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IL-17A and anti-col (V) humoral immunity in lung allograft rejection

IL-17A 和抗 col (V) 体液免疫在肺同种异体移植排斥反应中的作用

基本信息

批准号：
7810371
负责人：
David S Wilkes
金额：
$ 27.5万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7810371
关键词：
Acute Allogenic Antibodies Antibody Formation Anticol Antigen-Presenting Cells Antigens Autoantigens Autoimmune Diseases Autoimmunity Autologous B-Lymphocytes Biological Assay Blood specimen Bronchiolitis Bronchiolitis Obliterans Cause of Death Cell Line Cells Cessation of life Chronic Chronic lung disease Clinical Collaborations Collagen Collagen Type V Development Epitope Mapping Epitopes Frequencies Functional disorder Graft Rejection Human Human Herpesvirus 4 Humoral Immunities Immune response Immunity Immunization In Vitro Interleukin-17 Life Link Lung Lung Transplantation Lung diseases Mediating Minor Mononuclear Mus Pathogenesis Pathology Patients Production Proteins Rattus Regulatory T-Lymphocyte Reporting Risk Factors Role Staging Syndrome T-Lymphocyte T-Lymphocyte Epitopes Testing Therapeutic Intervention Tissue Banking Tissue Banks Transplant Recipients Transplantation allograft rejection cell mediated immune response cytokine cytotoxicity in vivo lung allograft macrophage monocyte peptide V prevent programs response

项目摘要

Lung transplantation is the only definitive therapy for many forms of endstage lung disease, but chronic rejection remains the major impediment to the long term survival of the lung transplant recipient. Allthough anti-donor (allo-)T and B cell immunity is known to be involved in the rejection response, the co-POIs of this Program have reported that T cell-mediated autoimmunity to a minor collagen, type V collagen [col(V)], is the major risk factor for chronic rejection, known as obliterative bronchiolitis/bronchiolitis obliterans syndrome, which is the leading cause of death in lung transplant recipients. In addition, the co-PIs have reported that anti-col(V) humoral immunity is the major risk factor for primary graft dysfunction (PGD) which is the leading cause of early death post transplantation and a risk factor for acute rejection and OB/BOS. IL-17A produced by col(V)-reactive T cells and known to key roles in autoimmune disease, also has a key role in col(V)- reactive T cell-mediated OB and PGD. However, the role of IL-17A in stimulating anti-col(V) antibody responses, and the eptitopes recognized by these antibodies are unknown. In addition, the role of macrophages, reported to have a central role in IL-17A induction, is unknown. This application tests the hypothesis that IL-17A induced anti-col(V) humoral immunity contributes to the pathogenesis of acute rejection and OB by examining the following specific aims: 1. Determine the epitopes recognized by anticol( V) producing B cells in patients post lung transplantation, as well as the pre-transplant conditions associated with this response. Aim 2. Determine if anti-col(V) antibody production is 1L-17A dependent and if IL-17A facilitates anti-col(V) antibody mediated pathology in lung transplants. Aim 3. Determine if macrophages are the antigen presenting cells responsible for stimulating anti-col(V) humoral immunity. Aim 4. Determine if col(V)-induced tolerance will prevent 1L-17A production and anti-col(V) antibody synthesis.

肺移植是许多终末期肺病的唯一确定性治疗方法，但慢性肺移植是一种有效的治疗方法。排斥反应仍然是肺移植受者长期存活的主要障碍。虽然已知抗供体（同种异体）T和B细胞免疫参与排斥反应，已经报道了T细胞介导的对次要胶原蛋白V型胶原蛋白[col（V）]的自身免疫是免疫系统的一个重要组成部分。慢性排斥反应的主要危险因素，称为闭塞性细支气管炎/闭塞性细支气管炎综合征，这是肺移植受者死亡的主要原因。此外，共同主要研究者报告说，抗col（V）体液免疫是原发性移植物功能障碍（PGD）的主要危险因素，移植后早期死亡的原因和急性排斥反应和OB/BOS的危险因素。IL-17 A产生 col（V）-反应性T细胞，已知在自身免疫性疾病中起关键作用，也在col（V）- 反应性T细胞介导的OB和PGD。然而，IL-17 A在刺激抗col（V）抗体中的作用是不明显的。这些抗体识别的表位是未知的。此外，据报道，巨噬细胞在IL-17 A诱导中具有中心作用，但这一点尚不清楚。此应用程序测试 IL-17 A诱导的抗col（V）体液免疫参与急性拒绝和OB通过检查以下具体目标：1。确定anticol识别的表位（ V）在肺移植后的患者中产生B细胞，以及移植前的状况与这个答案有关。目标2.确定抗col（V）抗体的产生是否依赖于1 L-17 A， IL-17 A促进肺移植中抗col（V）抗体介导的病理学。目标3.确定是否巨噬细胞是负责刺激抗col（V）体液免疫的抗原呈递细胞。目的 4.确定col（V）诱导的耐受性是否会阻止1 L-17 A的产生和抗col（V）抗体的合成。