INHIBITION OF ANTI-CD3 ANTIBODY-INDUCED MOUSE T-CELL ACTIVATION BY PENTOXIFYLLINE IN COMBINATION WITH RAPAMYCIN OR A77-1726 (LEFLUNOMIDE)

Pentoxifylline (PTX), rapamycin (RAP), and leflunomide are potent immu nomodulatory drugs with differing modes of action. In order to develop new drug combinations for immunotherapy, we tested the effects of PTX in combination with RAP or A77 1726 (the active metabolite of lefluno mide) on in vitro T cell activation in a mouse model system. T lymphoc ytes in spleen cell preparations were stimulated with anti-CD3 monoclo nal antibody alone, or in the presence of PTX (25-200 mu g/ml), RAP (0 .5-5.0 ng/ml), A77 1726 (2.5-10.0 mu M), PTX/RAP (25-200 mu g/ml and 0 .5-5.0 ng/ml, respectively), or PTX/A77 1726 (25-200 mu g/ml and 2.5-1 0.0 mu M, respectively). Anti-CD3-induced T cell proliferation was inh ibited in a dose-dependent fashion by the individual drugs. An additiv e inhibitory effect was observed in cultures treated with PTX/RAP or P TX/A77 1726. The effects of PTX, RAP, A77 1726, PTX/RAP, or PTX/A77 17 26 (at concentrations approximating the IC50 of individual drugs for i nhibition of lymphoproliferation) on antiCD3-activated killer (AK) cel l induction, CD25 expression, and interleukin (IL)-2 synthesis in anti -CD3-activated spleen cell cultures were also determined. Alone, each drug was able to suppress AK cell induction to varying degrees. PTX pl us RAP exhibited strong synergism, while the combination of PTX and A7 7 1726 had an additive inhibitory effect on AK cell induction. CD25 ex pression was only weakly inhibited by A77 1726, but the percentage of CD25-expressing cells was greatly reduced in cultures treated with PTX or RAP. The combination of PTX and RAP had an additive inhibitory eff ect on CD25 expression while PTX and A77 1726 together had an effect e quivalent to PTX alone. IL-2 synthesis was inhibited by PTX but was un affected by RAP or A77 1726. Treatment with PTX plus RAP led to a furt her reduction in IL-2 production but co-treatment with PTX and A77 172 6 approximated the inhibitory effect of PTX alone. We conclude that th e combination of PTX and RAP is noteworthy for its potent :immunomodul atory activity and may be of use in clinical situations where it is de sirable to prevent T cell activation. (C) 1998 International Society f or Immunopharmacology. Published by Elsevier Science Ltd.