USE OF THE METHYLXANTHINE DERIVATIVE A802715 IN TRANSPLANTATION IMMUNOLOGY .1. STRONG IN-VITRO INHIBITORY EFFECTS ON CD28-COSTIMULATED T-CELL ACTIVITIES

Background. Recently, methylxanthines such as pentoxifylline (PTX) wer e shown to be immunosuppressive in vitro. Unfortunately, when used in transplant patients, PTX was poorly active as an immunosuppressant, He re we report that the new methylxanthine derivative A802715 not only i s more active than PTX, it also suppresses the cyclosporine (CsA)-resi stant ''signal two''-dependent pathway of T cell proliferation, making it an interesting drug to associate with CsA. Methods. ''Signal one'' - and ''signal two''-dependent T cell activation was investigated with purified human T cells stimulated with immobilized anti-CD3 or anti-C D28 monoclonal antibody (mAb) plus phorbol myristate acetate (PMA) or with a 3T6 mouse fibroblast cell line presenting anti-CD3 mAb on trans fected human Fc gamma receptors II (Fc gamma RII) in the presence or a bsence of transfected B7-1 (CD80) molecules. Results. A802715 was more immunosuppressive in the mixed lymphocyte reaction (MLR) than PTX, A8 02715 dose-dependently suppressed polyclonal signal one-dependent T ce ll activation induced by anti-CD3 mAb/PMA. In addition, A802715 also s uppressed signal two-dependent T cell proliferation induced by anti-CD 28 mAb/PMA. The expression of the interleukin-a receptor on T cells st imulated by anti-CD3 mAb presented on 3T6/Fc gamma RII cells was equal ly well suppressed by A802715 and PTX, In contrast, interleukin-a rece ptor or CD40L (gp39) expression by T cells after stimulation with the same anti-CDS mAb- 3T6/Fc gamma RII cells, but coexpressing transfecte d B7-1, was only suppressed by A802715. The anticipated synergism betw een A802715 and CsA was confirmed in MLR assays, Moreover, generation of cytotoxic T lymphocytes during MLR with Epstein-Barr virus-transfor med B cells, which strongly express B7-1 and B7-2, was also inhibited by A802715. Conclusions. These in vitro data indicate that the A802715 (1) is a stronger immunosuppressant for T cells than PTX, (2) suppres ses T cell activation pathways that are resistant to PTX or CsA, and ( 3) acts synergistically with CsA.