Everolimus and basiliximab permit suppression by human CD4+CD25+ cells in vitro.
Immunosuppressive drugs are essential for the prevention of acute transplant rejection but some may not promote long-term tolerance. Tolerance is dependent on the presence and regulatory function of CD4(+)CD25(+) T cells in a number of animal models. The direct effects of immunosuppressive drugs on CD4(+)CD25(+) cells, particularly those that interfere with IL-2 signaling are uncertain. We studied the effects of the rapamycin derivative everolimus and the anti-CD25 monoclonal antibody basiliximab on the regulatory capacity of human CD4(+)CD25(+) cells in vitro. Both drugs permitted the suppression of proliferation and IFN-gamma secretion by CD4(+)CD25(-) cells responding to allogeneic and other polyclonal stimuli; CTLA-4 expression was abolished on CD4(+)CD25(+) cells without compromising their suppressive ability. Everolimus reduced IFN-gamma secretion by CD4(+)CD25(-) cells before the anti-proliferative effect: this is a novel finding. Exogenous IL-2 and IL-15 could prevent the suppression of proliferation by CD4(+)CD25(+) cells and the drugs could not restore suppression. By contrast, suppression of IFN-gamma secretion was only slightly impeded with the exogenous cytokines. Finally, CD4(+)CD25(+) cells were more resistant than CD4(+)CD25(-) cells to the pro-apoptotic action of the drugs. Together these data suggest that CD4(+)CD25(+) cells may still exert their effects in transplant patients taking immunosuppression that interferes with IL-2 signaling.
Game
David S
DS
Department of Immunology, Faculty of Medicine, Imperial College, Hammersmith Hospital, Du Cane Road, London, UK.
Hernandez-Fuentes
Maria P
MP
Lechler
Robert I
RI
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics; D000077552:Basiliximab; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen; D049109:Cell Proliferation / Q000187:drug effects; D000068338:Everolimus; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D017252:CD3 Complex; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D007166:Immunosuppressive Agents; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma; D000077552:Basiliximab; D000068338:Everolimus; D020123:Sirolimus