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More MS news articles for October 2002

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

Clin Exp Immunol 2002 Oct;130(1):85-92
Kalthoff FS, Chung J, Stuetz A.

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-alpha, IFN-gamma and IL-2 but low to undetectable levels of IL-4 and IL-10.

The synthesis of TNF-alpha and IFN-gamma 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.