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* Department of Nephrology,
Department of Immunology, and
Department of Pathology, Hospital de Bellvitge, Barcelona, Spain
Exploring new immunosuppressive strategies inducing donor-specific hyporesponsiveness is an important challenge in transplantation. For this purpose, a careful immune monitoring and graft histology assessment is mandatory. Here, we report the results of a pilot study conducted in twenty renal transplant recipients, analyzing the immunomodulatory effects of a protocol based on induction therapy with rabbit anti-thymocyte globulin low doses, sirolimus, and mofetil mycophenolate. Evolution of donor-specific cellular and humoral alloimmune response, peripheral blood lymphocyte subsets and apoptosis was evaluated. Six-month protocol biopsies were performed to assess histological lesions and presence of FOXP3+ regulatory T cells (Tregs) in interstitial infiltrates. After transplantation, there was an early and transient apoptotic effect, mainly within the CD8+HLADR+ T cells, combined with a sustained enhancement of CD4+CD25+high lymphocytes in peripheral blood. The incidence of acute rejection was 35%, all steroid sensitive. Importantly, only pretransplant donor-specific cellular alloreactivity could discriminate patients at risk to develop acute rejection. Two thirds of the patients became donor-specific hyporesponders at 6 and 24 mo, and the achievement of this immunologic state was not abrogated by prior acute rejection episodes. Remarkably, donor-specific hyporesponders had the better renal function and less chronic renal damage. Donor-specific hyporesponsiveness was inhibited by depleting CD4+CD25+high T cells, which showed donor-Ag specificity. FOXP3+CD4+CD25+high Tregs both in peripheral blood and in renal infiltrates were higher in donor-specific hyporesponders than in nonhyporesponders, suggesting that the recruitment of Tregs in the allograft plays an important role for renal acceptance. In conclusion, reaching donor-specific hyporesponsiveness is feasible after renal transplantation and associated with Treg recruitment in the graft.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was investigator promoted and partially supported by grants from Wyeth and Genzyme. O.B. received a grant from Institut d’Investigació Biomèdica de Bellvitge (IDIBELL) (06/IDB-001).
2 Address correspondence and reprint requests to Dr. Oriol Bestard, Department of Nephrology, Hospital Universitari de Bellvitge, Feixa Llarga s/n 08907, L’Hospitalet de Llobregat, Barcelona. Spain. E-mail address: 35830obm{at}comb.es
3 Abbreviations used in this paper: Treg, regulatory T cell; SRL, sirolimus; CNI, calcineurin inhibitor; MMF, mofetil mycophenolate; PRA, panel reactive Abs; BPAR, biopsy proven acute rejection; TAC, tacrolimus; rATG, rabbit anti-thymocyte globulin.
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