The role of complement system in alloimmune responses

补体系统在同种免疫反应中的作用

• 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
• 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

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（申请人提供）：同种异体干细胞移植（Allo-HSCT）是血液恶性肿瘤的有效疗法。但是，限制因子是移植物 - 疾病（GVHD），这是由供体T淋巴细胞引起的同种异体免疫反应对主要和次要抗原（MHA）引起的。该疾病的特征主要由皮肤，肠和肝脏中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的主要介体，但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，并开发出新的耐受性诱导和GVHD预防疗法。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。补体蛋白与树突状细胞（DC）和淋巴细胞之间相互作用的不同阶段有关：（1）DCS产生C3对于它们的成熟，分化和对T细胞的有效抗原表现至关重要。 （2）补体蛋白质对APC和T细胞也具有自分泌作用； （3）与野生型T细胞相比，T细胞还分泌补体蛋白质和C3缺陷的T细胞的凋亡更多。缺乏补体蛋白或补体受体会损害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。尽管在同种异体移植排斥反应的情况下，已经研究了补体蛋白在同种异体T细胞和APC之间的相关相互作用中的作用，但尚不清楚补体系统是否调节GVHD中的同种异体免疫反应。在我们的初步研究中，我们发现在骨髓移植（BMT）的鼠模型中，C3缺陷受体的GVHD死亡率和发病率大大降低。我们提出了一个假设，即补体激活在GVHD的发病机理中起重要作用。我们将研究C3在介导GVHD中涉及的供体T细胞和受体DC响应中的作用，并探索将补体系统靶向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：补体系统在调节T细胞和树枝状细胞功能中起重要作用。在我们的初步研究中，我们发现在骨髓移植的鼠模型中，GVHD死亡率和发病率大大降低了C3缺陷受体。拟议的研究是研究GVHD中同种免疫反应中补体系统的分子机制。