title: Tepoxalin, a novel immunomodulatory compound, synergizes with CsA in suppression of graft-versus-host reaction and allogeneic skin graft rejection.
abstract: Tepoxalin, a dual 5-lipoxygenase and cyclooxygenase inhibitor with nonsteroidal antiinflammatory effects, has recently been shown to suppress NF kappa B transactivation and inhibit T cell proliferation via a mechanism very different from cyclosporine (CsA). In this report, we demonstrate that this novel immunosuppressive effect of tepoxalin is manifested in in vivo transplantation models. Tepoxalin suppressed murine spleen cell proliferation in a mixed lymphocyte reaction (MLR) with an IC50 of 1.3 microM. Coadministration of tepoxalin and CsA in MLR cultures showed an additive inhibitory effect. Oral administration of tepoxalin at 12 mg/kg/day to mice suppressed local graft-versus-host (GVH) responses by about 40% (n = 10). Combination of tepoxalin and CsA at suboptimal doses synergized their immunosuppressive effects on GVH responses (n = 20). In skin transplantation, the median survival time of allogeneic BALB/cByJ (H-2d) mouse skin grafted onto C3H/HeJ (H-2 kappa) mice 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. Coadministration 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 survived for more than 40 days, n = 9). Taken together, these results demonstrate that tepoxalin is a potent immunomodulatory compound that, when combined with CsA, provides synergistic immunosuppressive activity. The fact that tepoxalin and CsA act on different transcription factors, NF kappa B and NFAT respectively, might explain the synergistic suppressive effects when both compounds were used. Tepoxalin could be an important addition to the cohort of immunosuppressive therapies currently used in solid organ and bone marrow transplantations.
authors.affiliation: R.W. Johnson Pharmaceutical Research Institute, Don Mills, Ontario, Canada.
authors.forename: W P
authors.initials: WP
authors.lastname: Fung-Leung
authors.forename: B L
authors.initials: BL
authors.lastname: Pope
authors.forename: E
authors.initials: E
authors.lastname: Chourmouzis
authors.forename: J A
authors.initials: JA
authors.lastname: Panakos
authors.forename: C Y
authors.initials: CY
authors.lastname: Lau
mesh_terms: D000818:Animals; D016572:Cyclosporine / Q000008:administration & dosage*; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival / Q000187:drug effects; D006087:Graft vs Host Reaction / Q000187:drug effects*; D007166:Immunosuppressive Agents; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000008:administration & dosage*; D016038:Skin Transplantation / Q000276:immunology
chemical_list: D007166:Immunosuppressive Agents; D016328:NF-kappa B; D011720:Pyrazoles; D016572:Cyclosporine; C073135:tepoxalin