Role of Novel Th17 cells in allograft rejection and tolerance

新型 Th17 细胞在同种异体移植排斥和耐受中的作用

基本信息

批准号：
8225391
负责人：
Mohammed Javeed Ansari
金额：
$ 12.62万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8225391
关键词：
Acute Affect Alloantigen Allograft Tolerance Allografting Animals Apoptosis CD28 gene CD4 Positive T Lymphocytes CD8B1 gene Cell Differentiation process Cells Chronic Clinical Clonal Expansion Combined Modality Therapy Data Development Dose Environment Evaluation Exhibits Fostering Generations Goals Graft Rejection Human Immune Immune response Immunity Immunosuppression Infiltration Inflammation Interferons Interleukin-10 Interleukin-13 Interleukin-17 Interleukin-4 Interleukin-5 Interleukin-6 Laboratories MHC Class II Genes Mediating Memory Modeling Mus Organ Transplantation Pathway interactions Play Prevention Principal Investigator Production Publishing Regulation Regulatory T-Lymphocyte Reporter Reporting Resistance Role Signal Transduction Sirolimus Solid Specificity T-Lymphocyte Therapeutic Transgenic Mice Translating Transplantation Transplantation Tolerance Vascular Diseases allograft rejection base clinically relevant cytokine design heart allograft immunoregulation in vivo insight interleukin-12 subunit p40 nonhuman primate novel novel strategies prevent resistance mechanism response tool vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): T-bet plays a crucial role in Th1 development. We investigated the role of T-bet in development of allograft rejection in an established MHC-II mismatched (bm12 into B6) model of chronic cardiac allograft rejection and vasculopathy (CAV). Intriguingly, and in contradistinction to IFN-?-/- mice that are protected from CAV, T-bet-/- recipients develop markedly accelerated allograft rejection accompanied by early severe vascular inflammation and vasculopathy, and infiltration by predominantly IL-17 producing CD4 T cells. Concurrently, T-bet-/- mice exhibit a Th1-deficient environment characterized by profound IFN-? deficiency, a Th2 switch characterized by increased production of IL-4, IL-5, IL-10, and IL-13 cytokines, and increased production of the proinflammatory cytokines IL-6, IL-12p40 and IL-17. Neutralization of IL-17 inhibits accelerated allograft rejection in T-bet-/- mice. Interestingly, CD4 but not CD8 T cell deficiency in T-bet-/- mice affords dramatic protection from vasculopathy and facilitates long-term graft acceptance. This is the first report establishing that in the absence of Th1 mediated alloimmune responses, CD4 Th17 cells mediate a proinflammatory response culminating in severe accelerated allograft rejection and vasculopathy. These results have important implications for development of novel therapies to target this intractable problem in clinical solid organ transplantation. Based on published and our preliminary data, T-bet by affecting T helper cell differentiation plays an important role in inhibiting a proinflammatory Th17 type immune response. Our central hypothesis is that Th17 immunity plays a critical role in mediating aggressive alloimmune responses, allograft rejection and resistance to tolerance induction, particularly in the absence of Th1 immunity. The main goal of this proposal is to define the functions and mechanisms of action of Th17 cells in mediating alloimmune responses in vivo and identifying targets for inhibition of Th17 immunity as a means of developing novel strategies to achieve durable and reproducible tolerance in murine transplant models to translate to non-human primates and ultimately to humans.

描述（由申请人提供）：T-BET在TH1开发中起着至关重要的作用。我们研究了T-BET在既定的MHC-II不匹配（BM12）中T-BET在慢性心脏同种异体移植抑制和血管疾病（CAV）的模型中的作用（BM12）。有趣的是，与受保护不受CAV的IFN - ？ - / - 相矛盾，T-bet - / - 受体显着加速了同种异体移植的排斥反应，并伴随着早期的严重血管炎症和血管性炎症和血管性炎症，并且主要由IL-17产生的CD4 T细胞浸润。同时，T-bet - / - 小鼠表现出一个缺陷的环境，其特征是深度IFN-？缺乏症，一种TH2开关，其特征是IL-4，IL-5，IL-10和IL-13细胞因子的产生增加，以及促炎细胞因子IL-6，IL-12P40和IL-17的产生增加。 IL-17的中和抑制了T-bet - / - 小鼠的同种异体移植排斥。有趣的是，T-bet - / - 小鼠中的CD4但不是CD8 T细胞缺乏症可抗血管病的保护，并促进了长期的移植物接受。这是第一个报告，确定在没有Th1介导的同种异体反应的情况下，CD4 TH17细胞介导了促炎反应，最终导致严重加速同种异体移植排斥和血管病。这些结果对新疗法的发展具有重要意义，以针对临床固体器官移植中的这一棘手的问题。根据已发布的和我们的初步数据，通过影响T辅助细胞分化的T-BET在抑制促炎性TH17型免疫反应中起着重要作用。我们的中心假设是，TH17免疫力在介导侵袭性的同种异体免疫反应，同种异体移植排斥和对耐受性诱导的抗性中起着至关重要的作用，尤其是在没有TH1免疫力的情况下。该提案的主要目的是定义Th17细胞在体内介导同种异体免疫反应时的作用和机制，并确定抑制Th17免疫力的靶标，以开发新型策略，以实现在鼠类中实现耐用和可复制的耐受性，以在鼠类中可转移模型，以转化为非人类自由群体和最终的tos tos to to to to to to tos tos to to human tos to to to to to to to to to to tos humans humans humans humans humans humans humans humans humans humans humans。