Role of Autoreactivity in Pathogenesis of Chronic GVHD

描述(申请人提供)：慢性移植物抗宿主病(GVHD)是一种自身免疫样胶原血管疾病，临床特征类似硬皮病和系统性红斑狼疮(SLE)，仍然是异基因造血细胞移植(HCT)长期存活者发病率和死亡率的主要原因。在过去的二十年里，在预防和治疗慢性移植物抗宿主病方面没有取得重大进展，部分原因是对这种疾病的发病机制缺乏了解。本研究的长期目标是揭示慢性GVHD中同种异体免疫和自身免疫发生发展的细胞和分子机制，并开发新的预防和治疗慢性GVHD的方法。在第一个资助期，我们建立了一种新的BALB/c宿主MHC相合的DBA/2供者慢性GVHD模型，在该模型中，受体出现高水平的自身抗体、肾小球肾炎和硬皮病样皮肤损害。移植物中的CD25-CD4T效应细胞和B细胞共同介导疾病，但移植物中的CD25Foxp3 Treg细胞以剂量依赖的方式预防或改善疾病。我们还观察到供体Treg扩增在MHC II-/-和B7H1-/-受体以及接受干扰素治疗的野生型(WT)受体中显著降低。中和抗体。相反，在接受MHC II-/-供者APC细胞的受者和接受供者B细胞耗竭移植的受者中，TJeff的扩张并没有减少，但在接受MHC II-/-供者APC细胞的受者中减少了。因此，我们推测：1)供体Treg在异基因宿主中的扩增需要与宿主APC和实质细胞相互作用，这些细胞在干扰素？2)供体APC，尤其是供体B细胞，是慢性移植物抗宿主病(GVHD)致病T细胞扩增所必需的；3)T细胞衍生的干扰素？不仅增强了供体Treg的扩增，而且通过B7H1/PD-1的相互作用直接抑制了Treg的扩增。为了验证这些假说，我们将1)使用新开发的MHCII-/-和B7H1-/-受体和骨髓嵌合体来测试这些分子在扩增Treg细胞方面的作用；2)使用新开发的MHCII-/-供体、荧光素酶供体和不能分泌抗体但具有完整B细胞受体的转基因供体来测试供体APC，特别是B细胞在慢性GVHD中的功能；3)使用一种新的组合来探索干扰素-R-/-和B7H1-/-宿主之间的相互作用。和B7H1在慢性移植物抗宿主病诱导的组织损伤的背景下。这些研究将为调节慢性GVHD受者供者TJeff和Treg激活和扩张的机制提供新的见解，并导致预防和治疗慢性GVHD的新方法的开发。公共卫生相关性：异基因造血细胞移植(HCT)是治疗血液系统恶性肿瘤的一种根治方法。然而，慢性移植物抗宿主病仍然是HCT长期存活者发病率和死亡率的主要原因。在过去的二十年里，慢性移植物抗宿主病的预防和治疗没有取得重大进展，部分原因是对慢性移植物抗宿主病的发病机制缺乏了解。通过新建立的慢性GVHD动物模型，我们的研究将剖析调节慢性GVHD受者致病T细胞激活和扩增的因素。这些研究将为开发预防和治疗慢性GVHD的新方法提供新的科学基础。

DESCRIPTION (provided by applicant): Chronic graft versus host disease (GVHD), an autoimmune-like collagen-vascular disease with clinical features similar to scleroderma and systemic lupus erythematosus (SLE), remains the major cause of morbidity and mortality in long-term survivors of allogeneic hematopoietic cell transplantation (HCT). No major improvements in the prevention and treatment of chronic GVHD have been made over the past two decades, due in part to a poor understanding of the pathogenesis of the disease. Our study's long-term goal is to unravel the cellular and molecular mechanisms involved in the development of alloimmunity and autoimmunity in chronic GVHD, and develop novel approaches to prevent and treat chronic GVHD. During the first funding period, we established a new autoimmune-like chronic GVHD model of MHC-matched DBA/2 donors to BALB/c hosts, in which the recipients developed high serum levels of autoantibodies, glomerulonephritis, and scleroderma-like skin damage. The disease is mediated by both donor CD25-CD4+ T effector (Teff) cells and B cells in transplants, but CD25+Foxp3+ Treg cells in transplants prevents or ameliorates the disease in a dose-dependent manner. We also observed that donor Treg expansion was markedly reduced in MHC II-/- and B7H1-/- recipients as well as in wild-type (WT) recipients treated with an IFN-? neutralizing antibody. In contrast, Teff expansion was not reduced in MHC II-/- recipients but was reduced in recipients given MHC II-/- donor APC cells and also reduced in recipients given donor B cell-depleted transplants. Therefore, we hypothesize 1) donor Treg expansion in allogeneic hosts requires interactions with host APCs and parenchymal cells that express MHC II and B7H1 after IFN-? induction; 2) donor APCs, especially donor B cells, are required for the expansion of pathogenic Teff cells in the context of chronic GVHD; 3) host parenchymal cell expression of B7H1 induced by Teff-derived IFN-? not only augments donor Treg expansion, but also directly suppresses Teff expansion via B7H1/PD-1 interactions. To test these hypotheses, we will 1) use newly developed MHCII-/- and B7H1-/- recipients and bone marrow chimeras to test the role of these molecules in expanding Treg cells; 2) use newly developed MHCII-/- donors, luciferase+ donors, and transgenic donors that cannot secrete antibodies but have intact B cell receptors to test the functions of donor APCs, especially B cells, in chronic GVHD; 3) use a novel combination of IFN-?-R-/- and B7H1-/- hosts to explore the interplay between IFN-? and B7H1 in the context of chronic GVHD-induced tissue damage. These studies will provide new insights into mechanisms that regulate donor Teff and Treg activation and expansion in chronic GVHD recipients and lead to the development of novel approaches for preventing and treating chronic GVHD. PUBLIC HEALTH RELEVANCE: Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for hematological malignancies. However, chronic GVHD remains the major cause for morbidity and mortality for long-term survivors of HCT. There has been no significant progress in the prevention and treatment of chronic GVHD over the past two decades, due in part to the poor understanding of the pathogenesis of chronic GVHD. With a newly established chronic GVHD animal model, our studies will dissect the factors that regulate the activation and expansion of pathogenic T cells in chronic GVHD recipients. These studies will provide a new scientific basis for developing novel approaches for preventing and treating chronic GVHD.