Regulatory T cells and T cell depletion: role of immunosuppressive drugs.
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(+)CD25(high) Treg expansion in renal transplant patients. These findings will be instrumental in developing "tolerance permissive" immunosuppressive regimens in the clinical setting.
Noris
Marina
M
Department of Immunology and Organ Transplantation, Ospedali Riuniti-Mario Negri Institute for Pharmacological Research, Bergamo, Italy. noris@marionegri.it
Casiraghi
Federica
F
Todeschini
Marta
M
Cravedi
Paolo
P
Cugini
Daniela
D
Monteferrante
Giuseppe
G
Aiello
Sistiana
S
Cassis
Linda
L
Gotti
Eliana
E
Gaspari
Flavio
F
Cattaneo
Dario
D
Perico
Norberto
N
Remuzzi
Giuseppe
G
D000328:Adult; D000368:Aged; D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000627:therapeutic use; D015703:Antigens, CD / Q000187:drug effects; D019703:Calcineurin / Q000378:metabolism; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006084:Graft Rejection / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007519:Isoantigens; D016030:Kidney Transplantation / Q000276:immunology*; D008231:Lymphopenia / Q000209:etiology; D008297:Male; D008875:Middle Aged; D015398:Signal Transduction / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D019172:Transplantation Conditioning
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D015703:Antigens, CD; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007166:Immunosuppressive Agents; D007519:Isoantigens; D000074323:Alemtuzumab; D016572:Cyclosporine; D003404:Creatinine; D019703:Calcineurin; D020123:Sirolimus