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: 7591064
• 负责人: Defu Zeng
• 金额: $ 35.37万
• 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 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7591064
• 关键词: Acute; Allogenic; Animal Model; Antigens; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; B-Lymphocytes; Blood; CD4 Positive T Lymphocytes; CSF3 gene; Cell Communication; Cell Transplantation; Cell Transplants; Cells; Chronic; Clinical; Collagen; Deposition; Development; Disease; Donor person; Glomerulonephritis; Hand; Hematopoietic; Inbred BALB C Mice; Interleukin-10; Lead; Long-Term Survivors; Mediating; Memory; Minor; Modeling; Morbidity - disease rate; PTPRC gene; Pathogenesis; Patients; Play; Prevention; Production; Refractory; Reporting; Role; Scleroderma; Serum; Skin; Sorting - Cell Movement; Source; Spleen; Systemic Lupus Erythematosus; T-Lymphocyte Subsets; Testing; Thymus Gland; Tissues; Transplantation; Vascular Diseases; autoreactive B cell; autoreactive T cell; autoreactivity; effective therapy; graft vs host disease; insight; mortality; novel strategies; prevent; skin lesion

DESCRIPTION (provided by applicant): Chronic graft-vs.-host disease (GVHD) is the major morbidity and mortality of long-term survivors of allogeneic hematopoietic cell transplantation (HCT), and therapies that prevent acute GVHD are unsuccessful in preventing chronic GVHD. Chronic GVHD is considered an autoimmune collagen-vascular disease with clinical features similar to autoimmune scleroderma and systemic lupus erythematosus (SLE). However, the pathogenesis of chronic GVHD is poorly understood. It is unclear how autoreactive T cells are generated in chronic GVHD recipients; it is largely unknown how B cells and autoantibodies contribute to the pathogenesis, although it was recently reported that anti-CD20 mAb ameliorated refractory chronic GVHD by depleting B cells. We recently developed a new model of chronic GVHD, in which DBA/2 donor (H-2d) spleen cells were injected into sub-lethally irradiated MHC matched but minor antigen mismatched BALB/c (H-2d) recipients, and the recipients developed autoimmune-like GVHD with high levels of serum autoantibodies, sclerodermatous skin damage, and glomerulonephritis. Disease induction required both donor CD4+ T and B220+ B cells in transplants. In contrast, addition of donor CD25+CD4+ regulatory T (Treg) cells to transplants prevented the disease development. Therefore, we hypothesize that activation and expansion of the quiescent donor autoreactive CD4+ T and B cells from transplants in allogeneic recipients lead to the development of chronic GVHD. Furthermore, the activated autoreactive B cells play a central role in the activation of autoreactive CD4+ T cells and amplification of the autoimmune response. In contrast, Treg cells suppress the autoimmune response in chronic GVHD. To test our hypothesis, we will 1) determine the origin of autoreactive CD4+ T cells by comparing disease induction in euthymic and athymic recipients; and identify the donor CD4+T cell subsets in transplants responsible for the disease induction; 2) determine the role of donor autoreactive B cells in transplants in the activation of autoreactive CD4+ T cells and the disease induction; 3) determine whether natural as well as Foxp3 transduced CD25+CD4+Treg cells can be used to prevent and treat autoimmune-like chronic GVHD. These studies will provide new insights into the pathogenesis of chronic GVHD, and provide new approaches for preventing and treating chronic GVHD.

描述（由申请人提供）：慢性移植物抗宿主病（GVHD）是同种异体造血细胞移植（HCT）长期幸存者的主要发病率和死亡率，预防急性GVHD的疗法无法成功预防慢性GVHD。慢性 GVHD 被认为是一种自身免疫性胶原血管疾病，其临床特征类似于自身免疫性硬皮病和系统性红斑狼疮 (SLE)。然而，人们对慢性 GVHD 的发病机制知之甚少。目前尚不清楚慢性 GVHD 受体中自身反应性 T 细胞是如何产生的；尽管最近有报道称抗 CD20 mAb 通过消耗 B 细胞来改善难治性慢性 GVHD，但 B 细胞和自身抗体如何参与发病机制尚不清楚。我们最近开发了一种新的慢性GVHD模型，其中DBA/2供体（H-2d）脾细胞被注射到亚致死照射的MHC匹配但轻微抗原不匹配的BALB/c（H-2d）受者中，受者出现自身免疫样GVHD，伴有高水平的血清自身抗体、硬皮病性皮肤损伤和肾小球肾炎。疾病诱导需要移植物中供体 CD4+ T 和 B220+ B 细胞。相反，添加供体 CD25+CD4+ 调节性 T (Treg) 细胞移植可阻止疾病的发展。因此，我们假设来自同种异体受体移植物的静止供体自身反应性 CD4+ T 和 B 细胞的激活和扩增导致慢性 GVHD 的发生。此外，激活的自身反应性 B 细胞在自身反应性 CD4+ T 细胞的激活和自身免疫反应的放大中发挥着核心作用。相反，Treg 细胞抑制慢性 GVHD 的自身免疫反应。为了检验我们的假设，我们将 1) 通过比较正常和无胸腺受体的疾病诱导来确定自身反应性 CD4+ T 细胞的起源；并鉴定移植物中负责疾病诱导的供体 CD4+T 细胞亚群； 2) 确定移植物中供体自身反应性B细胞在自身反应性CD4+ T细胞激活和疾病诱导中的作用； 3) 确定天然的以及Foxp3转导的CD25+CD4+Treg细胞是否可用于预防和治疗自身免疫样慢性GVHD。这些研究将为慢性GVHD的发病机制提供新的见解，并为预防和治疗慢性GVHD提供新的方法。