IgM Antileucocyte Autoantibodies Inhibit Kidney Allograft Rejections

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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.