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Published ahead of print on February 7, 2007
J Am Soc Nephrol 18: 1007-1018, 2007
© 2007 American Society of Nephrology
doi: 10.1681/ASN.2006101143
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Clinical Transplantation

Regulatory T Cells and T Cell Depletion: Role of Immunosuppressive Drugs

Marina Noris*,{dagger}, Federica Casiraghi*,{dagger}, Marta Todeschini*,{dagger}, Paolo Cravedi*,{dagger}, Daniela Cugini*,{dagger}, Giuseppe Monteferrante*,{dagger}, Sistiana Aiello*,{dagger}, Linda Cassis*,{dagger}, Eliana Gotti*, Flavio Gaspari*, Dario Cattaneo*,{dagger}, Norberto Perico* and Giuseppe Remuzzi*,{dagger}

* Department of Immunology and Organ Transplantation, Ospedali Riuniti–Mario Negri Institute for Pharmacological Research, and {dagger} 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: noris{at}marionegri.it

Received for publication October 23, 2006. Accepted for publication December 20, 2006.

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.


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