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  • (2023) Zheng, Shiying
    Thesis
    Immune thrombocytopenia (ITP) is an autoimmune disorder caused by dysregulated B and T cell functions, which lead to platelet destruction. ITP pathogenesis involves autologous antibodies that recognise membrane glycoprotein (GP) complexes, mainly GPIb/IX and GPIIb/IIIa, on platelets and megakaryocytes. Conversely, immune platelet refractoriness refers to the rapid destruction of transfused platelets secondary to alloimmune antibodies, most commonly anti-human leucocyte antigen (HLA) class I alloantibodies. Opsonised platelets are phagocytosed by macrophages. Certain antibodies may also induce platelet desialylation and apoptosis. Nevertheless, the exact relationship between these thrombocytopenic mechanisms and antibody specificities has not been established. This thesis examined in detail sera from 61 ITP patients and 20 controls. We found that ITP sera with detectable anti-platelet antibodies caused significant platelet desialylation and apoptosis relative to those without detectable antibodies. Anti-GPIIb/IIIa antibodies appeared more capable of causing neuraminidase surface translocation, leading to platelet desialylation, while anti-GPIb/IX complex antibodies resulted in a higher degree of platelet apoptosis. In a murine model of anti-GPIIb/IIIa antibodies-induced ITP, we showed that neuraminidase inhibitor oseltamivir could preserve human platelets. This thesis also investigated allo-HLA antibody mediated platelet refractoriness. In contrast to ITP, HLA antibodies did not cause platelet desialylation but induced platelet apoptosis after prolonged incubation. These findings suggest that antibody-induced desialylation and apoptosis are unlikely to be involved in platelet refractoriness due to the rapid platelet destruction observed in immune platelet refractoriness. We further explored whether HLA blockade with mouse anti-human HLA monoclonal antibody (mAb) W6/32 could reduce patients’ alloantibody binding, thus preventing transfused platelet destruction. W6/32 reduced patients’ antibody binding to platelets. Its fragment antibody-binding region (Fab) was effective in preserving human platelets from allo-HLA antibody mediated clearance in vivo. In summary, this thesis has furthered our understanding of the pathogenesis of immune platelet disorders. The findings shed light on potential therapeutic targets and paved the way for future collaborative clinical trials. Specifically, our results support future investigation of oseltamivir as a monotherapy for ITP and the development of HLA blocking agents for management of platelet refractoriness.