Abatacept modulates human dendritic cell-stimulated T-cell proliferation and effector function independent of IDO induction.
Abatacept, the first in a new class of agents for RA, modulates CD28-mediated T-cell costimulation. Abatacept was evaluated for its ability to regulate human T-cell proliferation and cytokine production initiated by dendritic cells. Abatacept reduced T-cell proliferation by >95% at concentrations between 0.3 and 3 microg/ml. The effect of abatacept on T-cell proliferation was not through induction of IDO activity, as no increase in IDO mRNA or kynurenine was observed and 1-methyl-D-tryptophan did not reverse the inhibition. In addition to the effect of abatacept on proliferation, T-cell cytokines, IL-2, TNFalpha and IFNgamma were also reduced. Abatacept also inhibited proliferation and cytokine production in a T-cell memory response. These data demonstrate that abatacept, independent of IDO activity, attenuates both naive and memory T-cell proliferation and effector function. Taken together, these data aid our understanding of the mechanism for efficacy of abatacept in patients with autoimmune disease.
Davis
Patricia M
PM
Department of Immunology and Inflammation, Bristol Myers Squibb Co Research and Development, Princeton, NJ 08543-4000, USA.
Nadler
Steven G
SG
Stetsko
Dawn K
DK
Suchard
Suzanne J
SJ
D000069594:Abatacept; D049109:Cell Proliferation; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D007156:Immunologic Memory; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D007737:Kynurenine / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D012333:RNA, Messenger / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013745:Tetanus Toxoid / Q000276:immunology
D016207:Cytokines; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D012333:RNA, Messenger; D013745:Tetanus Toxoid; D007737:Kynurenine; D000069594:Abatacept