Immunopathology of ITP

ITP的免疫病理学

• 批准号: 9249098
• 负责人: Karina Yazdanbakhsh
• 金额: $ 49.38万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9249098
• 关键词: Address; Affect; Aftercare; Autoantibodies; Autoimmune Process; Autoimmunity; B-Lymphocytes; Biological Assay; Blood Platelets; Cell Communication; Cell Maturation; Cells; Chronic; Cross-Sectional Studies; Data; Dendritic Cells; Development; Disease; Eragrostis; FCGR3B gene; FOXP3 gene; Foundations; Frequencies; Goals; Hemorrhage; Hyperactive behavior; Immune; Immune response; Immune system; Immunologic Factors; Impairment; Individual; Innate Immune Response; Interferons; Knowledge; Lead; Longitudinal Studies; Mediating; Multiple Abnormalities; Pathogenicity; Patients; Pharmaceutical Preparations; Platelet Count measurement; Play; Population; Production; Regulatory T-Lymphocyte; Role; T cell response; T-Lymphocyte; Testing; Thrombocytopenia; Tissues; adaptive immune response; adaptive immunity; base; immunopathology; improved; macrophage; molecular targeted therapies; monocyte; novel; novel therapeutics; polarized cell; potential biomarker; prevent; public health relevance; response; targeted treatment; therapeutic target; transcription factor

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.

描述（由申请方提供）：免疫性血小板减少症（ITP）是一种自身免疫性出血性疾病，其原因是血小板生成减少以及部分由基于自身抗体的破坏机制介导的血小板加速破坏。我们和其他人已经确定了ITP患者的免疫反应失调，这可以通过受损的调节性T和B细胞来证明，这可能是导致这种激活的自身免疫状态的原因。先天性和适应性免疫应答之间存在密切关系，我们的数据表明，可以影响T细胞应答的单核细胞亚群在ITP患者中抑制T细胞应答的能力发生改变，抑制Treg扩增，同时促进Th 1发育。此外，在用巨核细胞刺激血小板生成（TPO）剂治疗的ITP患者中，仅对治疗有反应者具有正常化的单核细胞和Treg区室。此外，我们还发现，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，ITP患者中的这些血小板衍生因子改变树突状细胞（DC）的成熟，从而抑制Treg增殖。我们 假设由于ITP患者中血小板反应性增加而导致的T细胞和先天免疫细胞之间的异常相互作用是ITP患者中Treg/Th发育改变的原因，并且对TPO试剂的反应性依赖于这些相互作用的正常化。我们将用以下具体目的来检验我们的假设：1）剖析ITP患者中改变的DC-Treg相互作用的机制，2）表征ITP患者中血小板在偏斜的Treg/Th应答中的作用，以及3）鉴定血小板反应性与TPO试剂治疗期间DC对Treg/Th应答的控制之间的关系。我们认为，拟议的研究将提供机制解释的方式，先天免疫异常可以有助于致病性自身免疫性ITP和调节反应或不响应TPO药物和其他可能的ITP治疗。