Novel platelet functions for in T-cell helper cell responses

T 细胞辅助细胞反应中的血小板新功能

基本信息

批准号：
8967578
负责人：
CRAIG N MORRELL
金额：
$ 38.38万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8967578
关键词：
Acute Affect Antibodies Antibody Formation B-Lymphocytes Back Biological Response Modifiers Blood Blood Platelets Blood Vessels CD4 Positive T Lymphocytes Cardiac Cell Communication Cell Differentiation process Cells Chronic Clinical Data Development Disease Distant Environment Equilibrium Graft Rejection Health Heart Transplantation Helper-Inducer T-Lymphocyte Heparin Homeostasis Immune Immune response Immune system Immunity Immunoglobulin Class Switching Incidence Inflammation Inflammatory Inflammatory Response Interleukin-1 Interleukin-17 Investigation LDL-Receptor Related Protein 1 Leukocyte Trafficking MPL gene Maintenance Measures Mediating Mediator of activation protein Modeling Mus Names Pathogenesis Pathway interactions Plasma Platelet Activation Platelet Factor 4 Play Prevention Process Production Publications RANTES Regulation Research Role Signal Transduction Site Source T cell differentiation T cell response T-Cell Activation T-Lymphocyte Thrombocytopenia Thrombosis Time Transplantation Vascular Diseases Work allograft rejection chemokine cytokine heart allograft immune function improved innovation insight liver transplantation macrophage monocyte mouse model neutrophil novel prevent receptor response trafficking translational study vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): We propose to demonstrate biologic and pathophysiologic roles for platelets via the chemokine platelet factor 4 (PF4) in T-helper cell homeostasis and chronic transplant immune responses. PF4 is best known for its role in the pathogenesis of heparin induced thrombocytopenia (HIT), but despite its high plasma concentration, biologic roles for PF4 are not well understood. Our new exciting data demonstrate that PF4 is needed to limit Th17 differentiation in both steady state and inflammatory conditions. We propose the hypothesis that platelets maintain T-helper balance in a PF4 dependent manner. This presents the novel concept of cross-talk between platelets and CD4+ T-cells and extends the role for platelets in immunity to an acquired immune role in the maintenance of T-helper balance. T-helper cells get their name from the fact that their cytokines influence many other cells such as increasing neutrophil and monocyte numbers and inflammatory profile and T-helper cells are necessary for B- cell antibody class switching. Therefore, platelet regulation of T-helper numbers and types implies a major role for platelets in immune homeostasis. T-helper cells are divided into Th1, Th2, Th17 and Tregs. Our data indicates that in the absence of PF4 there are greatly increased numbers of Th17 cells at steady state, and in a mouse model of vascularized cardiac transplant Th17 numbers increase greatly post-transplant. We have also discovered that PF4 expression and production is induced in T-cells post activation and T-cell PF4 also limits Th17 differentiation. As such we propose the following aims: Aim 1: To demonstrate that PF4 is a major mediator of T-helper differentiation. Aim 2: To demonstrate mechanisms for PF4 inhibition of Th17 differentiation. Results of our studies will impact many fields of inflammation related research, including transplant immune responses. Great progress has been made in reducing the incidence of acute transplant rejection, but less progress has been made in preventing chronic graft vasculopathy. Our results indicate a novel PF4 mediated pathway that regulates CD4+ T-cell responses to transplantation. These studies will also impact many other fields of inflammation and immune development by demonstrating a mechanism for platelet and T-cell cross-talk that directly affects immune development. We will use genetically modified thrombocytopenic and PF4 deficient mice in a chronic heart transplant model to pursue our novel and impactful studies.

描述（由申请人提供）：我们建议通过趋化因子血小板因子 4 (PF4) 证明血小板在 T 辅助细胞稳态和慢性移植免疫反应中的生物学和病理生理学作用。 PF4 因其在肝素诱导的血小板减少症 (HIT) 发病机制中的作用而闻名，但尽管其血浆浓度较高，但 PF4 的生物学作用尚不清楚。我们令人兴奋的新数据表明，在稳态和炎症条件下，需要 PF4 来限制 Th17 分化。我们提出这样的假设：血小板以 PF4 依赖性方式维持 T 辅助细胞平衡。这提出了血小板和 CD4+ T 细胞之间串扰的新概念，并将血小板在免疫中的作用扩展到维持 T 辅助细胞平衡中的获得性免疫作用。 T 辅助细胞之所以得名，是因为它们的细胞因子影响许多其他细胞，例如增加中性粒细胞和单核细胞数量以及炎症特征，并且 T 辅助细胞是 B 细胞抗体类别转换所必需的。因此，血小板对 T 辅助细胞数量和类型的调节意味着血小板在免疫稳态中发挥着重要作用。辅助性T细胞分为Th1、Th2、Th17和Treg。我们的数据表明，在没有 PF4 的情况下，稳定状态下 Th17 细胞的数量大大增加，并且在血管化心脏移植的小鼠模型中，移植后 Th17 细胞的数量大大增加。我们还发现，活化后的 T 细胞中会诱导 PF4 的表达和产生，并且 T 细胞 PF4 还限制 Th17 分化。因此，我们提出以下目标：目标 1：证明 PF4 是 T 辅助细胞分化的主要调节因子。目标 2：证明 PF4 抑制 Th17 分化的机制。我们的研究结果将影响炎症相关研究的许多领域，包括移植免疫反应。在降低急性移植排斥反应的发生率方面已取得了很大进展，但在预防慢性移植物血管病变方面进展甚少。我们的结果表明了一种新的 PF4 介导的途径，可调节 CD4+ T 细胞对移植的反应。这些研究还将通过展示直接影响免疫发育的血小板和 T 细胞串扰机制来影响炎症和免疫发育的许多其他领域。我们将在慢性心脏移植模型中使用转基因血小板减少症和 PF4 缺陷小鼠来开展我们新颖且有影响力的研究。