Contribution of Toll-like receptor signaling in islet transplantation

Toll样受体信号传导在胰岛移植中的贡献

• 批准号: 7881592
• 负责人: BERND SCHROPPEL
• 金额: $ 12.95万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7881592
• 关键词: Activation Analysis; Allogenic; Bone Marrow; Candidate Disease Gene; Cell Culture Techniques; Cell Survival; Cells; Cessation of life; Chronic Disease; Disease; Effector Cell; Event; Functional disorder; Graft Rejection; Immune; Immune response; Immune system; Inflammation; Inflammatory Response; Injury; Insulin-Dependent Diabetes Mellitus; Islet Cell; Islets of Langerhans Transplantation; Lead; Ligands; Ligation; Link; Mediating; Mediator of activation protein; Modeling; Molecular; Pattern; Persons; Process; Production; Receptor Activation; Receptor Signaling; Recovery; Regulation; Research Personnel; Role; Specificity; TLR2 gene; TLR4 gene; Testing; Toll-like receptors; Toxic effect; Transplantation; United States; Up-Regulation; Work; adaptive immunity; allograft rejection; base; chemokine; cytokine; gene transfer vector; graft failure; graft function; islet; islet allograft; isoimmunity; novel therapeutic intervention; pathogen; programs; receptor expression; response

DESCRIPTION (provided by applicant): Pancreatic islet transplantation is a potential cure for Type I diabetes, a disease which afflicts nearly 2 million persons in the United States, making it the second most common chronic disease in young people. A major challenge is the protection of the marginal islet cell mass. Within a short period after transplantation, inflammatory responses occur in and around the islet grafts, causing early graft failure. Therefore, reducing early inflammation should reduce cell loss and preserve islet cell mass and function. Toll-like receptors (TLRs) recognize pathogen- associated molecular patterns. Ligation via TLRs leads to upregulation of proinflammatory cytokines and chemokines. Islet cells are among the non-immune cells that express functional TLRs. We hypothesize that pre- and posttransplant events produce intrinsic TLR ligands. Islets detect these ligands locally through TLRs and participate in the regulation of immune responses. To test this we propose the following Aims: Aim 1-Determine the impact of Toll-like receptor expression and function on islet cells and their survival. In a syngeneic transplant model we will i) directly assess the role of TLR2 on islet cell survival following prolonged culture; ii) test the relevance of TLR2 expression on parenchymal or bone marrow-derived cells in this process; iii) determine the effect of pre-transplant TLR2 stimulation on the induced adaptive immune response; iv) confirm and define the specificity of TLR activation by analyzing islet-expressed TLRS, TLR4 and TLR9; v) assess mechanisms and potential mediators using a candidate gene analysis approach. Aim 2-Determine the role of islet cell-associated Toll-like receptor engagement in the alloimmune response and tolerance. In an allogeneic transplant model we will i) test the impact of TLR2 and TLR4 engagement on islet allograft rejection; ii) determine the impact of islet TLR2 and TLR4 expression on costimulatory blockade-mediated permanent islet allograft acceptance. Our studies will determine the contribution of the innate and adaptive immune response by focusing on TLRs. A detailed understanding of their role in islet recovery and transplantation may provide new therapeutic approaches in islet transplantation without toxic effects on islet cells and without compromising the whole immune system.

描述（由申请人提供）：胰岛移植是I型糖尿病的潜在治愈方法，这种疾病困扰着美国近200万人，使其成为年轻人中第二常见的慢性疾病。一个主要的挑战是保护边缘胰岛细胞质量。在移植后的短时间内，胰岛移植物周围和周围发生炎症反应，导致早期移植物失败。因此，减少早期炎症应减少细胞损失并保留胰岛细胞质量和功能。 Toll样受体（TLR）识别病原体相关的分子模式。通过TLR的结扎导致促炎细胞因子和趋化因子的上调。胰岛细胞是表达功能性TLR的非免疫细胞之一。我们假设移植前和后移植事件会产生内在的TLR配体。胰岛通过TLR检测这些配体并参与免疫反应的调节。为了测试这一点，我们提出以下目的： AIM 1测定，Toll样受体表达和功能对胰岛细胞及其存活的影响。在同步移植模型中，我们将i）直接评估TLR2在延长培养后胰岛细胞存活的作用； ii）在此过程中测试TLR2表达在实质或骨髓衍生细胞上的相关性； iii）确定移植前TLR2刺激对诱导的适应性免疫反应的影响； iv）通过分析胰岛表达的TLR，TLR4和TLR9来确认并确定TLR激活的特异性； v）使用候选基因分析方法评估机制和潜在介体。 AIM 2确定胰岛细胞相关的Toll样受体参与在同种免疫反应和耐受性中的作用。在同种异体移植模型中，我们将测试TLR2和TLR4参与对胰岛同种异体移植排斥的影响； ii）确定胰岛TLR2和TLR4表达对cont虫封锁介导的永久性胰岛的影响。 我们的研究将通过关注TLR来确定先天和适应性免疫反应的贡献。对它们在胰岛恢复和移植中的作用的详细理解可以在胰岛移植中提供新的治疗方法，而不会对胰岛细胞的毒性作用，也不会损害整个免疫系统。