Synergism between sirolimus and 1,25-dihydroxyvitamin D-3 in vitro and in vivo
(1997) Journal of Neuroimmunology — Vol. 79, n° 2, p. 138-147 (1997)
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- The active form of vitamin D, 1 alpha,25-(OH)(2)D-3, displays immunomodulatory effects in vitro and in vivo at pharmacological levels. We evaluated the dose-effect relationship of 1,25(OH)(2)D-3 and sirolimus (rapamycin, RAP) in vitro, on the inhibition of PHA-srimulated PBMC proliferation, by using the median effect analysis. Pharmacological concentrations of 1,25(OH)(2)D-3 (between 10(-9) and 3 x 10(-6) M) interacted synergistically with RAP (combination index value of 0.01 for 50% suppression of PBMC proliferation). In vivo, the effect of 1,25(OH),D, and RAP combinations on the evolution of experimental allergic encephalomyelitis in SJL mice was analyzed. 1,25(OH)(2)D-3, given ip, in monotherapy, at a dose of 2 mu g/kg every two days, from day -3 until day +19 after disease induction, or RAP, injected daily at a dose of 0.3 mg/kg for the same period, decreased EAE incidence (paralysis in 70 and 55% of the animals, respectively, versus 98% in the placebo treated group, p < 0.001). The combination treatment using the two drugs in these subtherapeutical doses provided near-total clinical (8% paralysis, p < 0.001 compared to monotherapy with 1,25(OH),D, or RAP) and histological protection, comparable to that obtained with RAP in monotherapy at a threefold higher dose (1 mg/kg/d). When the two drugs were given using an alternate day administration schedule (RAP at 0.6 mg/kg and 1,25(OH)(2)D-3 at 2 mu g/kg. each given on alternate days from day -3 to 19), near total protection was again obtained (13% paralysis, p < 0.001 versus control). These in vitro and in vivo data support the existence of synergistic interactions between 1,25(OH)(2)D-3 and RAP. Considering the narrow therapeutic windows of both RAP and vitamin D-related compounds in autoimmune disease models, combinations of these drugs could find clinical application in reducing their individual therapeutically efficient doses to non-toxic levels. (C) 1997 Elsevier Science B.V.
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Branisteanu, D., Mathieu, C., & Bouillon, R. (1997). Synergism between sirolimus and 1,25-dihydroxyvitamin D-3 in vitro and in vivo. Journal of Neuroimmunology, 79(2), 138-147. https://doi.org/10.1016/S0165-5728(97)00116-1 (Original work published 1997)