The impact of antinuclear antibodies on alloimmune responses to renal transplants

Abstract Autoantibodies (autoAb) are recognized as an important factor influencing the survival of transplanted solid organs. The vast majority of autoAbs implicated in poor transplant outcome target the components of extracellular matrix, cell surface and cytosolic proteins and are associated with chronic rejection months and years after transplantation. While anti-nuclear autoAb (ANA) are a hallmark feature of several autoimmune diseases, the data on the impact of ANA in transplant recipients is limited. Clinical studies in cardiac and renal transplantation revealed associations between high ANA levels and increased alloimmunity, development of antibody-mediated rejection, inferior graft function and increased mortality. Our published and preliminary data in a mouse kidney transplantation model demonstrate that ANA develop early after transplantation and that autoAb against representative nuclear antigen DNA Topoisomerase I enhance activation of donor-reactive T cells and lead to acute graft rejection of renal allografts. Thus, the experimental and clinical studies strongly suggest that autoimmunity to nuclear antigens can exacerbate alloimmune responses in renal transplant recipients. However, the mechanisms underlying the effects of ANA on MHC-reactive immune responses and graft injury remain poorly understood. The goal of the proposed studies is to investigate the mechanisms by which ANA promote activation and effector functions of alloreactive T cells and to test strategies for preventing pathogenic effects of ANA in renal allograft recipients. We hypothesize that pre-existing ANA bind the fragments of dying graft cells and enhance T cell activation by: 1) increasing posttransplant ischemia/reperfusion injury (IRI) through FcγR- and complement-mediated neutrophil recruitment and activation to exacerbate the release of donor alloantigens; and, 2) facilitating recipient DC activation and donor antigen presentation via FcγR/TLR/IFN axis. This results in increased priming and effector functions of alloreactive T cells and anti-MHC DSA generation leading to graft injury and rejection. Aim 1. To investigate the effects of ANA on donor alloantigen presentation to donor-reactive T cells following renal transplantation. Aim 2. To test whether ANA impacts donor antigen release and subsequent alloreactive T cell responses by increasing the magnitude of ischemia/reperfusion injury. The findings of the proposed studies may improve clinical prediction of poor transplant outcomes, guide therapeutic interventions in high-risk individuals, and identify new cellular and molecular targets to diminish the pathogenic impact of autoAbs in transplant recipients.