The role of complement system in alloimmune responses

描述(申请人提供)：异基因干细胞移植(allo-HSCT)是治疗血液系统恶性肿瘤的有效方法。但限制因素是移植物抗疾病(GVHD)，这是供者T淋巴细胞对主要和次要抗原(MHA)诱发同种异体免疫反应的结果。该病的主要特征是皮肤、肠道和肝脏的靶向性上皮细胞损伤。尽管供体T淋巴细胞和受体抗原提呈细胞(APC)是GVHD的主要介质，但其分子和细胞基础尚不清楚。我们的目标是阐明同种异体免疫反应的调节机制，并开发诱导耐受和预防GVHD的新疗法。在过去的十年中，天然免疫被证明通过补体系统和淋巴细胞之间的相互作用来调节适应性免疫。补体蛋白参与了树突状细胞(DC)与淋巴细胞相互作用的不同阶段：(1)树突状细胞(DC)产生C3对其成熟、分化和有效的抗原呈递是必不可少的；(2)补体蛋白对APC和T细胞也有自分泌作用；(3)T细胞也分泌补体蛋白，C3缺陷的T细胞比野生型T细胞经历更多的凋亡。补体蛋白或补体受体的缺乏会损害APC和T细胞之间的同源相互作用，从而阻止同种免疫反应和移植器官的排斥反应。虽然补体蛋白在同种异体反应性T细胞和APC之间的同源相互作用中的作用已经在同种异体移植排斥反应中进行了研究，但补体系统是否调节移植物抗宿主病的同种免疫反应尚不清楚。在我们的初步研究中，我们发现在小鼠骨髓移植(BMT)模型中，C3缺陷受体的GVHD死亡率和发病率显著降低。我们提出补体激活在GVHD发病机制中起重要作用的假说。我们将研究C3在介导GVHD的供体T细胞和受体DC反应中的作用，并探索将补体系统作为潜在的新型治疗干预措施在小鼠模型中的可能性。 公共卫生相关性：补体系统在调节T细胞和树突状细胞功能方面发挥重要作用。在我们的初步研究中，我们发现在小鼠骨髓移植模型中，补体C3缺乏的受者的GVHD死亡率和发病率显著降低。本研究旨在探讨补体系统在移植物抗宿主病(GVHD)同种免疫反应中的分子机制。

DESCRIPTION (provided by applicant): Allogeneic stem cell transplantation (allo-HSCT) is an effective therapy for hematological malignancies. But the limiting factor is Graft-versus-disease (GVHD), a result of alloimmune responses elicited by donor T lymphocytes to major and minor antigens (mHA). The disease is characterized primarily by targeted epithelial cell injury in skin, intestine and liver. Although donor T lymphocytes and recipient antigen presenting cells (APCs) are the primarily mediators of GVHD, the molecular and cellular basis are not well understood. Our goal is to elucidate the regulatory mechanisms of alloimmune responses and develop novel therapies for tolerance induction and GVHD prevention. During the last decade innate immunity has been shown to modulate adaptive immunity through the interaction between the complement system and lymphocytes. Complement proteins are involved in different stages of the interaction between dendritic cells (DCs) and lymphocytes: (1) C3 production by DCs is essential for their maturation, differentiation and effective antigen presentation to T cells; (2) Complement proteins also have an autocrine effect on APCs and T cells; (3) T cells also secrete complement proteins and C3-deficient T cells undergo more apoptosis than wild-type T cells. Lack of complement proteins or complement receptors impairs the cognate interaction between APCs and T cells, and thus prevents alloimmune response and rejection of transplanted organs. Although the role of complement proteins in the cognate interaction between alloreactive T cells and APCs has been studied in the setting of allograft rejection, it is unknown whether complement system regulates alloimmune responses in GVHD. In our preliminary studies, we found significantly reduced GVHD mortality and morbidity in C3-deficient recipients in a murine model of bone marrow transplantation (BMT). We put forward the hypothesis that complement activation plays an important role in the pathogenesis of GVHD. We will investigate the role of C3 in donor T cell and recipient DCs responses that have been implicated in mediating GVHD, and explore the possibility of targeting the complement system as potential novel therapeutic interventions in mouse model. PUBLIC HEALTH RELEVANCE: Complement system play an important role in the regulation of T cell and dendrtic cell function. In our preliminary studies, we found significantly reduced GVHD mortality and morbidity in complement C3-deficient recipients in a murine model of bone marrow transplantation. The proposed research is to investigate the molecular mechanisms of complement system in alloimmune responses in GVHD.