Studies are proposed exploring the mechanisms of increased platelet destruction and decreased platelet production focusing on anti-GPIIIa antibodies directed at what appears to be an immunodominant determinant, GPIIIa 49-66, in the serum of HIV-ITP patients. Previous work has revealed that amounts of antibodies isolated from immune complexes of HIV-ITP patients are inversely related to platelet count levels, and induce thrombocytopenia in mice which can be reversed by infusion of GPIIIa 49-66 conjugated with albumin. Therefore, it is hypothesized that antibodies to this particular region of GPIIIa might have particular significance in the pathogenesis of HIV related immune thrombocytopenia. The applicants seek to determine whether anti-49-66 antibodies are polyclonal or oligoclonal; whether they might be the result of molecular mimicry of antigens of infectious origin; and whether or not there is a unique idiotype repertoire for anti-49-66. They will also explore whether elevated CD5+ B cells, which are primitive B cells described in HIV-ITP patients, might be responsible for anti-49-66 as well as for anti-idiotype antibodies. Finally, they will analyze the mechanism(s) by which anti-GPIIIa inhibits MK development via apoptosis determining whether the specificity of these antibodies is to 49-66; which stage of MK maturation is inhibited; the mechanism of apoptosis; and whether anti-GPIIIa impairs megakaryocytopoiesis in vivo.
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