Resumen
Pentoxifylline (PTX), rapamycin (RAP), and leflunomide are potent immunomodulatory 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 leflunomide) on in vitro T cell activation in a mouse model system. T lymphocytes in spleen cell preparations were stimulated with anti-CD3 monoclonal antibody alone, or in the presence of PTX (25-200 μg/ml), RAP (0.5-5.0 ng/ml), A77 1726 (2.5-10.0 μM), PTX/RAP (25-200 μg/ml and 0.5-5.0 ng/ml, respectively), or PTX/A77 1726 (25-200 μg/ml and 2.5-10.0 μM, respectively). Anti-CD3-induced T cell proliferation was inhibited in a dose-dependent fashion by the individual drugs. An additive inhibitory effect was observed in cultures treated with PTX/RAP or PTX/A77 1726. The effects of PTX, RAP, A77 1726, PTX/RAP, or PTX/A77 1726 (at concentrations approximating the IC50 of individual drugs for inhibition of lymphoproliferation) on anti-CD3-activated killer (AK) cell 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 plus RAP exhibited strong synergism, while the combination of PTX and A77 1726 had an additive inhibitory effect on AK cell induction. CD25 expression 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 effect on CD25 expression while PTX and A77 1726 together had an effect equivalent to PTX alone. IL-2 synthesis was inhibited by PTX but was unaffected by RAP or A77 1726. Treatment with PTX plus RAP led to a further-reduction in IL-2 production but co-treatment with PTX and A77 1726 approximated the inhibitory effect of PTX alone. We conclude that the combination of PTX and RAP is noteworthy for its potent immunomodulatory activity and may be of use in clinical situations where it is desirable to prevent T cell activation.
Idioma original | English |
---|---|
Páginas (desde-hasta) | 241-252 |
Número de páginas | 12 |
Publicación | International Journal of Immunopharmacology |
Volumen | 20 |
N.º | 4-5 |
DOI | |
Estado | Published - ago. 26 1998 |
Nota bibliográfica
Funding Information:This work was supported by a grant to D.W.H. from the Natural Sciences and Engineering Research Council of Canada. We thank Dr L. Best for assistance with the flow cytometric analysis and Dr A. MacDonald for facilitating the gift of A77 1726 from Hoechst AG.
ASJC Scopus Subject Areas
- Immunology
- Pharmacology