The role of complement system in alloimmune responses

补体系统在同种免疫反应中的作用

基本信息

批准号：
8364475
负责人：
Vahid Afshar-Kharghan
金额：
$ 23.7万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8364475
关键词：
Affect Allogenic Antibodies Antigen Presentation Antigen-Presenting Cells Antigens Apoptosis Automobile Driving Bone Marrow Transplantation CD4 Positive T Lymphocytes CD8B1 gene Cell physiology Cells Clinical Complement Complement Activation Complement Receptor Dendritic Cells Dendritic cell activation Disease Epithelial Cells Exhibits Functional disorder Future Goals Graft Rejection Graft Survival Health Hematologic Neoplasms Hematopoietic Stem Cell Transplantation Histocompatibility Antigens Class II Human ITGAX gene In Vitro Intestines Knowledge Liver Lymphocyte Lymphoid Mediating Mediator of activation protein Minor Modeling Molecular Morbidity - disease rate Mus Natural Immunity Organ Organ Transplantation Pathogenesis Patients Phenotype Pilot Projects Play Prevention Production Regulatory T-Lymphocyte Research Role Skin Staging Stem cell transplant T cell regulation T cell response T-Cell Activation T-Cell Proliferation T-Lymphocyte Tissues Transplantation adaptive immunity allograft rejection autocrine base cell injury complement system cytokine effective therapy graft vs host disease mortality mouse model novel novel therapeutic intervention prevent response

项目摘要

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.

描述（由申请人提供）：同种异体干细胞移植（allo-HSCT）是治疗血液恶性肿瘤的有效疗法。但限制因素是移植物抗病 (GVHD)，这是供体 T 淋巴细胞对主要和次要抗原 (mHA) 引发同种免疫反应的结果。该疾病的主要特征是皮肤、肠道和肝脏的靶向上皮细胞损伤。尽管供体 T 淋巴细胞和受体抗原呈递细胞 (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，先天免疫已被证明可以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。补体蛋白参与树突状细胞（DC）与淋巴细胞相互作用的不同阶段：（1）DC产生的C3对其成熟、分化和向T细胞有效抗原呈递至关重要； (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。尽管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在同种异体移植排斥的情况下进行了研究，但补体系统是否调节 GVHD 中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 死亡率和发病率显着降低。我们提出补体激活在GVHD发病机制中发挥重要作用的假设。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小鼠模型中潜在的新型治疗干预措施的可能性。公共卫生相关性：补体系统在 T 细胞和树突细胞功能的调节中发挥着重要作用。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 死亡率和发病率显着降低。本研究旨在探讨补体系统在GVHD同种免疫反应中的分子机制。