globulin therapy in antibody-mediated autoimmune diseases.
      ]. Evidence for this FcRn function stems from the observations that patients with mutated and non-functional FcRn have severely reduced serum IgG and albumin concentrations due to significantly higher catabolic rates [
      • Baker K.
      • Qiao S.W.
      • Kuo T.
      • Kobayashi K.
      • Yoshida M.
      • Lencer W.I.
      • et al.
      Immune and non-immune functions of the (not so) neonatal Fc receptor, FcRn.
      ,
      • Wani M.A.
      • Haynes L.D.
      • Kim J.
      • Bronson C.L.
      • Chaudhury C.
      • Mohanty S.
      • et al.
      Familial hypercatabolic hypoproteinemia caused by deficiency of the neonatal Fc receptor, FcRn, due to a mutant beta2-microglobulin gene.
      ]. Additionally, FcRn deficient mice were found to have much lower IgG (∼20–30 % of wild-type mice) and albumin levels (∼40 % of wild-type mice), and the half-life of both proteins was also decreased [
      • Roopenian D.C.
      • Akilesh S.
      FcRn: the neonatal Fc receptor comes of age.
      ,
      • Ghetie V.
      • Hubbard J.G.
      • Kim J.K.
      • Tsen M.F.
      • Lee Y.
      • Ward E.S.
      Abnormally short serum half-lives of IgG in beta 2-microglobulin-deficient mice.
      ,
      • Hansen R.J.
      • Balthasar J.P.
      Intravenous immunoglobulin mediates an increase in anti-platelet antibody clearance via the FcRn receptor.
      ,
      • Roopenian D.C.
      • Christianson G.J.
      • Sproule T.J.
      • Brown A.C.
      • Akilesh S.
      • Jung N.
      • et al.
      The MHC class I-like IgG receptor controls perinatal IgG transport, IgG homeostasis, and fate of IgG-Fc-coupled drugs.
      ].
      As a homeostatic receptor, FcRn prolongs the half life of IgG antibodies [
      • Roopenian D.C.
      • Akilesh S.
      FcRn: the neonatal Fc receptor comes of age.
      ,
      • Ghetie V.
      • Hubbard J.G.
      • Kim J.K.
      • Tsen M.F.
      • Lee Y.
      • Ward E.S.
      Abnormally short serum half-lives of IgG in beta 2-microglobulin-deficient mice.
      ,
      • Brambell F.W.
      • Hemmings W.A.
      • Morris I.G.
      A theoretical model of gamma-globulin catabolism.
      ,
      • Ghetie V.
      • Ward E.S.
      FcRn: the MHC class I-related receptor that is more than an IgG transporter.
      ]. Administration of IVIg increases the IgG levels above the equilibrium set point causing hypergammaglobulinemia and FcRn saturation [
      • Roopenian D.C.
      • Akilesh S.
      FcRn: the neonatal Fc receptor comes of age.
      ,
      • Yu Z.
      • Lennon V.A.
      Mechanism of intravenous immune globulin therapy in antibody-mediated autoimmune diseases.
      ]. As such, excess IgG (potentially including the pathogenic antibody in IgG-mediated diseases, such as the anti-HPA antibody in FNAIT) would compete for binding to the limited FcRn sites and therefore be degraded more rapidly in comparison to the pre-IVIg treatment condition [
      • Roopenian D.C.
      • Akilesh S.
      FcRn: the neonatal Fc receptor comes of age.
      ,
      • Sesarman A.
      • Vidarsson G.
      • Sitaru C.
      The neonatal Fc receptor as therapeutic target in IgG-mediated autoimmune diseases.
      ,
      • Yu Z.
      • Lennon V.A.
      Mechanism of intravenous immune globulin therapy in antibody-mediated autoimmune diseases.
      ]. In fact, IVIg therapy dosed at 1 g/kg effectively doubles the plasma IgG concentration and increases the IgG catabolism rate to 180 % [
      • Hansen R.J.
      • Balthasar J.P.
      Effects of intravenous immunoglobulin on platelet count and antiplatelet antibody disposition in a rat model of immune thrombocytopenia.
      ,
      • Masson P.L.
      Elimination of infectious antigens and increase of IgG catabolism as possible modes of action of IVIg.
      ]. Based on this principle, IVIg therapy in FNAIT should cause accelerated clearance of the pathogenic anti-HPA antibody preventing it from harming the fetus and thus ameliorating the disease. However, whether the increased catabolism of the anti-HPA antibody is sufficient to account for the beneficial effect of IVIg in FNAIT is unknown.
      This mechanism of action of IVIg has been supported heavily in the literature. Several independent reports have indicated that treatment with IVIg leads to a reduction in serum pathogenic IgG concentration in both humans and mice [
      • Crow A.R.
      • Lazarus A.H.
      The mechanisms of action of intravenous immunoglobulin and polyclonal anti-d immunoglobulin in the amelioration of immune thrombocytopenic purpura: what do we really know?.
      ,
      • Fateh-Moghadam A.
      • Wick M.
      • Besinger U.
      • Geursen R.G.
      High-dose intravenous gammaglobulin for myasthenia gravis.
      ,
      • Dalakas M.C.
      • Fujii M.
      • Li M.
      • Lutfi B.
      • Kyhos J.
      • McElroy B.
      High-dose intravenous immune globulin for stiff-person syndrome.
      ,
      • Jayne D.R.
      • Esnault V.L.
      • Lockwood C.M.
      ANCA anti-idiotype antibodies and the treatment of systemic vasculitis with intravenous immunoglobulin.
      ,
      • Hammarström L.
      • Abedi M.R.
      • Hassan M.S.
      • Smith C.I.
      The SCID mouse as a model for autoimmunity.
      ,
      • Li N.
      • Zhao M.
      • Hilario-Vargas J.
      • Prisayanh P.
      • Warren S.
      • Diaz L.A.
      • et al.
      Complete FcRn dependence for intravenous Ig therapy in autoimmune skin blistering diseases.
      ]. Indeed, IVIg has been shown to exert its therapeutic effect primarily through FcRn in animal models of many IgG-mediated diseases, such as FNAIT, immune thrombocytopenia, autoimmune myasthenia gravis, skin blistering diseases and arthritis [
      • Crow A.R.
      • Lazarus A.H.
      The mechanisms of action of intravenous immunoglobulin and polyclonal anti-d immunoglobulin in the amelioration of immune thrombocytopenic purpura: what do we really know?.
      ,
      • Kuo T.T.
      • Aveson V.G.
      Neonatal Fc receptor and IgG-based therapeutics.
      ,
      • Hansen R.J.
      • Balthasar J.P.
      Intravenous immunoglobulin mediates an increase in anti-platelet antibody clearance via the FcRn receptor.
      ,
      • Li N.
      • Zhao M.
      • Hilario-Vargas J.
      • Prisayanh P.
      • Warren S.
      • Diaz L.A.
      • et al.
      Complete FcRn dependence for intravenous Ig therapy in autoimmune skin blistering diseases.
      ,
      • Ni H.
      • Chen P.
      • Spring C.M.
      • Sayeh E.
      • Semple J.W.
      • Lazarus A.H.
      • et al.
      A novel murine model of fetal and neonatal alloimmune thrombocytopenia: response to intravenous IgG therapy.
      ,
      • Akilesh S.
      • Petkova S.
      • Sproule T.J.
      • Shaffer D.J.
      • Christianson G.J.
      • Roopenian D.
      The MHC class I-like Fc receptor promotes humorally mediated autoimmune disease.
      ]. IVIg and an anti-FcRn blocking antibody displayed very similar therapeutic effects in a murine model of immune thrombocytopenia, indicating that IVIg could be exerting its effect as an FcRn block [
      • Smith B.
      • Christodoulou L.
      • Clargo A.
      • Eddleston A.
      • Greenslade K.
      • Lightwood D.
      • et al.
      Generation of two high affinity anti-mouse FcRn antibodies: inhibition of IgG recycling in wild type mice and effect in a mouse model of immune thrombocytopenia.
      ]. However, evidence to the contrary has also been presented. Reports of IVIg remaining therapeutically active in mice genetically deficient in FcRn as well as in mice with non-functional FcRn have seriously questioned the significance of this phenomenon and indicated that other prominent mechanisms may likely be at play [
      • Crow A.R.
      • Suppa S.J.
      • Chen X.
      • Mott P.J.
      • Lazarus A.H.
      The neonatal Fc receptor (FcRn) is not required for IVIg or anti-CD44 monoclonal antibody–mediated amelioration of murine immune thrombocytopenia.
      ,
      • Chen P.
      • Li C.
      • Lang S.
      • Zhu G.
      • Reheman A.
      • Spring C.M.
      • et al.
      Animal model of fetal and neonatal immune thrombocytopenia: role of neonatal Fc receptor in the pathogenesis and therapy.
      ]. While more work is required to fully understand the importance of competitive FcRn blockade (and the resulting IgG catabolism), evidence suggests that it could be one of the mechanisms through which IVIg exerts its therapeutic activity.

      4.1.2 Placental transfer of IgG antibodies

      FcRn has also been established as a transmitter of passive humoral immunity [
      • Baker K.
      • Qiao S.W.
      • Kuo T.
      • Kobayashi K.
      • Yoshida M.
      • Lencer W.I.
      • et al.
      Immune and non-immune functions of the (not so) neonatal Fc receptor, FcRn.
      ]. It has been implicated in mediating the antenatal maternofetal transfer of IgG antibodies starting in the first trimester, and peaking in the third [
      • Baker K.
      • Qiao S.W.
      • Kuo T.
      • Kobayashi K.
      • Yoshida M.
      • Lencer W.I.
      • et al.
      Immune and non-immune functions of the (not so) neonatal Fc receptor, FcRn.
      ,
      • Wilcox C.R.
      • Holder B.
      • Jones C.E.
      Factors affecting the FcRn-mediated transplacental transfer of antibodies and implications for vaccination in pregnancy.
      ,
      • Simister N.E.
      Placental transport of immunoglobulin G.
      ,
      • Martinez D.R.
      • Fouda G.G.
      • Peng X.
      • Ackerman M.E.
      • Permar S.R.
      Noncanonical placental Fc receptors: what is their role in modulating transplacental transfer of maternal IgG?.
      ,
      • Story C.M.
      • Mikulska J.E.
      • Simister N.E.
      A major histocompatibility complex class I-like Fc receptor cloned from human placenta: possible role in transfer of immunoglobulin G from mother to fetus.
      ].
      IgG antibodies translocating from the mother’s circulation to the fetus must cross three anatomical barriers within the placenta: (1) the syncytiotrophoblasts, (2) the villous stroma and (3) the fetal endothelium [
      • Martinez D.R.
      • Fouda G.G.
      • Peng X.
      • Ackerman M.E.
      • Permar S.R.
      Noncanonical placental Fc receptors: what is their role in modulating transplacental transfer of maternal IgG?.
      ]. Of the three layers, syncytiotrophoblasts are the only ones known to significantly express FcRn and to be in direct contact with maternal blood [
      • Roopenian D.C.
      • Akilesh S.
      FcRn: the neonatal Fc receptor comes of age.
      ,
      • Wilcox C.R.
      • Holder B.
      • Jones C.E.
      Factors affecting the FcRn-mediated transplacental transfer of antibodies and implications for vaccination in pregnancy.
      ]. Research using placental models has concluded that syncytiotrophoblasts passively uptake IgG present in the maternal circulation via pinocytosis [
      • Wilcox C.R.
      • Holder B.
      • Jones C.E.
      Factors affecting the FcRn-mediated transplacental transfer of antibodies and implications for vaccination in pregnancy.
      ,
      • Simister N.E.
      • Story C.M.
      • Chen H.L.
      • Hunt J.S.
      An IgG-transporting Fc receptor expressed in the syncytiotrophoblast of human placenta.
      ]. The acidic environment of the resulting endosome would encourage the IgG–FcRn binding and prevents the IgG from degrading [
      • Baker K.
      • Qiao S.W.
      • Kuo T.
      • Kobayashi K.
      • Yoshida M.
      • Lencer W.I.
      • et al.
      Immune and non-immune functions of the (not so) neonatal Fc receptor, FcRn.
      ,
      • Roopenian D.C.
      • Akilesh S.
      FcRn: the neonatal Fc receptor comes of age.
      ,
      • Wilcox C.R.
      • Holder B.
      • Jones C.E.
      Factors affecting the FcRn-mediated transplacental transfer of antibodies and implications for vaccination in pregnancy.
      ,
      • Simister N.E.
      Placental transport of immunoglobulin G.
      ,
      • Martinez D.R.
      • Fouda G.G.
      • Peng X.
      • Ackerman M.E.
      • Permar S.R.
      Noncanonical placental Fc receptors: what is their role in modulating transplacental transfer of maternal IgG?.
      ]. The bound IgG could then be trancytosed from the apical side of the syncytiotrophoblasts to the basolateral side. Once exposed to the physiological pH at the basolateral membrane, the IgG dissociates from the FcRn which shuttles back to repeat this process [
      • Roopenian D.C.
      • Akilesh S.
      FcRn: the neonatal Fc receptor comes of age.
      ,
      • Wilcox C.R.
      • Holder B.
      • Jones C.E.
      Factors affecting the FcRn-mediated transplacental transfer of antibodies and implications for vaccination in pregnancy.
      ,
      • Simister N.E.
      Placental transport of immunoglobulin G.
      ,
      • Martinez D.R.
      • Fouda G.G.
      • Peng X.
      • Ackerman M.E.
      • Permar S.R.
      Noncanonical placental Fc receptors: what is their role in modulating transplacental transfer of maternal IgG?.
      ,
      • Simister N.E.
      • Story C.M.
      • Chen H.L.
      • Hunt J.S.
      An IgG-transporting Fc receptor expressed in the syncytiotrophoblast of human placenta.
      ].
      Depending on the region where the IgG is deposited, it may or may not need to cross the stroma before reaching the fetal endothelium [
      • Simister N.E.
      Placental transport of immunoglobulin G.
      ,
      • Palmeira P.
      • Quinello C.
      • Silveira-Lessa A.L.
      • Zago C.A.
      • Carneiro-Sampaio M.
      IgG placental transfer in healthy and pathological pregnancies.
      ]. The cells in both the stroma and the fetal endothelium are not known to express FcRn but do express other receptors such as FcγRII and FcγRIII. Although the role of these receptors here remains unclear, they are not thought to be involved in the transport of monomeric IgG but instead may potentially be preventing maternal immune complexes from reaching the fetus [
      • Simister N.E.
      Placental transport of immunoglobulin G.
      ,
      • Martinez D.R.
      • Fouda G.G.
      • Peng X.
      • Ackerman M.E.
      • Permar S.R.
      Noncanonical placental Fc receptors: what is their role in modulating transplacental transfer of maternal IgG?.
      ,
      • Story C.M.
      • Mikulska J.E.
      • Simister N.E.
      A major histocompatibility complex class I-like Fc receptor cloned from human placenta: possible role in transfer of immunoglobulin G from mother to fetus.
      ]. The details regarding the translocation of IgG across the stroma and the endothelium to the fetal circulation are poorly understood and remain to be fully elucidated [
      • Simister N.E.
      Placental transport of immunoglobulin G.
      ,
      • Martinez D.R.
      • Fouda G.G.
      • Peng X.
      • Ackerman M.E.
      • Permar S.R.
      Noncanonical placental Fc receptors: what is their role in modulating transplacental transfer of maternal IgG?.
      ].
      This transplacental passage applies to all IgG antibodies present in the maternal circulation, including those that may be harmful to the fetus (such as the anti-HPA antibodies in FNAIT). Additionally, exogenous IVIg administered to the mother is also known to mimic this transport and translocate to the fetus [
      • Sidiropoulos D.
      • Herrmann U.
      • Morell A.
      • von Muralt G.
      • Barandun S.
      Transplacental passage of intravenous immunoglobulin in the last trimester of pregnancy.
      ]. It has been suggested that IVIg therapy in FNAIT competitively occupies the FcRn sites on the placenta, thus preventing the anti-HPA antibodies from reaching the fetus [
      • Winkelhorst D.
      • Oepkes D.
      Foetal and neonatal alloimmune thrombocytopenia.
      ,
      • Bussel J.B.
      • Berkowitz R.L.
      • McFarland J.G.
      • Lynch L.
      • Chitkara U.
      Antenatal treatment of neonatal alloimmune thrombocytopenia.
      ]. Treating mothers with IVIg was found to increase the fetal IgG concentration suggesting that the IVIg is being transported from the mother to the fetus therefore potentially inhibiting the transport of the pathogenic antibodies [
      • Bussel J.B.
      • Berkowitz R.L.
      • McFarland J.G.
      • Lynch L.
      • Chitkara U.
      Antenatal treatment of neonatal alloimmune thrombocytopenia.
      ,
      • Sidiropoulos D.
      • Herrmann U.
      • Morell A.
      • von Muralt G.
      • Barandun S.
      Transplacental passage of intravenous immunoglobulin in the last trimester of pregnancy.
      ]. Additionally, in-vitro perfusion models of the placenta have demonstrated that IVIg can inhibit the transport of anti-red blood cell and anti-HPA antibodies from the maternal to the fetal circuit [
      • Morgan C.L.
      • Cannell G.R.
      • Addison R.S.
      • Minchinton R.M.
      The effect of intravenous immunoglobulin on placental transfer of a platelet-specific antibody: anti-P1A1.
      ,
      • Urbaniak S.J.
      • Duncan J.I.
      • Armstrong-Fisher S.S.
      • Abramovich D.R.
      • Page K.R.
      Transfer of anti-D antibodies across the isolated perfused human placental lobule and inhibition by high-dose intravenous immunoglobulin: a possible mechanism of action.
      ], supporting the idea of placental FcRn blockade as its mechanism of action. Murine studies have also demonstrated that the therapeutic effects seen in the fetus after therapy with IVIg or an anti-FcRn specific antibody are very similar, indicating that IVIg could ameliorate FNAIT by blocking FcRn [
      • Li C.
      • Piran S.
      • Chen P.
      • Lang S.
      • Zarpellon A.
      • Jin J.W.
      • et al.
      The maternal immune response to fetal platelet GPIbα causes frequent miscarriage in mice that can be prevented by intravenous IgG and anti-FcRn therapies.
      ].

      4.2 Other mechanisms of action

      While the competitive blocking of FcRn is considered to be the most prominent mechanism of action of IVIg in FNAIT, other mechanisms should not be rulled out [
      • Winkelhorst D.
      • Oepkes D.
      Foetal and neonatal alloimmune thrombocytopenia.
      ,
      • Siragam V.
      • Crow A.R.
      • Brinc D.
      • Song S.
      • Freedman J.
      • Lazarus A.H.
      Intravenous immunoglobulin ameliorates ITP via activating Fcγ receptors on dendritic cells.
      ,
      • Crow A.R.
      • Suppa S.J.
      • Chen X.
      • Mott P.J.
      • Lazarus A.H.
      The neonatal Fc receptor (FcRn) is not required for IVIg or anti-CD44 monoclonal antibody–mediated amelioration of murine immune thrombocytopenia.
      ,
      • Chen P.
      • Li C.
      • Lang S.
      • Zhu G.
      • Reheman A.
      • Spring C.M.
      • et al.
      Animal model of fetal and neonatal immune thrombocytopenia: role of neonatal Fc receptor in the pathogenesis and therapy.
      ]. IVIg could potentially lead to the dilution of maternal antibodies [
      • Crow A.R.
      • Lazarus A.H.
      The mechanisms of action of intravenous immunoglobulin and polyclonal anti-d immunoglobulin in the amelioration of immune thrombocytopenic purpura: what do we really know?.
      ], which would be lowering the concentration of pathogenic anti-HPA antibodies binding to FcRn and decrease their transport across the placenta [
      • Winkelhorst D.
      • Oepkes D.
      Foetal and neonatal alloimmune thrombocytopenia.
      ]. Secondly, the presence of anti-idiotypic antibodies in IVIg could lead to the neutralisation of the pathogenic anti-HPA antibodies. Although anti-idiotypic antibodies against platelets have been shown to be reactive in vitro [
      • Berchtold P.
      • Dale G.L.
      • Tani P.
      • McMillan R.
      Inhibition of autoantibody binding to platelet glycoprotein IIb/IIIa by anti-idiotypic antibodies in intravenous gammaglobulin.
      ] and in vivo [
      • Bussel J.B.
      • Kimberly R.P.
      • Inman R.D.
      • Schulman I.
      • Cunningham-Rundles C.
      • Cheung N.
      • et al.
      Intravenous gammaglobulin treatment of chronic idiopathic thrombocytopenic purpura.
      ,
      • Bussel J.B.
      Modulation of Fc receptor clearance and antiplatelet antibodies as a consequence of intravenous immune globulin infusion in patients with immune thrombocytopenic purpura.
      ], their small quantities limit their effectiveness [
      • Ballow M.
      The IgG molecule as a biological immune response modifier: mechanisms of action of intravenous immune serum globulin in autoimmune and inflammatory disorders.
      ]. In fact, recent research has shown that anti-idiotypic antibodies are not required for the amelioration of thrombocytopenia in animal models of ITP [
      • Crow A.R.
      • Song S.
      • Semple J.W.
      • Freedman J.
      • Lazarus A.H.
      IVIg inhibits reticuloendothelial system function and ameliorates murine passive-immune thrombocytopenia independent of anti-idiotype reactivity.
      ] and a murine model of FNAIT [
      • Ni H.
      • Chen P.
      • Spring C.M.
      • Sayeh E.
      • Semple J.W.
      • Lazarus A.H.
      • et al.
      A novel murine model of fetal and neonatal alloimmune thrombocytopenia: response to intravenous IgG therapy.
      ]. Lastly, it is possible that IVIg that has crossed the placenta can block the fetal mononuclear phagocytic system, thus preventing the clearance of antibody-sensitized platelets [
      • Crow A.R.
      • Song S.
      • Semple J.W.
      • Freedman J.
      • Lazarus A.H.
      IVIg inhibits reticuloendothelial system function and ameliorates murine passive-immune thrombocytopenia independent of anti-idiotype reactivity.
      ,
      • Ni H.
      • Chen P.
      • Spring C.M.
      • Sayeh E.
      • Semple J.W.
      • Lazarus A.H.
      • et al.
      A novel murine model of fetal and neonatal alloimmune thrombocytopenia: response to intravenous IgG therapy.
      ].

      5. A replacement for IVIg?

      Although IVIg is now used as a gold-standard treatment in a variety of different diseases, its previously discussed limitations and manufacturing challenges (see 2.1) have provided an incentive to develop alternative therapies that could replace it [
      • Zuercher A.W.
      • Spirig R.
      • Baz Morelli A.
      • Käsermann F.
      IVIG in autoimmune disease — potential next generation biologics.
      ]. Additionally, IVIg is expensive – the treatment of a single FNAIT risk pregnancy can cost up to $300,000 in the US [
      • Zdravic D.
      • Yougbare I.
      • Vadasz B.
      • Li C.
      • Marshall A.H.
      • Chen P.
      • et al.
      Fetal and neonatal alloimmune thrombocytopenia.
      ] and 100,000€ in Europe [
      • European Commission Research and Innovation DG
      Final Report Summary - PROFNAIT (Development of a prophylactic treatment for the prevention of fetal/neonatal alloimmune thrombocytopenia (FNAIT)).
      ]. Consequently, replacing IVIg is especially desirable in diseases where the therapeutic effect is thought to be mediated by the Fc portion of the molecule [
      • Zuercher A.W.
      • Spirig R.
      • Baz Morelli A.
      • Käsermann F.
      IVIG in autoimmune disease — potential next generation biologics.
      ].

      5.1 FNAIT prophylaxis with anti-HPA antibodies

      Contrary to its red blood cell counterpart HDFN where immunization mainly occurs during delivery and consequently only affects second or subsequent pregnancies, FNAIT was thought to frequently occur primigravidae [
      • Tiller H.
      • Killie M.K.
      • Chen P.
      • Eksteen M.
      • Husebekk A.
      • Skogen B.
      • et al.
      Toward a prophylaxis against fetal and neonatal alloimmune thrombocytopenia: induction of antibody-mediated immune suppression and prevention of severe clinical complications in a murine model.
      ]. However, a Norwegian study has shown that only 8 % of women were actually immunized during their first pregnancy [
      • Killie M.K.
      • Husebekk A.
      • Kjeldsen-Kragh J.
      • Skogen B.
      A prospective study of maternal anti-HPA 1a antibody level as a potential predictor of alloimmune thrombocytopenia in the newborn.
      ]. Consequently, administering anti-HPA-1a antibodies could prevent FNAIT, similar to how administration of anti-D has been able to prevent HDFN for over 50 years. This principle was recently proven in a murine model using glycoprotein integrin β3 (GPIIIa)-deficient mice. The authors were able to show that injection of anti-HPA-1a antibodies after HPA-1a platelet transfusion were able to suppress the immune response, increase the platelet count of pups and decrease the number of miscarriages [
      • Tiller H.
      • Killie M.K.
      • Chen P.
      • Eksteen M.
      • Husebekk A.
      • Skogen B.
      • et al.
      Toward a prophylaxis against fetal and neonatal alloimmune thrombocytopenia: induction of antibody-mediated immune suppression and prevention of severe clinical complications in a murine model.
      ]. This has led to the establishment of the European PROFNAIT consortium which aims to develop a prophylactic treatment for the prevention of FNAIT. Plasma collected from HPA-1a-immunized women has been collected, and the first drug, tentatively called NAITgam, has now been manufactured by Emergent BioSolutions (Winnipeg, Canada) leveraging their proven platform for manufacturing of plasma-derived hyperimmune drug products [
      • Prophylix
      Emergent biosolutions to manufacture prophylix AS developmental drug for fetal-neonatal alloimmune thrombocytopenia.
      ]. The rights to develop NAITgam up to clinical approval has recently been acquired by Rallybio, an American pharmaceutical company with the aim of identifying and accelerating the development of transformative breakthrough therapies for patients with severe and rare disorders [
      • Prophylix
      Prophylix AS rare disease programs to be acquired by rallybio.
      ].

      5.2 Anti-FcRn antibodies

      In FNAIT, IVIg blockage of FcRn is considered by some to be the most important mechanism of action by which IVIg could excert its therapeutic function. Consequently, blockage of the receptor through anti-FcRn antibodies offers the possibility of replicating the therapeutic effect without the limitations that are associated with IVIg use. In fact, anti-FcRn antibodies have been studied in various animal models of autoimmune diseases with promising results [
      • Zdravic D.
      • Yougbare I.
      • Vadasz B.
      • Li C.
      • Marshall A.H.
      • Chen P.
      • et al.
      Fetal and neonatal alloimmune thrombocytopenia.
      ]. They were able to prevent the development of FNAIT and ITP in their respective mouse models [
      • Smith B.
      • Christodoulou L.
      • Clargo A.
      • Eddleston A.
      • Greenslade K.
      • Lightwood D.
      • et al.
      Generation of two high affinity anti-mouse FcRn antibodies: inhibition of IgG recycling in wild type mice and effect in a mouse model of immune thrombocytopenia.
      ,
      • Chen P.
      • Li C.
      • Lang S.
      • Zhu G.
      • Reheman A.
      • Spring C.M.
      • et al.
      Animal model of fetal and neonatal immune thrombocytopenia: role of neonatal Fc receptor in the pathogenesis and therapy.
      ] and have been associated with a decrease in miscarriages, improved angiogenesis and lower bleeding incidents [
      • Zdravic D.
      • Yougbare I.
      • Vadasz B.
      • Li C.
      • Marshall A.H.
      • Chen P.
      • et al.
      Fetal and neonatal alloimmune thrombocytopenia.
      ]. Additionally, the therapeutic dose of the antibodies was significantly lower than that of IVIg and their preparation does not require the use of human plasma making it a potentially safer and cost-effective treatment [
      • Chen P.
      • Li C.
      • Lang S.
      • Zhu G.
      • Reheman A.
      • Spring C.M.
      • et al.
      Animal model of fetal and neonatal immune thrombocytopenia: role of neonatal Fc receptor in the pathogenesis and therapy.
      ]. Although promising, anti-FcRn antibodies’ safety and efficacy needs to be further addressed in clinical trials as completely blocking transplacental transport may lead to significant side effects [
      • Zdravic D.
      • Yougbare I.
      • Vadasz B.
      • Li C.
      • Marshall A.H.
      • Chen P.
      • et al.
      Fetal and neonatal alloimmune thrombocytopenia.
      ].

      5.3 Multimerisation of Fc fragments

      The majority of IVIg effector mechanisms in autoimmune diseases is largely considered to be mediated by the Fc fragment of the antibody. Consequently, recombinant multimers of the Fc fragment might harness the therapeutic effect at a lower dose [
      • Zuercher A.W.
      • Spirig R.
      • Baz Morelli A.
      • Käsermann F.
      IVIG in autoimmune disease — potential next generation biologics.
      ]. Such complexes have been shown to target Fc receptors and inhibit antibody-mediated phagocytosis in vitro, while partially protecting against ITP and collagen-induced arthritis in vivo [
      • Zhang X.
      • Owens J.
      • Olsen H.S.
      • So E.
      • Burch E.
      • McCroskey M.C.
      • et al.
      A recombinant human IgG1 Fc multimer designed to mimic the active fraction of IVIG in autoimmunity.
      ]. Additionally, they have been effective in the prevention and treatment of complement-mediated diseases in rodent models [
      • Sun H.
      • Olsen H.S.
      • Mérigeon E.Y.
      • So E.
      • Burch E.
      • Kinsey S.
      • et al.
      Recombinant human IgG1 based Fc multimers, with limited FcR binding capacity, can effectively inhibit complement-mediated disease.
      ]. While these results are promising, a multimerisation of Fc fragments could lead to an overactivation of Fc receptors resulting in inflammatory reactions. Although none of the pre-clinical studies have reported any adverse effects so far, safety studies and human clinical trials are needed to assess the suitability of Fc multimers as a replacement for IVIg [
      • Zuercher A.W.
      • Spirig R.
      • Baz Morelli A.
      • Käsermann F.
      IVIG in autoimmune disease — potential next generation biologics.
      ].

      6. Conclusion

      Alloimmunisation to paternally inherited platelet antigens during pregnancy can lead to FNAIT, the leading cause of severe neonatal thrombocytopenia. Although its incidence is rare, it can lead to ICH which is associated with a high mortality and morbidity rate. In known risk pregnancies, IVIg is given antenatally to prevent ICH and is considered the gold-standard treatment. It is thought to exert the majority of its therapeutic effect through competitive blockage of the neonatal receptor FcRn, however its exact mechanism of action has remained unclear. Consequently, a better understanding of the mechanism of IVIg is required which would address issues regarding the dosage, timing and duration of IVIg treatment and potentially allow for the development of a replacement for IVIg which could potentially address the side effects and safety concerns that are associated with IVIg use. While some progress has been made in developing a prophylactic treatment for FNAIT, it seems unlikely that IVIg will be replaced soon.

      Funding

      Funding was provided by Canadian Blood Services Intramural Grant Program and Grant CBS221511 from Health Canada as part of the Canadian Blood Services/Canadian Institutes of Health Research partnership fund (to Alan H. Lazarus).

      CRediT authorship contribution statement

      Hanna Wabnitz: Conceptualization, Writing - original draft, Writing - review & editing. Ramsha Khan: Conceptualization, Writing - original draft, Writing - review & editing. Alan H. Lazarus: Conceptualization, Writing - review & editing, Supervision.

      Declaration of Competing Interest

      None.

      References

        • Baker J.M.
        • Shehata N.
        • Bussel J.
        • Murphy M.F.
        • Greinacher A.
        • Bakchoul T.
        • et al.
        Postnatal intervention for the treatment of FNAIT: a systematic review.
        J Perinatol. 2019; 39: 1329-1339
        • Winkelhorst D.
        • Oepkes D.
        Foetal and neonatal alloimmune thrombocytopenia.
        Best Pract Res Clin Obstet Gynaecol. 2019; 58: 15-27
        • Arnold D.M.
        • Smith J.W.
        • Kelton J.G.
        Diagnosis and management of neonatal alloimmune thrombocytopenia.
        Transfus Med Rev. 2008; 22: 255-267
        • Bertrand G.
        • Kaplan C.
        How do we treat fetal and neonatal alloimmune thrombocytopenia?.
        Transfusion. 2014; 54: 1698-1703
        • Lieberman L.
        • Greinacher A.
        • Murphy M.F.
        • Bussel J.
        • Bakchoul T.
        • Corke S.
        • et al.
        Fetal and neonatal alloimmune thrombocytopenia: recommendations for evidence-based practice, an international approach.
        Br J Haematol. 2019; 185: 549-562
        • Winkelhorst D.
        • Kamphuis M.M.
        • Steggerda S.J.
        • Rijken M.
        • Oepkes D.
        • Lopriore E.
        • et al.
        Perinatal outcome and long-term neurodevelopment after intracranial haemorrhage due to fetal and neonatal alloimmune thrombocytopenia.
        Fetal Diagn Ther. 2019; 45: 184-191
        • Serrarens-Janssen V.M.
        • Semmekrot B.A.
        • Novotny V.M.
        • Porcelijn L.
        • Lotgering F.K.
        • Delemarre F.M.
        • et al.
        Fetal/neonatal allo-immune thrombocytopenia (FNAIT): past, present, and future.
        Obstet Gynecol Surv. 2008; 63: 239-252
        • Winkelhorst D.
        • Oepkes D.
        • Lopriore E.
        Fetal and neonatal alloimmune thrombocytopenia: evidence based antenatal and postnatal management strategies.
        Expert Rev Hematol. 2017; 10: 729-737
        • Winkelhorst D.
        • Murphy M.F.
        • Greinacher A.
        • Shehata N.
        • Bakchoul T.
        • Massey E.
        • et al.
        Antenatal management in fetal and neonatal alloimmune thrombocytopenia: a systematic review.
        Blood. 2017; 129: 1538-1547
        • Radder C.M.
        • Brand A.
        • Kanhai H.H.H.
        Will it ever be possible to balance the risk of intracranial haemorrhage in fetal or neonatal alloimmune thrombocytopenia against the risk of treatment strategies to prevent it?.
        Vox Sang. 2003; 84: 318-325
        • Kamphuis M.M.
        • Oepkes D.
        Fetal and neonatal alloimmune thrombocytopenia: prenatal interventions.
        Prenat Diagn. 2011; 31: 712-719
        • van den Akker E.S.
        • Oepkes D.
        • Lopriore E.
        • Brand A.
        • Kanhai H.H.
        Noninvasive antenatal management of fetal and neonatal alloimmune thrombocytopenia: safe and effective.
        BJOG. 2007; 114: 469-473
        • Bussel J.B.
        • Berkowitz R.L.
        • McFarland J.G.
        • Lynch L.
        • Chitkara U.
        Antenatal treatment of neonatal alloimmune thrombocytopenia.
        N Engl J Med. 1988; 319: 1374-1378
        • Paridaans N.P.
        • Kamphuis M.M.
        • Taune Wikman A.
        • Tiblad E.
        • Van den Akker E.S.
        • Lopriore E.
        • et al.
        Low-dose versus standard-dose intravenous immunoglobulin to prevent fetal intracranial hemorrhage in fetal and neonatal alloimmune thrombocytopenia: a randomized trial.
        Fetal Diagn Ther. 2015; 38: 147-153
        • Crighton G.L.
        • Scarborough R.
        • McQuilten Z.K.
        • Phillips L.E.
        • Savoia H.F.
        • Williams B.
        • et al.
        Contemporary management of neonatal alloimmune thrombocytopenia: good outcomes in the intravenous immunoglobulin era: results from the Australian neonatal alloimmune thrombocytopenia registry.
        J Matern Fetal Neonatal Med. 2017; 30: 2488-2494
        • Kiefel V.
        • Bassler D.
        • Kroll H.
        • Paes B.
        • Giers G.
        • Ditomasso J.
        • et al.
        Antigen-positive platelet transfusion in neonatal alloimmune thrombocytopenia (NAIT).
        Blood. 2006; 107: 3761-3763
        • te Pas A.B.
        • Lopriore E.
        • van den Akker E.S.
        • Oepkes D.
        • Kanhai H.H.
        • Brand A.
        • et al.
        Postnatal management of fetal and neonatal alloimmune thrombocytopenia: the role of matched platelet transfusion and IVIG.
        Eur J Pediatr. 2007; 166: 1057-1063
        • Galeotti C.
        • Kaveri S.V.
        • Bayry J.
        IVIG-mediated effector functions in autoimmune and inflammatory diseases.
        Int Immunol. 2017; 29: 491-498
        • Pyne D.
        • Ehrenstein M.
        • Morris V.
        The therapeutic uses of intravenous immunoglobulins in autoimmune rheumatic diseases.
        Rheumatology. 2002; 41: 367-374
        • Imbach P.
        • Barandun S.
        • Baumgartner C.
        • Hirt A.
        • Hofer F.
        • Wagner H.P.
        High-dose intravenous gammaglobulin therapy of refractory, in particular idiopathic thrombocytopenia in childhood.
        Helv Paediatr Acta. 1981; 36: 81-86
        • De Ranieri D.
        • Fenny N.S.
        Intravenous immunoglobulin in the treatment of primary immunodeficiency diseases.
        Pediatr Ann. 2017; 46: e8-e12
        • Committee for Medicinal Products for Human Use (CHMP)
        Guideline on core SmPC for human normal immunoglobulin for intravenous administration (IVIg).
        European Medicines Agency, London, United Kingdom2018
        • Pierce L.R.
        • Jain N.
        Risks associated with the use of intravenous immunoglobulin.
        Transfus Med Rev. 2003; 17: 241-251
        • Chaigne B.
        • Mouthon L.
        Mechanisms of action of intravenous immunoglobulin.
        Transfus Apher Sci. 2017; 56: 45-49
        • Zuercher A.W.
        • Spirig R.
        • Baz Morelli A.
        • Käsermann F.
        IVIG in autoimmune disease — potential next generation biologics.
        Autoimmun Rev. 2016; 15: 781-785
        • Schwab I.
        • Nimmerjahn F.
        Intravenous immunoglobulin therapy: how does IgG modulate the immune system?.
        Nat Rev Immunol. 2013; 13: 176
        • Rossi K.Q.
        • Lehman K.J.
        • O’Shaughnessy R.W.
        Effects of antepartum therapy for fetal alloimmune thrombocytopenia on maternal lifestyle.
        J Matern Fetal Neonatal Med. 2016; 29: 1783-1788
        • Katz U.
        • Achiron A.
        • Sherer Y.
        • Shoenfeld Y.
        Safety of intravenous immunoglobulin (IVIG) therapy.
        Autoimmun Rev. 2007; 6: 257-259
        • Limited B.P.L.
        Package insert GAMMAPLEX®.
        US Food and Drug Administration, 2015
        • Lazarus A.H.
        Mechanisms of action and immunomodulation by IVIg.
        in: Imbach P. Antibody therapy: substitution – immunomodulation – monoclonal immunotherapy. Springer International Publishing, Cham2018: 73-83
        • Crow A.R.
        • Song S.
        • Siragam V.
        • Lazarus A.H.
        Mechanisms of action of intravenous immunoglobulin in the treatment of immune thrombocytopenia.
        Pediatr Blood Cancer. 2006; 47: 710-713
        • Kaveri S.V.
        Intravenous immunoglobulin: exploiting the potential of natural antibodies.
        Autoimmun Rev. 2012; 11: 792-794
        • Bayary J.
        • Dasgupta S.
        • Misra N.
        • Ephrem A.
        • Duong Van Huyen J.-P.
        • Delignat S.
        • et al.
        Intravenous immunoglobulin in autoimmune disorders: an insight into the immunoregulatory mechanisms.
        Int Immunopharmacol. 2006; 6: 528-534
        • Crow A.R.
        • Song S.
        • Semple J.W.
        • Freedman J.
        • Lazarus A.H.
        IVIg inhibits reticuloendothelial system function and ameliorates murine passive-immune thrombocytopenia independent of anti-idiotype reactivity.
        Br J Haematol. 2001; 115: 679-686
        • Baerenwaldt A.
        • Biburger M.
        • Nimmerjahn F.
        Mechanisms of action of intravenous immunoglobulins.
        Expert Rev Clin Immunol. 2010; 6: 425-434
        • Fehr J.
        • Hofmann V.
        • Kappeler U.
        Transient reversal of thrombocytopenia in idiopathic thrombocytopenic purpura by high-dose intravenous gamma globulin.
        N Engl J Med. 1982; 306: 1254-1258
        • Salama A.
        • Mueller-Eckhardt C.
        • Kiefel V.
        Effect of intravenous immunoglobulin in immune thrombocytopenia: competitive inhibition of reticuloendothelial system function by sequestration of autologous red blood cells?.
        Lancet. 1983; 322: 193-195
        • Siragam V.
        • Brinc D.
        • Crow A.R.
        • Song S.
        • Freedman J.
        • Lazarus A.H.
        Can antibodies with specificity for soluble antigens mimic the therapeutic effects of intravenous IgG in the treatment of autoimmune disease?.
        J Clin Invest. 2005; 115: 155-160
        • Crow A.R.
        • Lazarus A.H.
        The mechanisms of action of intravenous immunoglobulin and polyclonal anti-d immunoglobulin in the amelioration of immune thrombocytopenic purpura: what do we really know?.
        Transfus Med Rev. 2008; 22: 103-116
        • Crow A.R.
        • Song S.
        • Suppa S.J.
        • Ma S.
        • Reilly M.P.
        • Andre P.
        • et al.
        Amelioration of murine immune thrombocytopenia by CD44 antibodies: a potential therapy for ITP?.
        Blood. 2011; 117: 971-974
        • Teeling J.L.
        • Jansen-Hendriks T.
        • Kuijpers T.W.
        • de Haas M.
        • van de Winkel J.G.
        • Hack C.E.
        • et al.
        Therapeutic efficacy of intravenous immunoglobulin preparations depends on the immunoglobulin G dimers: studies in experimental immune thrombocytopenia.
        Blood. 2001; 98: 1095-1099
        • Nagelkerke S.Q.
        • Kuijpers T.W.
        Immunomodulation by IVIg and the role of Fc-gamma receptors: classic mechanisms of action after all?.
        Front Immunol. 2015; 5: 674
        • Crow A.R.
        • Song S.
        • Freedman J.
        • Helgason C.D.
        • Humphries R.K.
        • Siminovitch K.A.
        • et al.
        IVIg-mediated amelioration of murine ITP via FcγRIIB is independent of SHIP1, SHP-1, and Btk activity.
        Blood. 2003; 102: 558-560
        • Samuelsson A.
        • Towers T.L.
        • Ravetch J.V.
        Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor.
        Science. 2001; 291: 484-486
        • Tackenberg B.
        • Jelcic I.
        • Baerenwaldt A.
        • Oertel W.H.
        • Sommer N.
        • Nimmerjahn F.
        • et al.
        Impaired inhibitory Fc gamma receptor IIB expression on B cells in chronic inflammatory demyelinating polyneuropathy.
        Proc Natl Acad Sci U S A. 2009; 106: 4788-4792
        • Siragam V.
        • Crow A.R.
        • Brinc D.
        • Song S.
        • Freedman J.
        • Lazarus A.H.
        Intravenous immunoglobulin ameliorates ITP via activating Fcγ receptors on dendritic cells.
        Nat Med. 2006; 12: 688-692
        • Crow A.R.
        • Brinc D.
        • Lazarus A.H.
        New insight into the mechanism of action of IVIg: the role of dendritic cells.
        J Thromb Haemost. 2009; 7: 245-248
        • Ben Mkaddem S.
        • Benhamou M.
        • Monteiro R.C.
        Understanding Fc receptor involvement in inflammatory diseases: from mechanisms to new therapeutic tools.
        Front Immunol. 2019; 10
        • Crow A.R.
        • Suppa S.J.
        • Chen X.
        • Mott P.J.
        • Lazarus A.H.
        The neonatal Fc receptor (FcRn) is not required for IVIg or anti-CD44 monoclonal antibody–mediated amelioration of murine immune thrombocytopenia.
        Blood. 2011; 118: 6403-6406
        • Ballow M.
        The IgG molecule as a biological immune response modifier: mechanisms of action of intravenous immune serum globulin in autoimmune and inflammatory disorders.
        J Allergy Clin Immunol. 2011; 127: 315-323
        • Cooper N.
        • Heddle N.M.
        • Haas M.
        • Reid M.E.
        • Lesser M.L.
        • Fleit H.B.
        • et al.
        Intravenous (IV) anti-D and IV immunoglobulin achieve acute platelet increases by different mechanisms: modulation of cytokine and platelet responses to IV anti-D by FcgammaRIIa and FcgammaRIIIa polymorphisms.
        Br J Haematol. 2004; 124: 511-518
        • Anthony R.M.
        • Kobayashi T.
        • Wermeling F.
        • Ravetch J.V.
        Intravenous gammaglobulin suppresses inflammation through a novel TH2 pathway.
        Nature. 2011; 475: 110
        • Dalakas M.C.
        • Illa I.
        • Dambrosia J.M.
        • Soueidan S.A.
        • Stein D.P.
        • Otero C.
        • et al.
        A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis.
        N Engl J Med. 1993; 329: 1993-2000
        • Basta M.
        • Illa I.
        • Dalakas M.C.
        Increased in vitro uptake of the complement C3b in the serum of patients with Guillain-Barre syndrome, myasthenia gravis and dermatomyositis.
        J Neuroimmunol. 1996; 71: 227-229
        • Dalakas M.C.
        Intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: present status and practical therapeutic guidelines.
        Muscle Nerve. 1999; 22: 1479-1497
        • Pyzik M.
        • Rath T.
        • Lencer W.I.
        • Baker K.
        • Blumberg R.S.
        FcRn: the architect behind the immune and nonimmune functions of IgG and albumin.
        J Immunol. 2015; 194: 4595-4603
        • Baker K.
        • Qiao S.W.
        • Kuo T.
        • Kobayashi K.
        • Yoshida M.
        • Lencer W.I.
        • et al.
        Immune and non-immune functions of the (not so) neonatal Fc receptor, FcRn.
        Semin Immunopathol. 2009; 31: 223-236
        • Simister N.E.
        • Mostov K.E.
        An Fc receptor structurally related to MHC class I antigens.
        Nature. 1989; 337: 184-187
        • Roopenian D.C.
        • Akilesh S.
        FcRn: the neonatal Fc receptor comes of age.
        Nat Rev Immunol. 2007; 7: 715-725
        • Wilcox C.R.
        • Holder B.
        • Jones C.E.
        Factors affecting the FcRn-mediated transplacental transfer of antibodies and implications for vaccination in pregnancy.
        Front Immunol. 2017; 8: 1294
        • Sesarman A.
        • Vidarsson G.
        • Sitaru C.
        The neonatal Fc receptor as therapeutic target in IgG-mediated autoimmune diseases.
        Cell Mol Life Sci. 2010; 67: 2533-2550
        • Yu Z.
        • Lennon V.A.
        Mechanism of intravenous immune globulin therapy in antibody-mediated autoimmune diseases.
        N Engl J Med. 1999; 340: 227-228
        • Kuo T.T.
        • Aveson V.G.
        Neonatal Fc receptor and IgG-based therapeutics.
        MAbs. 2011; 3: 422-430
        • Wani M.A.
        • Haynes L.D.
        • Kim J.
        • Bronson C.L.
        • Chaudhury C.
        • Mohanty S.
        • et al.
        Familial hypercatabolic hypoproteinemia caused by deficiency of the neonatal Fc receptor, FcRn, due to a mutant beta2-microglobulin gene.
        Proc Natl Acad Sci U S A. 2006; 103: 5084-5089
        • Ghetie V.
        • Hubbard J.G.
        • Kim J.K.
        • Tsen M.F.
        • Lee Y.
        • Ward E.S.
        Abnormally short serum half-lives of IgG in beta 2-microglobulin-deficient mice.
        Eur J Immunol. 1996; 26: 690-696
        • Hansen R.J.
        • Balthasar J.P.
        Intravenous immunoglobulin mediates an increase in anti-platelet antibody clearance via the FcRn receptor.
        Thromb Haemost. 2002; 88: 898-899
        • Roopenian D.C.
        • Christianson G.J.
        • Sproule T.J.
        • Brown A.C.
        • Akilesh S.
        • Jung N.
        • et al.
        The MHC class I-like IgG receptor controls perinatal IgG transport, IgG homeostasis, and fate of IgG-Fc-coupled drugs.
        J Immunol. 2003; 170: 3528-3533
        • Brambell F.W.
        • Hemmings W.A.
        • Morris I.G.
        A theoretical model of gamma-globulin catabolism.
        Nature. 1964; 203: 1352-1354
        • Ghetie V.
        • Ward E.S.
        FcRn: the MHC class I-related receptor that is more than an IgG transporter.
        Immunol Today. 1997; 18: 592-598
        • Hansen R.J.
        • Balthasar J.P.
        Effects of intravenous immunoglobulin on platelet count and antiplatelet antibody disposition in a rat model of immune thrombocytopenia.
        Blood. 2002; 100: 2087-2093
        • Masson P.L.
        Elimination of infectious antigens and increase of IgG catabolism as possible modes of action of IVIg.
        J Autoimmun. 1993; 6: 683-689
        • Fateh-Moghadam A.
        • Wick M.
        • Besinger U.
        • Geursen R.G.
        High-dose intravenous gammaglobulin for myasthenia gravis.
        Lancet. 1984; 1: 848-849
        • Dalakas M.C.
        • Fujii M.
        • Li M.
        • Lutfi B.
        • Kyhos J.
        • McElroy B.
        High-dose intravenous immune globulin for stiff-person syndrome.
        N Engl J Med. 2001; 345: 1870-1876
        • Jayne D.R.
        • Esnault V.L.
        • Lockwood C.M.
        ANCA anti-idiotype antibodies and the treatment of systemic vasculitis with intravenous immunoglobulin.
        J Autoimmun. 1993; 6: 207-219
        • Hammarström L.
        • Abedi M.R.
        • Hassan M.S.
        • Smith C.I.
        The SCID mouse as a model for autoimmunity.
        J Autoimmun. 1993; 6: 667-674
        • Li N.
        • Zhao M.
        • Hilario-Vargas J.
        • Prisayanh P.
        • Warren S.
        • Diaz L.A.
        • et al.
        Complete FcRn dependence for intravenous Ig therapy in autoimmune skin blistering diseases.
        J Clin Invest. 2005; 115: 3440-3450
        • Ni H.
        • Chen P.
        • Spring C.M.
        • Sayeh E.
        • Semple J.W.
        • Lazarus A.H.
        • et al.
        A novel murine model of fetal and neonatal alloimmune thrombocytopenia: response to intravenous IgG therapy.
        Blood. 2006; 107: 2976-2983
        • Akilesh S.
        • Petkova S.
        • Sproule T.J.
        • Shaffer D.J.
        • Christianson G.J.
        • Roopenian D.
        The MHC class I-like Fc receptor promotes humorally mediated autoimmune disease.
        J Clin Invest. 2004; 113: 1328-1333
        • Smith B.
        • Christodoulou L.
        • Clargo A.
        • Eddleston A.
        • Greenslade K.
        • Lightwood D.
        • et al.
        Generation of two high affinity anti-mouse FcRn antibodies: inhibition of IgG recycling in wild type mice and effect in a mouse model of immune thrombocytopenia.
        Int Immunopharmacol. 2019; 66: 362-365
        • Chen P.
        • Li C.
        • Lang S.
        • Zhu G.
        • Reheman A.
        • Spring C.M.
        • et al.
        Animal model of fetal and neonatal immune thrombocytopenia: role of neonatal Fc receptor in the pathogenesis and therapy.
        Blood. 2010; 116: 3660-3668
        • Simister N.E.
        Placental transport of immunoglobulin G.
        Vaccine. 2003; 21: 3365-3369
        • Martinez D.R.
        • Fouda G.G.
        • Peng X.
        • Ackerman M.E.
        • Permar S.R.
        Noncanonical placental Fc receptors: what is their role in modulating transplacental transfer of maternal IgG?.
        PLoS Pathog. 2018; 14: e1007161
        • Story C.M.
        • Mikulska J.E.
        • Simister N.E.
        A major histocompatibility complex class I-like Fc receptor cloned from human placenta: possible role in transfer of immunoglobulin G from mother to fetus.
        J Exp Med. 1994; 180: 2377-2381
        • Simister N.E.
        • Story C.M.
        • Chen H.L.
        • Hunt J.S.
        An IgG-transporting Fc receptor expressed in the syncytiotrophoblast of human placenta.
        Eur J Immunol. 1996; 26: 1527-1531
        • Palmeira P.
        • Quinello C.
        • Silveira-Lessa A.L.
        • Zago C.A.
        • Carneiro-Sampaio M.
        IgG placental transfer in healthy and pathological pregnancies.
        Clin Dev Immunol. 2012; 2012: 985646
        • Sidiropoulos D.
        • Herrmann U.
        • Morell A.
        • von Muralt G.
        • Barandun S.
        Transplacental passage of intravenous immunoglobulin in the last trimester of pregnancy.
        J Pediatr. 1986; 109: 505-508
        • Morgan C.L.
        • Cannell G.R.
        • Addison R.S.
        • Minchinton R.M.
        The effect of intravenous immunoglobulin on placental transfer of a platelet-specific antibody: anti-P1A1.
        Transfus Med. 1991; 1: 209-216
        • Urbaniak S.J.
        • Duncan J.I.
        • Armstrong-Fisher S.S.
        • Abramovich D.R.
        • Page K.R.
        Transfer of anti-D antibodies across the isolated perfused human placental lobule and inhibition by high-dose intravenous immunoglobulin: a possible mechanism of action.
        Br J Haematol. 1997; 96: 186-193
        • Li C.
        • Piran S.
        • Chen P.
        • Lang S.
        • Zarpellon A.
        • Jin J.W.
        • et al.
        The maternal immune response to fetal platelet GPIbα causes frequent miscarriage in mice that can be prevented by intravenous IgG and anti-FcRn therapies.
        J Clin Invest. 2011; 121: 4537-4547
        • Berchtold P.
        • Dale G.L.
        • Tani P.
        • McMillan R.
        Inhibition of autoantibody binding to platelet glycoprotein IIb/IIIa by anti-idiotypic antibodies in intravenous gammaglobulin.
        Blood. 1989; 74: 2414-2417
        • Bussel J.B.
        • Kimberly R.P.
        • Inman R.D.
        • Schulman I.
        • Cunningham-Rundles C.
        • Cheung N.
        • et al.
        Intravenous gammaglobulin treatment of chronic idiopathic thrombocytopenic purpura.
        Blood. 1983; 62: 480-486
        • Bussel J.B.
        Modulation of Fc receptor clearance and antiplatelet antibodies as a consequence of intravenous immune globulin infusion in patients with immune thrombocytopenic purpura.
        J Allergy Clin Immunol. 1989; 84 (discussion 77-8): 566-577
        • Zdravic D.
        • Yougbare I.
        • Vadasz B.
        • Li C.
        • Marshall A.H.
        • Chen P.
        • et al.
        Fetal and neonatal alloimmune thrombocytopenia.
        Semin Fetal Neonatal Med. 2016; 21: 19-27
        • European Commission Research and Innovation DG
        Final Report Summary - PROFNAIT (Development of a prophylactic treatment for the prevention of fetal/neonatal alloimmune thrombocytopenia (FNAIT)).
        2019 (Accessed: 01 September 2019)
        • Tiller H.
        • Killie M.K.
        • Chen P.
        • Eksteen M.
        • Husebekk A.
        • Skogen B.
        • et al.
        Toward a prophylaxis against fetal and neonatal alloimmune thrombocytopenia: induction of antibody-mediated immune suppression and prevention of severe clinical complications in a murine model.
        Transfusion. 2012; 52: 1446-1457
        • Killie M.K.
        • Husebekk A.
        • Kjeldsen-Kragh J.
        • Skogen B.
        A prospective study of maternal anti-HPA 1a antibody level as a potential predictor of alloimmune thrombocytopenia in the newborn.
        Haematologica. 2008; 93: 870
        • Prophylix
        Emergent biosolutions to manufacture prophylix AS developmental drug for fetal-neonatal alloimmune thrombocytopenia.
        2019
        • Prophylix
        Prophylix AS rare disease programs to be acquired by rallybio.
        2019
        • Zhang X.
        • Owens J.
        • Olsen H.S.
        • So E.
        • Burch E.
        • McCroskey M.C.
        • et al.
        A recombinant human IgG1 Fc multimer designed to mimic the active fraction of IVIG in autoimmunity.
        JCI Insight. 2019; 4
        • Sun H.
        • Olsen H.S.
        • Mérigeon E.Y.
        • So E.
        • Burch E.
        • Kinsey S.
        • et al.
        Recombinant human IgG1 based Fc multimers, with limited FcR binding capacity, can effectively inhibit complement-mediated disease.
        J Autoimmun. 2017; 84: 97-108