Role of Autoreactivity in Pathogenesis of Chronic GVHD

自身反应性在慢性 GVHD 发病机制中的作用

• 批准号: 8628732
• 负责人: Defu Zeng
• 金额: $ 41.09万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2015-08-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8628732
• 关键词: Agonist; Allogenic; Animal Model; Antibodies; Autoantibodies; Autoimmune Process; Autoimmunity; B-Lymphocytes; Bone Marrow; Cells; Chimera organism; Clinical; Clonal Expansion; Collagen; Development; Disease; Disease model; Dose; Effector Cell; Engraftment; Funding; Glomerulonephritis; Goals; Hematologic Neoplasms; IL2RA gene; Image; Inbred BALB C Mice; Infusion procedures; Interferons; Lead; Long-Term Survivors; Longitudinal Studies; Luciferases; Mediating; Molecular; Morbidity - disease rate; Pathogenesis; Prevention; Receptors, Antigen, B-Cell; Regulatory T-Lymphocyte; Role; Scleroderma; Serum; Skin; Surface Immunoglobulins; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Tissues; Transgenic Organisms; Transplantation; Vascular Diseases; autoreactivity; base; chronic graft versus host disease; graft vs host disease; hematopoietic cell transplantation; in vivo; insight; isoimmunity; mortality; neutralizing antibody; novel; novel strategies; prevent; public health relevance; receptor; research study

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.

描述（由申请人提供）：一种慢性移植与宿主疾病（GVHD），这是一种自身免疫性的胶原蛋白血管疾病，具有类似于硬皮硬皮病和全身性红斑红细胞（SLE）的临床特征（SLE），仍然是同种型血型替代（HCT）长期生存的发病率和死亡率的主要原因。在过去的二十年中，没有对慢性GVHD的预防和治疗进行重大改善，部分原因是对疾病的发病机理的了解不足。我们的研究的长期目标是阐明慢性GVHD中同种异体免疫性和自身免疫性发展的细胞和分子机制，并开发了预防和治疗慢性GVHD的新方法。在第一个资金期间，我们建立了一种新的自身免疫性慢性GVHD模型，该模型是MHC匹配的DBA/2供体的BALB/C宿主，其中受体在该模型中发展了高血清的自身抗体，肾小球肾小球肾炎和硬皮病性皮肤样皮肤损伤。该疾病是由供体CD25-CD4+ T效应子（TEFF）细胞和移植物中的B细胞介导的，但是移植物中的CD25+ FOXP3+ Treg细胞以剂量依赖性的方式预防或改善该疾病。我们还观察到，在MHC II - / - 和B7H1 - / - 受体以及用IFN-处理的野生型（WT）受体中，供体Treg的扩张显着降低。中和抗体。相反，在给定MHC II - / - 供体APC细胞的受体中，MHC II - / - 受体中的TEFF扩张并未减少，并且在给定给予供体B细胞耗尽的移植物的受体中也降低了。因此，我们假设1）同种异体宿主中的供体Treg扩展需要与ifn-之后表达MHC II和B7H1的宿主APC和实质细胞相互作用？就职; 2）在慢性GVHD的背景下，供体APC，尤其是供体B细胞，需要致病性TEFF细胞的扩展； 3）由TEFF衍生的IFN-诱导的B7H1的宿主实质细胞表达？不仅增加了供体Treg扩展，而且还可以通过B7H1/PD-1相互作用直接抑制TEFF扩展。为了检验这些假设，我们将使用新开发的MHCII - / - 和B7H1 - / - 受体和骨髓嵌合体来测试这些分子在扩展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的B细胞受体的转基因供体来测试慢性GVHD中供体APC，尤其是B细胞的功能； 3）使用IFN - ？ - r - / - 和B7H1 - / - 主机的新型组合来探索IFN-之间的相互作用？在慢性GVHD诱导的组织损伤的背景下，B7H1。这些研究将提供有关调节捐赠者TEFF和Treg激活和扩展在慢性GVHD接受者中的机制的新见解，并导致开发用于预防和治疗慢性GVHD的新方法。