Clinical TransplantationRegulatory T Cells and T Cell Depletion Role of Immunosuppressive DrugsNoris, Marina*, †; Casiraghi, Federica*, †; Todeschini, Marta*, †; Cravedi, Paolo*, †; Cugini, Daniela*, †; Monteferrante, Giuseppe*, †; Aiello, Sistiana*, †; Cassis, Linda*, †; Gotti, Eliana*; Gaspari, Flavio*; Cattaneo, Dario*, †; Perico, Norberto*; Remuzzi, Giuseppe*, † Author Information *Department of Immunology and Organ Transplantation, Ospedali Riuniti–Mario Negri Institute for Pharmacological Research, and †Center for Research on Organ Transplantation, Chiara Cucchi De Alessandri & Gilberto Crespi, Bergamo, Italy Address correspondence to: Dr. Marina Noris, Mario Negri Institute for Pharmacological Research, Via Gavazzeni 11, 24125, Bergamo, Italy. Phone: +39-035-319888; Fax: +39-035-319331; E-mail: [email protected] Accepted December 20, 2006 Received October 23, 2006 Journal of the American Society of Nephrology 18(3):p 1007-1018, March 2007. | DOI: 10.1681/ASN.2006101143 Buy Metrics Abstract Allogeneic immune responses are modulated by a subset of host T cells with regulatory function (Treg) contained within the CD4+CD25high subset. Evidence exists that Treg expand after peritransplantation lymphopenia, inhibit graft rejection, and induce and maintain tolerance. Little, however, is known about the role of Treg in the clinical setting. IL-2 and activation by T cell receptor engagement are instrumental to generate and maintain Treg, but the influence of immunosuppressants on Treg homeostasis in humans in vivo has not been investigated. This study monitored Treg phenotype and function during immune reconstitution in renal transplant recipients who underwent profound T cell depletion with Campath-1H and received sirolimus or cyclosporine (CsA) as part of their maintenance immunosuppressive therapy. CD4+CD25high cells that expressed FOXP3 underwent homeostatic peripheral expansion during immune reconstitution, more intense in patients who received sirolimus than in those who were given CsA. T cells that were isolated from peripheral blood long term after transplantation were hyporesponsive to alloantigens in both groups. In sirolimus- but not CsA-treated patients, hyporesponsiveness was reversed by Treg depletion. T cells from CsA-treated patients were anergic. Thus, lymphopenia and calcineurin-dependent signaling seem to be primary mediators of CD4+CD25high Treg expansion in renal transplant patients. These findings will be instrumental in developing “tolerance permissive” immunosuppressive regimens in the clinical setting. Copyright © 2007 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.