Long-lasting effects of anti-rejection therapy on natural antibodies and alloreactive T cells in kidney transplant patients
Nicole M. van Besouw1, Sarah B. See3, Aleixandra Mendoza Rojas1, Marjolein Dieterich1, Marian C. Clahsen-van Groningen2, Dennis A. Hesselink1, Emmanuel Zorn3, Carla C. Baan1.
1Internal Medicine - Nephrology & Transplantation, Erasmus MC, Rotterdam, Netherlands; 2Pathology, Erasmus MC, Rotterdam, Netherlands; 3Columbia Center for Translational Immunology - Medicine, Columbia University Medical Irving Center, New York, Netherlands
Introduction: It is speculated that an adequate control of T cell-dependent humoral immune response will improve graft survival. However, the relationship of circulating effector memory T and B cells long after transplantation, and their susceptibility to immunosuppression, is unknown.
Material and Methods: To investigate the impact on anti-rejection therapy (high-dose of methylprednisolone, T cell-depleting antibody therapy or intravenous immune globulin (IvIg)) on T cell-B cell coordinated immune responses, we assessed circulating IFN-γ producing memory cells and natural antibodies (nAbs), that potentially bind to autoantigens on the graft. In a cross-sectional study plasma levels of IgG nAbs were measured by ELISA in 154 transplant recipients at 5-7 years after kidney transplantation. In 57 of these patients the number of donor and third-party reactive IFN-γ producing cells were determined by Elispot assay.
Results: Thirty-five out of 154 patients experienced a rejection episode (n=20 aTCMR, n=3 aABMR, n=2 aTCMR+aABMR, n=6 caABMR, n=2 cTCMR, n=2 caABMR+cTCMR). Eighteen rejections occurred within 1 year of transplantation (median: 0.26 year, range: 0.02-0.96), and 17 rejections occurred after one year post-transplantation (3.7 years (1.2-7.0)). At 5-7 years after transplantation the number of donor-reactive IFN-γ producing cells and the levels of nAbs were comparable between rejectors and non-rejectors. Remarkably, the nAbs levels were positively correlated with the number of donor-reactive IFN-γ producing cells (rs=0.40, p=0.002), whereas the number of completely HLA mismatched third-party reactive IFN-γ producing cells did not. The positive correlation was only observed in rejectors (rs=0.52, p=0.004; non-rejectors: rs=0.32, p=0.10). Moreover, we observed that IvIg treatment affected the level of nAbs and this effect was found in patients who experienced a late cABMR compared to non-rejectors (p=0.008).
Conclusion: The positive correlation found between alloreactive T cells and nAbs in rejectors suggests an intricate role for both components of the immune response even late after the rejection process.
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