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: 7392801
• 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/7392801
• 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; Cells; Chronic; Clinical; Collagen; Deposition; Development; Disease; Donor person; Glomerulonephritis; Hand; Hematopoietic; Inbred BALB C Mice; Interleukin-10; Lead; Lesion; Long-Term Survivors; Lupus Erythematosus; Mediating; Memory; Minor; Modeling; Morbidity - disease rate; PTPRC gene; Pathogenesis; Patients; Play; Prevention therapy; Production; Refractory; Reporting; Role; Serum; Skin; Sorting - Cell Movement; Source; Spleen; Systemic Lupus Erythematosus; Systemic Scleroderma; T-Lymphocyte Subsets; Testing; Thinking; Thymus Gland; Tissues; Transplantation; Vascular Diseases; autoreactive B cell; autoreactive T cell; autoreactivity; graft vs host disease; insight; mortality; novel strategies; prevent

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vs.-宿主疾病（GVHD）是同种异体造血细胞移植（HCT）长期存活者的主要发病率和死亡率，并且预防急性GVHD的疗法在预防慢性GVHD方面是不成功的。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，慢性GVHD的发病机制知之甚少。目前尚不清楚慢性GVHD受者中自身反应性T细胞是如何产生的; B细胞和自身抗体如何参与发病机制在很大程度上是未知的，尽管最近报道抗CD 20 mAb通过耗尽B细胞来改善难治性慢性GVHD。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剂量照射的MHC匹配但次要抗原不匹配的BALB/c（H-2d）受体中，并且受体发展为具有高水平血清自身抗体、硬皮病皮肤损伤和肾小球肾炎的自身免疫样GVHD。在移植中，疾病诱导需要供体CD 4 + T和B220+ B细胞。相反，加入供体CD 25 + CD 4+调节性T细胞， （Treg）细胞移植阻止了疾病的发展。因此，我们推测，同种异体受者移植物中静止供体自身反应性CD 4 + T和B细胞的激活和扩增导致慢性GVHD的发展。此外，活化的自身反应性B细胞在自身反应性CD 4 + T细胞的活化和自身免疫应答的扩增中起核心作用。相比之下，Treg细胞抑制慢性GVHD中的自身免疫反应。为了验证我们的假设，我们将1）通过比较正常胸腺和无胸腺受者的疾病诱导来确定自身反应性CD 4 + T细胞的来源;并鉴定移植物中负责疾病诱导的供体CD 4 +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CD 4 + T细胞活化和疾病诱导中的作用; 3）确定天然以及Foxp 3转导的CD 25 + CD 4 +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认识，并为慢性GVHD的预防和治疗提供新的途径。