TY - JOUR
T1 - Regulatory T cells and T cell depletion
T2 - Role of immunosuppressive drugs
AU - Noris, Marina
AU - Casiraghi, Federica
AU - Todeschini, Marta
AU - Cravedi, Paolo
AU - Cugini, Daniela
AU - Monteferrante, Giuseppe
AU - Aiello, Sistiana
AU - Cassis, Linda
AU - Gotti, Eliana
AU - Gaspari, Flavio
AU - Cattaneo, Dario
AU - Perico, Norberto
AU - Remuzzi, Giuseppe
PY - 2007/3
Y1 - 2007/3
N2 - Allogeneic immune responses are modulated by a subset of host T cells with regulatory function (Treg) contained within the CD4+CD25 high 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+CD25 high 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.
AB - Allogeneic immune responses are modulated by a subset of host T cells with regulatory function (Treg) contained within the CD4+CD25 high 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+CD25 high 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.
UR - http://www.scopus.com/inward/record.url?scp=33947249410&partnerID=8YFLogxK
U2 - 10.1681/ASN.2006101143
DO - 10.1681/ASN.2006101143
M3 - Article
C2 - 17287424
AN - SCOPUS:33947249410
SN - 1046-6673
VL - 18
SP - 1007
EP - 1018
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 3
ER -