Role of Autoreactivity in Pathogenesis of Chronic GVHD

描述（由申请人提供）：慢性移植物vs。-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的治疗方法无法预防慢性GVHD。慢性GVHD被认为是一种自身免疫性胶原血管疾病，其临床特征与自身免疫性硬皮病和系统性红斑狼疮（SLE）相似。然而，慢性GVHD的发病机制尚不清楚。目前尚不清楚慢性GVHD受体如何产生自身反应性T细胞；尽管最近有报道称抗cd20单抗通过消耗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其发病机制在很大程度上尚不清楚。我们最近开发了一种新的慢性GVHD模型，将DBA/2供体（H-2d）脾细胞注射到亚致死照射的MHC匹配但抗原不匹配的BALB/c （H-2d）受者中，受者出现自身免疫样GVHD，血清自身抗体水平高，硬化性皮肤损伤和肾小球肾炎。在移植中，疾病诱导需要供体CD4+ T和B220+ B细胞。相比之下，供体CD25+CD4+调节性T的加入

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.