scholarly journals Successful prenatal therapy of anti-CD36-mediated severe FNAIT by deglycosylated antibodies in a novel murine model

Blood ◽  
2021 ◽  
Author(s):  
Xiuzhang Xu ◽  
Dawei Chen ◽  
Xin Ye ◽  
Wenjie Xia ◽  
Yaori Xu ◽  
...  
Keyword(s):  
Animal Model ◽  
Fetal Death ◽  
Polyclonal Antibodies ◽  
African Populations ◽  
Wild Type Male ◽  
Therapy Success ◽  
Alloimmune Thrombocytopenia ◽  
Pup Mortality ◽  
Antenatal Treatment ◽  
Ivig Administration

Recent studies have demonstrated that maternal anti-CD36 antibodies represent a frequent cause of fetal/neonatal alloimmune thrombocytopenia (FNAIT) in Asian and African populations. However, little is known about the pathomechanism and antenatal treatment of anti-CD36-mediated FNAIT. Here, we established a novel animal model to examine the clinical features of pups from immunized Cd36-/- female mice after breeding with wild-type male mice. Mild thrombocytopenia was observed, but high pup mortality was also documented (40.26%). IVIG (1 g/kg) administration on days 7, 12, and 17 to immunized Cd36-/- mothers after breeding reduced fetal death (12.70%). However, delaying the IVIG administration series on days 10, 15, and 20 did not reduce fetal death (40.00%). In contrast, injection of deglycosylated anti-CD36 (deg-anti-CD36) polyclonal antibodies (5 mg/kg) on days 10, 15, and 20 significantly reduced fetal death (5.26%). Subsequently, monoclonal antibodies (mAbs) against mouse CD36 were developed, and one clone producing high-affinity anti-CD36 (termed 32-106) effectively inhibited maternal antibody binding and was therefore selected. Using the same approach of deg-anti-CD36, the administration of deg-32-106 significantly reduced fetal death (2.17%). Furthermore, immunized Cd36-/- mothers showed placenta deficiency. Accordingly, maternal anti-CD36 antibodies inhibited angiogenesis of placenta endothelial cells, which could be restored by deg-32-106. In summary, maternal anti-CD36 antibodies caused a high frequency of fetal death in our animal model, associated with placental dysfunction. This deleterious effect could be diminished by the antenatal administration of IVIG and deg-mAb 32-106. Interestingly, treatment with deg-32-106 appears more beneficial considering the lower dose, later start of treatment, and therapy success.

scholarly journals A novel murine model of fetal and neonatal alloimmune thrombocytopenia: response to intravenous IgG therapy

Blood ◽  
2006 ◽  
Vol 107 (7) ◽  
pp. 2976-2983 ◽  
Author(s):  
Heyu Ni ◽  
Pingguo Chen ◽  
Christopher M. Spring ◽  
Ebrahim Sayeh ◽  
John W. Semple ◽  
...  
Keyword(s):  
High Titer ◽  
Maternal Antibodies ◽  
Platelet Glycoprotein ◽  
Wild Type ◽  
Wild Type Male ◽  
Glycoprotein Iiia ◽  
Life Threatening ◽  
Β3 Integrin ◽  
Pathogenic Antibodies ◽  
Alloimmune Thrombocytopenia

AbstractFetal and neonatal alloimmune thrombo cytopenia (FNAITP) is a life-threatening bleeding disorder caused by maternal antibodies directed against fetal platelet antigens. The immunoreactive epitopes in FNAITP are primarily located in the extracellular regions of the platelet glycoprotein IIIa (β3 integrin). Here we have established a novel animal model of FNAITP using β3 integrin–deficient (β3-/-) mice. We demonstrated first that these mice are immunoresponsive to β3 integrin; β3-/- mice transfused with wild-type platelets generated specific anti–β3 antibodies which were able to induce thrombocytopenia in wild-type mice. Subsequently, β3-/- female mice (both naive and immunized) were bred with wild-type male mice to recapitulate the features of FNAITP. The titer of generated maternal antibodies correlated with the severity of FNAITP. High titer maternal anti–β3 anti-bodies caused severe fetal thrombocytopenia, intracranial hemorrhage, and even miscarriage. Furthermore, maternal administration of intravenous immunoglobulin G (IgG) ameliorated FNAITP and down-regulated pathogenic antibodies in both the maternal and fetal circulations.

scholarly journals Antenatal management in fetal and neonatal alloimmune thrombocytopenia: a systematic review

Blood ◽  
2017 ◽  
Vol 129 (11) ◽  
pp. 1538-1547 ◽  
Author(s):  
Dian Winkelhorst ◽  
Michael F. Murphy ◽  
Andreas Greinacher ◽  
Nadine Shehata ◽  
Taman Bakchoul ◽  
...  
Keyword(s):  
Systematic Review ◽  
Adverse Outcomes ◽  
High Rate ◽  
First Line ◽  
Key Points ◽  
Antenatal Management ◽  
Alloimmune Thrombocytopenia ◽  
Ivig Administration

Key Points The systematic review suggests that first-line antenatal management in FNAIT is weekly IVIG administration. Noninvasive management is effective without the relatively high rate of adverse outcomes seen in invasive strategies.

scholarly journals Recombinant HPA-1a antibody therapy for treatment of fetomaternal alloimmune thrombocytopenia: proof of principle in human volunteers

Blood ◽  
2013 ◽  
Vol 122 (3) ◽  
pp. 313-320 ◽  
Author(s):  
Cedric Ghevaert ◽  
Nina Herbert ◽  
Louise Hawkins ◽  
Nicola Grehan ◽  
Philip Cookson ◽  
...  
Keyword(s):  
Therapeutic Agent ◽  
Antibody Therapy ◽  
Potential Therapeutic Agent ◽  
Human Volunteers ◽  
Key Points ◽  
Alloimmune Thrombocytopenia ◽  
Antenatal Treatment ◽  
Proof Of Principle

Key Points Recombinant HPA-1a antibody B2G1Δnab protects platelets from destruction by anti–HPA-1a in the circulation of HPA-1a1b human volunteers. B2G1Δnab is a potential therapeutic agent for antenatal treatment of fetomaternal alloimmune thrombocytopenia due to HPA-1a antibodies.

Follow up of children after antenatal treatment for alloimmune thrombocytopenia

2004 ◽  
Vol 80 (1) ◽  
pp. 65-76 ◽  
Author(s):  
Celine M. Radder ◽  
Monique J.J. de Haan ◽  
Anneke Brand ◽  
Gerlinde M.S.J. Stoelhorst ◽  
Sylvia Veen ◽  
...  
Keyword(s):  
Alloimmune Thrombocytopenia ◽  
Antenatal Treatment

The effect of recombinant IgG antibodies against the leucine-33 form of the platelet β3 integrin (HPA-1a) on platelet function

2004 ◽  
Vol 91 (04) ◽  
pp. 743-754 ◽  
Author(s):  
Lotta Joutsi-Korhonen ◽  
Sandy Preston ◽  
Peter Smethurst ◽  
Martin IJsseldijk ◽  
Elisabeth Schaffner-Reckinger ◽  
...  
Keyword(s):  
Platelet Function ◽  
Polyclonal Antibodies ◽  
Antibody Fragment ◽  
Inhibitory Effect ◽  
Effector Functions ◽  
Β3 Integrin ◽  
Flowing Blood ◽  
Alloimmune Thrombocytopenia ◽  
Induced Aggregation

SummaryRecombinant HPA-1a antibodies with Fc, mutated to remove destructive effector functions, have been developed as a potential therapy for fetomaternal alloimmune thrombocytopenia (FMAIT), via blockade of binding of human HPA-1a polyclonal antibodies to fetal HPA-1a1b platelets. We have assessed the effect of the IgG1 HPA-1a antibody B2G1 and two mutated derivatives in various functional assays in resting and agoniststimulated platelets of the three HPA-1 genotypes. With HPA-1a1b platelets (fetal genotype), the antibodies did not activate signalling or CD62P expression in resting platelets, did not change in vitro bleeding time (IVBT), and did not inhibit platelet adhesion to collagen in flowing blood. Adhesion of HPA-1a1b platelets to fibrinogen was reduced by 20%, and aggregation induced by ADP by 50%, but collagen-related peptide (CRP-XL)-induced aggregation was normal. With HPA-1a1a platelets, aggregation to both ADP and CRP-XL was inhibited, with total blockade of adhesion to fibrinogen and of IVBT responses. Interestingly, a monovalent antibody fragment with identical specificity had no inhibitory effect on aggregation. In static adhesion assays using human αIIbβ3 or αVβ3 transfectants of HPA-1a (Leu33) phenotype, attachment to fibrinogen of the latter but not of the former was completely blocked by the HPA-1a antibodies. These observations are best explained by antibody-mediated blockade of the RGD binding site on β3 by a mechanism of steric hindrance. As the effect on platelet function is modest with HPA-1a1b (fetal type) platelets, the mutated HPA-1a antibodies described here could be developed further for FMAIT therapy.

Antenatal treatment of fetal immune thrombocytopenias

1998 ◽  
Vol 10 (1) ◽  
pp. 1-19 ◽  
Author(s):  
Daniel W Skupski ◽  
James B Bussel
Keyword(s):  
At Risk ◽  
Immune Thrombocytopenic Purpura ◽  
Current Knowledge ◽  
Imaging Techniques ◽  
Severe Disease ◽  
Diagnosis And Treatment ◽  
Thrombocytopenic Purpura ◽  
Alloimmune Thrombocytopenia ◽  
Review Current ◽  
Antenatal Treatment

Advances in both imaging techniques and in treatments for immune thrombocytopenias affecting the fetus have allowed for more accurate antenatal predictions of severe disease and effective antenatal treatments for those fetuses who are at risk of sequelae. This article will review current knowledge of the diagnosis and treatment of affected fetuses in alloimmune thrombocytopenia and in immune thrombocytopenic purpura.

scholarly journals Protection against Congenital CMV Infection Conferred by MVA-Vectored Subunit Vaccines Extends to a Second Pregnancy after Maternal Challenge with a Heterologous, Novel Strain Variant

Viruses ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2551
Author(s):  
Claudia Fernández-Alarcón ◽  
Grace Buchholz ◽  
Heidi Contreras ◽  
Felix Wussow ◽  
Jenny Nguyen ◽  
...  
Keyword(s):  
Animal Model ◽  
Cmv Infection ◽  
Subunit Vaccines ◽  
Previous Pregnancy ◽  
Congenital Cmv Infection ◽  
Guinea Pig Cytomegalovirus ◽  
Combined Vaccine ◽  
Pup Mortality ◽  
Congenital Cmv

Maternal reinfection of immune women with novel human cytomegalovirus (HCMV) strains acquired during pregnancy can result in symptomatic congenital CMV (cCMV) infection. Novel animal model strategies are needed to explore vaccine-mediated protections against maternal reinfection. To investigate this in the guinea pig cytomegalovirus (GPCMV) model, a strictly in vivo-passaged workpool of a novel strain, the CIDMTR strain (dose, 1 × 107 pfu) was used to infect dams that had been challenged in a previous pregnancy with the 22122 strain, following either sham-immunization (vector only) or vaccination with MVA-vectored gB, gH/gL, or pentameric complex (PC) vaccines. Maternal DNAemia cleared by day 21 in the glycoprotein-vaccinated dams, but not in the sham-immunized dams. Mean pup birth weights were 72.85 ± 10.2, 80.0 ± 6.9, 81.4 ± 14.1, and 89.38 ± 8.4 g in sham-immunized, gB, gH/gL, and PC groups, respectively (p < 0.01 for control v. PC). Pup mortality in the sham-immunized group was 6/12 (50%), but reduced to 3/35 (8.6%) in combined vaccine groups (p = 0.0048). Vertical CIDMTR transmission occurred in 6/12 pups (50%) in the sham-vaccinated group, compared to 2/34 pups (6%) in the vaccine groups (p = 0.002). We conclude that guinea pigs immunized with vectored vaccines expressing 22122 strain-specific glycoproteins are protected after a reinfection with a novel, heterologous clinical isolate (CIDMTR) in a second pregnancy.

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