title: Costimulatory blockade with mTor inhibition abrogates effector T-cell responses allowing regulatory T-cell survival in renal transplantation.
abstract: The advent of novel immunosuppressive strategies in renal transplantation, with immunomodulatory properties, might facilitate long-term allograft survival. T-cell depletion, costimulation-blockade and mTor inhibition have been shown to favour anti-donor hyporesponsiveness. Recently, the combination of rATG, belatacept (Bela) and sirolimus (SRL) has been used in kidney transplantation, showing very low incidence of acute rejection and excellent 12-month graft and patient survival. Herein, we have analysed the 1-year evolution of memory/effector and regulatory T cells and assessed the donor-specific T-cell alloimmune response in a group of these patients and compared with others treated with a calcineurin-inhibitor(CNI)-based (rATG/tacrolimus/MMF), and two other Bela-based regimens (rATG/Bela/MMF and basiliximab/Bela/MMF/steroids). During the first year after transplantation, patients receiving rATG/Bela/SRL had significantly higher percentage of Tregs upon the memory T-cell compartment and showed a potent anti-donor suppressive activity. In an in vitro naive and memory/effector T-cell co-culture, the combination of costimulation-blockade and SRL could abrogate both antigen-specific T-cell responses as efficiently as using a CNI drug. The combination of T-cell depletion, costimulation-blockade and mTor inhibition seems to be able to allow Treg survival and inhibit donor-specific alloreactive effector immune responses after kidney transplantation in humans.
authors.affiliation: Nephrology Department, Renal Transplant Unit, Bellvitge University Hospital, University of Barcelona, Barcelona, Spain. 35830obm@comb.cat
authors.forename: Oriol
authors.initials: O
authors.lastname: Bestard
authors.forename: Linda
authors.initials: L
authors.lastname: Cassis
authors.forename: Josep M
authors.initials: JM
authors.lastname: Cruzado
authors.forename: Joan
authors.initials: J
authors.lastname: Torras
authors.forename: Marcella
authors.initials: M
authors.lastname: Franquesa
authors.forename: Salvador
authors.initials: S
authors.lastname: Gil-Vernet
authors.forename: Marc
authors.initials: M
authors.lastname: Lucia
authors.forename: Josep M
authors.initials: JM
authors.lastname: Grinyó
mesh_terms: D000069594:Abatacept; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000077552:Basiliximab; D002469:Cell Separation; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016030:Kidney Transplantation / Q000009:adverse effects*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D013256:Steroids / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D016559:Tacrolimus / Q000037:antagonists & inhibitors / Q000494:pharmacology; D023001:Transplantation Tolerance; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D011993:Recombinant Fusion Proteins; D013256:Steroids; D000069594:Abatacept; D000077552:Basiliximab; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus; D016559:Tacrolimus