IgM Antileucocyte Autoantibodies Inhibit Kidney Allograft Rejections

描述（由申请人提供）：本研究项目涉及研究与白细胞结合的天然IgM自身抗体（IgM-ALA）。假设：我们提出，IgM-ALA提供了一种抑制炎症过程的先天机制，例如在许多肾脏疾病或肾脏或心脏移植后观察到的炎症过程。支持这一假设的初步数据来自两个观察结果：（i）人肾和心脏移植的临床研究，其中在具有高水平IgM-ALA的患者亚组中观察到较少的移植物排斥，和（ii）初步体外观察，其中我们表明从人血清中纯化的IgM抑制T细胞活化和增殖以及抑制白细胞迁移，即趋化性。我们还表明，IgM-ALA介导这些抑制作用，通过结合细胞膜受体介导T细胞活化和白细胞趋化性，即CD 3，CD 4，和趋化因子受体，如CCR 5。在这个建议中，我们计划使用小鼠模型（即小鼠缺乏IgM，但没有其他免疫球蛋白），以确定是否IgM-ALA保护小鼠心脏移植排斥反应。我们的研究有两个目的：目的#1：确定鼠IgM是否像人IgM一样与CD 3，CD 4，CCR 5和CXCR 3结合，并在体外抑制白细胞趋化性和T细胞活化。目标二：通过确定IgM敲除小鼠中是否存在加速的和更严重的心脏排斥反应，以及其次，将鼠IgM施用到IgM敲除小鼠中是否会抑制加速的排斥反应，来检验我们的假设。该假设显然是新颖的，源于临床观察。如果拟议的研究支持这一假设，那么这项研究工作可能会推动炎症研究（例如，如在肾脏疾病中或在肾或心脏移植后所见）进入另一个新的方向，此外还可能具有治疗意义。 公共卫生相关性这项研究，如果支持我们的假设，可能会导致新的策略，以制服涉及肾脏和其他器官的炎症过程的发展。人们可以开发增加体内IgM-ALA的策略，例如通过开发疫苗，从而最大限度地减少具有几种副作用的免疫抑制药物的使用。此外，具有固有高水平IgM-ALA的移植受者亚组可以在较少的免疫抑制下维持。

DESCRIPTION (provided by applicant): This research project involves studying naturally occurring IgM autoantibodies that bind to leucocytes (IgM-ALA). Hypothesis: We propose that IgM-ALA provide an innate mechanism to inhibit inflammatory processes as for example that observed in many kidney diseases or after a kidney or heart transplant. Preliminary data to support this hypothesis comes from two observations (i) Clinical studies in human kidney and heart transplants where one observes less graft rejections in the subset of patients having high levels of IgM-ALA and (ii) preliminary in vitro observations where we show that IgM purified from human serum inhibit T cell activation and proliferation as well as inhibit leucocyte migration i.e. chemotaxis. We also show that IgM-ALA mediates these inhibitory effects by binding to cell membrane receptors which mediate T cell activation and leucocyte chemotaxis i.e. CD3, CD4, and chemokine receptors e.g. CCR5. In this proposal we plan to use a mouse model (i.e. mice deficient only in IgM but not other immunoglobulins) to determine if IgM-ALA protects against rejections in murine cardiac transplants. Our research studies have two aims: Aim #1: To determine if murine IgM, like human IgM, binds to CD3, CD4, CCR5 and CXCR3 and inhibits leucocyte chemotaxis and T cell activation in vitro. Aim #2: testing our hypothesis by determining if there is accelerated and more severe cardiac rejection in the IgM knockout mice and secondly, whether administration of murine IgM into IgM knockouts will inhibit the accelerated rejections. The hypothesis is clearly novel and stems from clinical observations. If the proposed studies support this hypothesis, then this research work could move inflammatory research (e.g., as seen in kidney diseases or after renal or cardiac transplant) into another new direction and in addition could have therapeutic implications. PUBLIC HEALTH RELEVANCE this research, if supportive of our hypothesis, could lead to development of new strategies to subdue an inflammatory process involving the kidney and other organs. One could develop strategies to increase in-vivo IgM-ALA e.g. by developing a vaccine, thus minimizing the use of immunosuppressive drugs, which have several side effects. Additionally, the subset of transplant recipients having intrinsically high levels of IgM-ALA could be maintained on less immunosuppression.