Role of Autoreactivity in Pathogenesis of Chronic GVHD

描述（由申请方提供）：慢性移植物抗宿主病（GVHD）是一种自身免疫样胶原血管疾病，其临床特征与硬皮病和系统性红斑狼疮（SLE）相似，仍然是异基因造血细胞移植（HCT）长期存活者发病和死亡的主要原因。在过去的二十年里，慢性GVHD的预防和治疗没有取得重大进展，部分原因是对该疾病的发病机制了解不足。我们研究的长期目标是揭示慢性GVHD中同种免疫和自身免疫发展所涉及的细胞和分子机制，并开发预防和治疗慢性GVHD的新方法。在第一个资助期间，我们建立了一个新的自身免疫样慢性GVHD模型的MHC匹配的DBA/2捐助者BALB/c主机，其中收件人开发高血清水平的自身抗体，肾小球肾炎，硬皮病样皮肤损伤。该疾病由移植物中的供体CD 25-CD 4 + T效应（Teff）细胞和B细胞介导，但移植物中的CD 25 + Foxp 3 + Treg细胞以剂量依赖性方式预防或改善该疾病。我们还观察到，供体Treg扩增显着减少在MHC II-/-和B7 H1-/-受体以及野生型（WT）受体与IFN-？中和抗体相反，Teff扩增在MHC II-/-受体中没有减少，但在给予MHC II-/-供体APC细胞的受体中减少，并且在给予供体B细胞耗尽的移植物的受体中也减少。因此，我们假设：1）供体Treg在同种异体宿主中的扩增需要与宿主APC和表达MHC II和B7 H1的实质细胞在IFN-？归纳; 2）供体APC，特别是供体B细胞，是慢性GVHD背景下致病性Teff细胞扩增所必需的; 3）由Teff衍生的IFN-？不仅增强供体Treg扩增，而且通过B7 H1/PD-1相互作用直接抑制Teff扩增。为了验证这些假设，我们将1）使用新开发的MHCII-/-和B7 H1-/-受体和骨髓嵌合体来测试这些分子在扩增Treg细胞中的作用; 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IFN-？R-/-和B7 H1-/-主机探索IFN-？和B7 H1在慢性GVHD诱导的组织损伤的情况下。这些研究将为调节慢性GVHD受者中供体Teff和Treg激活和扩增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。

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.