Analogs of 1,25-dihydroxyvitamin D3 as dose-reducing agents for classical immunosuppressants

Background. Most immunosuppressants have a narrow margin between efficacy and side effects. A major goal in the development of immunomodulatory strategies is the discovery of combinations of drugs exerting synergistic immunomodulatory effects, The active form of vitamin D, 1,25(OH)(2)D-3, is an immunomodulator that interacts with T cells but mainly targets antigen-presenting cells. We have demonstrated synergism between 1,25(OH)(2)D-3 and cyclosporine, rapamycin, and FK506. The aim of this study was to investigate whether this synergism could be observed with other immunosuppressants (mycophenolate mofetil, leflunomide, and the methylxanthine A802715) and whether analogs of 1,25(OH)(2)D-3 share this synergistic capacity in vivo. Methods, In vitro, the median effect analysis was applied to the inhibition of phytohemagglutinin A-induced lymphocyte proliferation. In vivo, synergism between analogs of 1,25(OH)(2)D-3 and cyclosporine or mycophenolate mofetil was evaluated in experimental autoimmune encephalomyelitis. Results. In vitro, all combinations with 1,25(OH)(2)D-3 were synergistic, The strongest synergism was seen with the inhibitors of interleukin 2 secretion, cyclosporine and FR506 (indexes 0.16 and 0.27, respectively). The weakest synergism was observed in combinations using A802715, a second-signal inhibitor (index 0.52), or the nucleotide synthesis inhibitor mycophenolate mofetil (index 0.43). In vivo, analogs of 1,25(OH)(2)D-3 share the in vitro-observed synergism with 1,25(OH)(2)D-3. Moreover, the differences in synergism with different immunomodulators were also present in vivo, where the best synergism was again seen in combination with cyclosporine (up to 100% paralysis protection). Conclusions. These data confirm that 1,25(OH)(2)D-3 and its analogs are potent dose-reducing drugs for other immunomodulators, making them potentially interesting for clinical use in autoimmunity and transplantation.