Renal transplantation is the preferred treatment for most patients with kidney failure, but is limited by poor long-term graft survival (50% at 10 years). Chronic allograft nephropathy (CAN) is responsible for much of this late graft damage, and occurs in part due to chronic antibody-mediated rejection (AMR). Pathogenic antibodies include those binding human leukocyte antigens (HLA) and non-HLA antigens, including some autoantigens. Little is currently known about which recipient factors control alloantibody production or the inflammatory response to alloantibody deposition in the graft.

Fcγ receptors bind antibody (IgG), and may be activatory (FcγRI, FcγRIIA, FcγRIII and FcγRIV) or inhibitory (FcγRIIB). FcγRIIB inhibits antibody and immune complex-mediated activation of immune cells such as macrophages, neutrophils and dendritic cells (DCs). It also controls the activation threshold of B cells (cells responsible for antibody production). Furthermore, FcγRIIB modulates antigen presentation by both DCs and B cells, and therefore, controls T cell activation. A variant (polymorphism) in the gene encoding FcγRIIB (FcγRIIBT232) is associated with receptor dysfunction and autoimmunity. Based on our studies in autoimmunity and infection, we believe that this polymorphism is likely to be an important genetic factor in determining the risk of developing harmful antibodies following transplantation, and the magnitude of the inflammatory response resulting from these antibodies.

To test this hypothesis, we plan to genotype a cohort of 1500 randomly selected Caucasian renal transplant recipients, using DNA collected by Prof. Gerhard Opelz and colleagues at the Collaborative Transplant Study (http://www.ctstransplant.org/). We will assess if there is an association between FCGR2B genotype and rejection, patient survival, and death-censored allograft survival and using appropriate techniques to control for important confounding factors. Any association will be confirmed in a validation cohort of a further 1500 transplant recipients. Potentially, this project may yield important information on immunopathological mechanisms of chronic graft damage and may validate FcγRIIB as a therapeutic target in transplantation.