TEPOXALIN, A NOVEL IMMUNOMODULATORY COMPOUND, SYNERGIZES WITH CSA IN SUPPRESSION OF GRAFT-VERSUS-HOST REACTION AND ALLOGENEIC SKIN-GRAFT REJECTION

Tepoxalin, a dual B-Lipoxygenase and cyclooxygenase inhibitor with non steroidal antiinflammatory effects, has recently been shown to suppres s NF kappa B transactivation and inhibit T cell proliferation via a me chanism very different from cyclosporine (CsA). In this report, we dem onstrate that this novel immunosuppressive effect of tepoxalin is mani fested in in vivo transplantation models, Tepoxalin suppressed murine spleen cell proliferation in a mixed lymphocyte reaction (MLR) with an IC50 of 1.3 mu M. Coadministration of tepoxalin and CsA in MLR cultur es showed an additive inhibitory effect. Oral administration of tepoxa lin at 12 mg/kg/day to mice suppressed local graft-versus-host (GVH) r esponses by about 40% (n = 10). Combination of tepoxalin and CsA at su boptimal doses synergized their immunosuppressive effects on GVH respo nses (n = 20), In skin transplantation, the median survival time of al logeneic BALB/cByJ (H-2(d)) mouse skin grafted onto C3H/HeJ (H-2(k)) m ice was 10.5 days (n = 8), and was prolonged to 15.0 days (n = 9) for recipient mice administered tepoxalin at 50 mg/kg/day. Coadministratio n of suboptimal doses of tepoxalin (12.5 mg/kg/day) and CsA (50 mg/kg/ day) prolonged skin graft rejections dramatically (55% of the grafts s urvived for more than 40 days, n = 9). Taken together, these results d emonstrate that tepoxalin is a potent immunomodulatory compound that, when combined with CsA, provides synergistic immunosuppressive activit y. The fact that tepoxalin and CsA act on different transcription fact ors, NF kappa B and NFAT respectively, might explain the synergistic s uppressive effects when both compounds were used. Tepoxalin could be a n important addition to the cohort of immunosuppressive therapies curr ently used in solid organ and bone marrow transplantations.