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

• 批准号: 8814885
• 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
• 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/8814885
• 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; 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; public health relevance; receptor; response; trafficking; translational study; vascular inflammation

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）在T辅助细胞稳态和慢性移植免疫反应中通过趋化因子血小板因子4（PF4）来证明血小板的生物学和病理生理作用。 PF4以其在肝素诱导的血小板减少症的发病机理中的作用而闻名，但是尽管血浆浓度很高，但对PF4的生物学作用却尚未得到很好的了解。我们的新令人兴奋的数据表明，需要PF4来限制稳态和炎症条件下的Th17分化。我们提出了以下假设，即血小板以PF4依赖性方式保持T-馆量平衡。这提出了血小板和CD4+ T细胞之间的串扰的新概念，并将血小板在免疫中的作用扩展到在维持T-助血器平衡中获得的免疫作用。 T-助血细胞的名字从它们的细胞因子会影响许多其他细胞的事实，例如增加中性粒细胞和单核细胞数量以及炎症性谱，而T助血细胞对于B细胞抗体类切换是必需的。因此，T馆数量和类型的血小板调节意味着血小板在免疫稳态中的主要作用。 T-助血细胞分为Th1，Th2，Th17和Tregs。我们的数据表明，在没有PF4的情况下，稳定状态下的Th17细胞数量大大增加，并且在血管化心脏移植的小鼠模型中，TH17数量的增加后移植剂大大增加了。我们还发现，在激活后T细胞中诱导PF4表达和产生，T细胞PF4也限制了Th17的分化。因此，我们提出了以下目的：目标1：证明PF4是T-助手分化的主要中介者。目标2：证明PF4抑制Th17分化的机制。 我们的研究结果将影响许多相关研究领域，包括移植免疫反应。在减少急性移植排斥反应的发生率方面取得了巨大进展，但是在防止慢性移植血管病中取得了更少的进步。我们的结果表明，一种新型的PF4介导的途径，可调节CD4+ T细胞对移植的反应。这些研究还将通过证明直接影响免疫发育的血小板和T细胞串扰的机制来影响许多其他炎症和免疫发育领域。我们将在慢性心脏移植模型中使用转基因的血小板减少型和PF4缺乏小鼠来进行我们的新颖和有影响力的研究。