Immunopathology of ITP

描述（由申请人提供）：免疫性血小板减少症（ITP）是一种自身免疫性出血性疾病，由于血小板产生减少以及部分由自身抗体破坏机制介导的血小板破坏加速。我们和其他人已经在ITP患者中发现了一种失调的免疫反应，其证据是调节性T细胞和B细胞受损，这可能是导致这种激活的自身免疫状态的原因。先天免疫反应和适应性免疫反应之间存在密切的关系，我们的数据表明，单核细胞亚群可以影响T细胞反应，在ITP患者中，它们极化T细胞反应的能力发生了改变，抑制Treg扩增，同时促进Th1的发育。此外，在接受巨核细胞刺激血小板生成（TPO）药物治疗的ITP患者中，只有对治疗有反应的患者单核细胞和Treg区室正常化。此外，我们发现血小板计数低的慢性ITP患者的血小板表达高水平的促炎分子，这些血小板衍生因子在ITP患者中改变树突状细胞（DC）成熟，从而抑制Treg增殖。我们

DESCRIPTION (provided by applicant): Immune thrombocytopenia (ITP) is an autoimmune bleeding disease due to decreased platelet production as well as accelerated platelet destruction mediated in part by autoantibody-based destruction mechanisms. We and others have identified a dysregulated immune response in ITP patients as evidenced by impaired regulatory T and B cells which may be responsible for this activated autoimmune state. There is a tight relationship between innate and adaptive immune responses and our data indicate that monocyte subsets, which can influence T cell responses, are altered in their ability to polarize T cell responses in ITP patients, suppressing Treg expansion while promoting Th1 development. Furthermore, in ITP patients who are treated with megakaryocytic stimulating thrombopoietic (TPO) agents only responders to treatment have normalized monocyte and Treg compartments. In addition, we have discovered that platelets from chronic ITP patients with low platelet counts express high levels of proinflammatory molecules and those platelet-derived factors in ITP patients alter dendritic cell (DC) maturation such that they in turn inhibit Treg proliferation. We hypothesize that aberrant interactions between T cells and innate immune cells due to increased platelet reactivity in ITP patients are responsible for altered Treg/Th development in ITP patients and that responsiveness to TPO agents is dependent on normalization of these interactions. We will test our hypothesis with the following specific aims: 1) to dissect mechanisms of altered DC-Treg interactions in patients with ITP, 2) to characterize the role of platelets in skewed Treg/Th responses in ITP patients, and 3) to identify the relationship between platelet reactivity and control of Treg/Th responses by DCs during treatment with TPO agents. We believe that the proposed studies will provide mechanistic explanations for the ways in which innate immune abnormalities can contribute to pathogenic autoimmunity in ITP and modulate response or non-responsive to TPO agents and possibly other ITP therapies.