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Pimecrolimus inhibits up‐regulation of OX40 and synthesis of inflammatory cytokines upon secondary T cell activation by allogeneic dendritic cells

Pimecrolimus is a new non‐steroidal inhibitor of T cell and mast cell activation. In the present study, we compared the potency of pimecrolimus and cyclosporin A (CyA) to inhibit cytokine synthesis of alloantigen‐primed T cells and the expression of CD134 (OX40), an inducible co‐receptor molecule thought to be critical for the survival and expansion of inflammation‐mediating T cells. To mimic the physiological situation of recurrent antigenic stimulation, we have used dendritic cells (DC) as stimulators of purified CD4+ T cells in the primary and secondary allogeneic mixed lymphocyte culture (allo‐MLC). Pimecrolimus inhibited surface expression of OX40 and prevented the up‐regulation of CD25 and CD54 with a 10‐fold higher potency compared to CyA. Similarly, 50% inhibition of allo‐DC‐mediated T cell proliferation by pimecrolimus was obtained at 0·55 nm, compared to about 12 nm for CyA. Furthermore, pimecrolimus blocked the increase of OX40 on primed T cells restimulated on day 10 in secondary allo‐MLC. Allo‐DC‐primed T cells showed a restricted cytokine profile characterized by the production of TNF‐α, IFN‐γ and IL‐2 but low to undetectable levels of IL‐4 and IL‐10. The synthesis of TNF‐α and IFN‐γ and the up‐regulation of OX40 on T cells after secondary allogeneic stimulation were almost entirely blocked by 10 nm pimecrolimus. Taken together, pimecrolimus inhibits T cell proliferation and Th1 cytokine synthesis and also prevents the up‐regulation of the OX40 co‐receptor on primed T cells indicating its potential in the therapy of chronic inflammation and autoimmunity.