Complement and Platelets in Antibody-Medicated Rejection

抗体排斥反应中的补体和血小板

• 批准号: 7891951
• 负责人: William M Baldwin
• 金额: $ 32.6万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-08 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7891951
• 关键词: Acute; Allografting; Antibodies; Awareness; B-Lymphocytes; Binding; Blood Circulation; Blood Platelets; Blood Vessels; CCR5 gene; CD4 Positive T Lymphocytes; Chronic; Clinical; Coagulation Process; Complement; Complement Activation; Data; Dose; Endothelial Cells; Exocytosis; Fc Receptor; Hand; Helper-Inducer T-Lymphocyte; Inflammation; Injury; Intravenous Immunoglobulins; Isoantibodies; Kidney; Kidney Transplantation; Knowledge; Leukocytes; Link; Mediating; Mediator of activation protein; Memory; Modeling; Mus; Neutrophil Activation; P-Selectin; Pathogenesis; Pathology; Plasmapheresis; Platelet Activation; Prausnitz-Kustner Test; Properdin; Reporting; Review Literature; Role; SCID Mice; Skin Transplantation; Skin graft; Source; Specificity; System; T cell response; T memory cell; T-Lymphocyte; Testing; Therapeutic immunosuppression; Transplant Recipients; Transplantation; Work; activation product; base; chemokine; clinically relevant; design; kidney allograft; macrophage; monocyte; mouse model; neutrophil; novel diagnostics; receptor; research study; response; skin allograft; tool; von Willebrand Factor

New diagnostic tools and heightened clinical awareness have increased the recognition of antibodymediated rejecfion (AMR). However, the pathogenesis of AMR is incompletely understood, and not all of the mediators of AMR have been defined. After a review of the literature, we concluded that platelets could be critical links in propagafing antibody inifiated inflammation. Experiments using skin allografts allowed us to visualize the engagement of platelets by alloantibodies. Immunohistology demonstrated that alloantibodies are associated with the release of von Willebrand factor (vWO and P-selectin from endothelial cells. Platelets express receptors for both vWf and P-selectin. Our hypothesis is that antibodies initiate platelet responses that augment leukocyte interactions with endothelial cells in the transplant and that complement activafion products intensify each of these interactions. This project is designed to examine interactions of antibody and complement with endothelial cells, platelets and leukocytes in the following 3 specific aims: 1) Determine the effects of antibodies and complement on the localization and activation of platelets in renal transplants; 2) Determine the effects of platelet and complement activation on localization and activation of neutrophils, macrophages and T cells in transplants; and 3) Determine the effects of platelets and complement activation on alloantibody-induced rejection. To accomplish these specific aims, we will use a combinafion of models developed by the leaders of all 3 projects. For Specific Aims 1 and 2, we will use our model in which monoclonal anfibodies are passively transferred to SCID recipients of renal allografts. SCID mice permit complete control of the dose, fiming, anfigenic specificity and isotype of the anfibodies under investigafion in the absence of confounding additional responses from T cells or B cells. For Specific Aim 3, we will take advantage of models based on extensive work of Dr. Rob Fairchild in Project 1 and Dr. Anna Valujskikh in Project 3. In these models mice produce high titers of alloantibodies that cause complete rejection of renal transplants. Using these models, we will test the effects of depleting platelets on acute and chronic rejection. These are clinically relevant models that will provide data of mechanisfic and therapeufic importance.

新的诊断工具和提高的临床意识增加了对抗体介导的排斥反应（AMR）的认识。然而，AMR的发病机制还不完全清楚，并不是所有的AMR介质已被定义。在回顾文献后，我们得出结论，血小板可能是传播抗体诱导炎症的关键环节。使用同种异体皮肤移植物的实验使我们能够可视化血小板与同种抗体的结合。免疫组织学证实同种抗体与血管性血友病因子（vWO）和P-选择素从内皮细胞的释放有关。血小板表达vWf和P-选择素的受体。我们的假设是抗体启动血小板反应 在移植物中增加白细胞与内皮细胞的相互作用，并且补体激活产物增强这些相互作用中的每一种。本课题旨在研究抗体和补体与内皮细胞、血小板和白细胞的相互作用，具体目的有三：1）确定抗体和补体对肾移植中血小板定位和活化的影响; 2)确定血小板和补体活化对移植物中中性粒细胞、巨噬细胞和T细胞的定位和活化的影响;和3）确定血小板和补体活化对同种抗体诱导的排斥的影响。为了实现这些具体目标，我们将使用所有3个项目的领导者开发的模型组合。对于特定目标1和2，我们将使用我们的模型，其中单克隆抗体被动转移到肾脏移植物的SCID受体。在不存在来自T细胞或B细胞的混杂额外应答的情况下，SCID小鼠允许完全控制所研究的抗抗体的剂量、成膜、抗基因特异性和同种型。对于具体目标3，我们将 基于项目1中Rob费尔柴尔德博士和项目3中安娜Valujskikh博士的大量工作的模型的优势。在这些模型中，小鼠产生高滴度的同种抗体，导致肾移植完全排斥。使用这些模型，我们将测试消耗血小板对急性和慢性排斥反应的影响。 这些是临床相关模型，将提供具有机制和治疗重要性的数据。