Antibody responses to chemical adducts in human kidney allograft rejection

Columbia University Health Sciences, New York NY

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Abstract

PROJECT SUMMARY Immune rejection is a major cause of long-term graft failure following kidney transplant. While the actual mechanisms are still being investigated, the pivotal role of antibodies specific to mismatched donor HLA molecules (DSA) in different types of rejection is now beyond doubt. DSA are associated with progressive signs of graft deterioration including complement activation, capillaritis and glomerulitis. Although central, DSA are not the only elements of humoral immunity implicated in kidney graft rejection. An overwhelming amount of evidence now attests to the generation of non-HLA antibodies reactive to self-antigens post-transplant. These antibodies have been associated with rejection and graft loss in numerous studies even in the absence of DSA. In light of this growing data, novel Luminex-based assays were recently developed by leading diagnostic tool providers to standardize measurement of non-HLA antibodies reactive to nearly 100 autoantigens and evaluate their clinical significance in large patient cohorts. Unexpectedly, results have been inconsistent thus far. Some studies reported higher reactivity to several autoantigens in patients with rejection when compared to control but interstudy reproducibility was minimal. In addition, with only few exceptions, the functions of these autoantibodies are still enigmatic. During the last funding period, we investigated the contribution of natural antibodies (Nabs), defined by their apparent polyreactivity, in the outcome of kidney transplant. Our studies repeatedly supported the involvement of Nabs in rejection and graft loss following renal transplantation. In more recent investigations, we observed that polyreactive Nabs often react to autoantigens included in the commercialized assays mentioned above for the detection of non-HLA antibodies. Moreover, we also uncovered that the apparent polyreactivity of Nabs can often be explained by their specificity to chemical adducts such as post-translational modifications (PTM) exposed on proteins. Further, as we recently published, these anti-adduct antibodies constitute an important component of humoral immunity maintained across the human lifespan. Collectively, these findings provided novel elements to understand some of the elusive observations related to non-HLA antibodies in the transplant setting. We now hypothesize that anti-adduct antibodies are largely responsible for serum reactivity attributed to Nabs or non-HLA antibodies. Based on the known implication of Nabs in apoptotic cell clearance (efferocytosis) and immunoregulation, we hypothesize that anti-adduct antibodies contribute to graft rejection through similar functions. Our proposed research will test these hypotheses and provide much needed clarification about the development and significance of non-HLA antibodies in kidney transplant recipients. Aim 1. To characterize antibody responses to specific chemical adducts in kidney transplant recipients. Aim 2. To characterize B cells producing anti-adduct antibodies. Aim 3. To elucidate pathological mechanisms of anti-adduct antibodies in graft rejection.