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: 7204111
• 负责人: Defu Zeng
• 金额: $ 36.05万
• 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/7204111
• 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 - 宿主病（GVHD）是同种异体造血细胞移植（HCT）的长期幸存者的主要发病率和死亡率，并且可以防止急性GVHD的疗法在防止慢性GVHD方面不成功。慢性GVHD被认为是一种自身免疫性胶原蛋白血管疾病，其临床特征类似于自身免疫性硬皮病和全身性红斑狼疮（SLE）。但是，慢性GVHD的发病机理知之甚少。目前尚不清楚如何在慢性GVHD受体中产生自动反应性T细胞。 B细胞和自身抗体在很大程度上尚不清楚，尽管最近有报道称抗CD20 MAB通过耗尽B细胞来改善难治性慢性GVHD。 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.疾病诱导需要移植中的供体CD4+ T和B220+ B细胞。相反，添加供体CD25+ CD4+调节t （Treg）细胞进行移植阻止了疾病的发展。因此，我们假设静态供体自动反应性CD4+ T和B细胞的激活和扩展来自同种异体受体中的移植物，导致慢性GVHD的发展。此外，活化的自动反应性B细胞在自动反应性CD4+ T细胞的激活和自身免疫反应的扩增中起着核心作用。相反，Treg细胞抑制了慢性GVHD中的自身免疫反应。为了检验我们的假设，我们将通过比较精神分子和无胸腺接受者的疾病诱导来确定自动反应性CD4+ T细胞的起源；并确定负责疾病诱导的移植物中的供体CD4+T细胞子集； 2）确定供体自动反应性B细胞在移植中的作用在自动反应性CD4+ T细胞激活和疾病诱导中的作用； 3）确定自然和FOXP3转导的CD25+CD4+Treg细胞是否可用于预防和治疗自身免疫性慢性GVHD。这些研究将为慢性GVHD的发病机理提供新的见解，并提供预防和治疗慢性GVHD的新方法。