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

Summary 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 n m , compared to about 12 n m 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 n m 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.