Introduction: Although current standard immunosuppressants have various adverse effects, transplanted patients are forced to reluctantly receive them to suppress immune rejection. Furthermore, they also have serious adverse effects on transplanted grafts, including diabetogenesis and neovascularization inhibition. We previously reported that mocravimod, a sphingosine 1 phosphate receptor agonist, not only suppresses immune rejection but also induces no adverse effects on grafts (Transplantation 106:963-972:2022). Given that mocravimod also has strong anti-inflammatory effects, it is logical to consider that its benefits of mocravimod further improve engraftment rather than merely not interfering with graft survival. Therefore, we verified the hypothesis that mocravimod improves transplant outcomes, even in a syngeneic islet transplantation model in which immune rejection does not occur.

Methods: We performed transplant experiments in a syngeneic combination using C57BL/6 mice. Diabetes was induced by intravenous injection of streptozotocin. To investigate the effects of mocravimod on the outcomes of intraportal islet transplantation and the pharmacokinetics of mocravimod, the islet-transplanted recipients were divided into 4 groups: the Moc (Day-1) group (once a day for 1 day), the Moc (Day-2) group (twice a day for 2 days), the Moc (Day-5) group (once a day for 5 days), and the Control group (0.5% Methylcellulose; once a day for 5 days). Blood glucose levels and glucose tolerance were measured to evaluate islet engraftment. In the mechanism analysis experiments, the recipients were divided into two groups: the Moc group (once a day for 5 days) and the Control group (0.5% MC; once a day for 5 days). Flow cytometry, immunoassay, coagulation/complement cascade, and histological analyses were performed to examine the detailed mechanisms of mocravimod.

Results: Mocravimod significantly improved islet engraftment even in a syngeneic model, in sharp contrast to the various adverse effects induced by current immunosuppressants. The cure rates of the diabetic mice in the Moc (Day -5) and Moc (Day -2) groups were significantly higher than those in the Moc (Day -1) and Control groups (p<0.05). In pharmacokinetics of mocravimod, significant differences were observed in both the trough levels and AUC among all groups (p<0.05). All mechanistic assays performed in this study revealed that the main mechanisms of these effects were synergistic inhibition of the instant blood-mediated inflammatory reaction (IBMIR) and inflammatory mediator-related attack on islet grafts.

Conclusion: The present study showed that mocravimod, unlike current standard immunosuppressants, does not induce diabetogenesis or inhibit angiogenesis but improves islet engraftment through the synergistic inhibition of IBMIR and inflammatory mediators in addition to suppressing immune rejection.