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HPA‐1a‐mediated platelet interaction with monocytes in vitro: involvement of Fcγ receptor (FcγR) classes and inhibition by humanised monoclonal anti‐FcγRI H22

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Abstract: To gain insight into mechanisms of platelet destruction and its possible inhibition during fetal/neonatal alloimmune thrombocytopenia (FAIT/NAIT) the binding to monocytes (Mo) of anti‐HPA‐1a‐sensitised platelets, the initial step in IgG‐mediated destruction by effector cells, was evaluated in an in vitro assay. Neonatal Mo were compared with adult Mo as effectors in the assay. Moreover, the potential involvement of Fcγ receptor (FcγR) classes during platelet destruction in the disease was tested by using FcγR class‐specific reagents as inhibitors of the binding reaction. Neonatal Mo were 37% less active than adult Mo in their interaction with anti‐HPA‐1a‐sensitised platelets (p<0.05). The FcγRI‐specific reagents human monomeric IgG and humanised anti‐FcγRI monoclonal H22 caused virtually complete inhibition of platelet binding to Mo. When compared to an intravenous immunoglobulin preparation the inhibitory activity of H22 was 10–100× greater than that of the latter compound. Monoclonal anti‐FcγRII IV.3 and anti‐FcγRIII 3G8 decreased platelet binding by 70% and 64%, respectively, but only the anti‐FcγRII inhibition was statistically significant (p<0.001). Finally, anti‐HPA‐1a‐sensitised platelets bound to 131H‐ but not to 131R‐ FcγRIIa transfected 3T6 mouse fibroblasts (p<0.01), in an anti‐HPA‐1a‐concentration‐dependent manner.

The results suggest that FcγRI and FcγRIIa may be involved in anti‐HPA‐1a‐mediated platelet destruction by mononuclear phagocytes during FAIT/NAIT. Moreover, the much greater potency of monoclonal H22 than of intravenous immunoglobulin as an inhibitor of anti‐HPA‐1a‐mediated Mo‐platelet interaction, might render it superior to the latter agent in the maternal therapy of the disorder.
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Keywords: FAIT/NAIT; FcγR; H22; anti‐HPA‐1a; monocytes; platelets

Document Type: Research Article

Affiliations: 1: Department of Haematology, Imperial College School of Medicine, St Mary's Campus, London, UK, 2: Fetal Medicine Unit, Department Obstetrics and Gynaecology, University College London Medical School, and 3: Medarex Inc Annandale, New Jersey, USA

Publication date: December 1, 2000

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