Novel sphingosine-1-phosphate receptor modulator KRP203 combined with locally delivered regulatory T cells induces permanent acceptance of pancreatic islet allografts

BACKGROUND: KRP203, a structural FTY720 analogue, has 5-fold greater selectivity for binding to sphingosine-1-phosphate receptor (S1PR) 1 (S1PR1) versus S1PR3 and 100-fold greater selectivity over S1PR2 and S1PR5. Although the immunoregulatory effects of FTY720 have been tested in clinical and experimental research, the therapeutic efficacy of KRP203 in allograft models remains elusive. In this study, we investigated the potential of KRP203 alone and in combination with intragraft injection of CD4CD25FoxP3 regulatory T cells (Tregs) to induce islet allograft tolerance. METHODS: BALB/c (H-2) mice received transplants of fresh C57BL/10 (H-2) islet allografts under the kidney capsule and were treated for 7 days with 0.3, 1.0, or 3.0 mg/kg KRP203 alone or in combination with intragraft-infused Tregs. RESULTS: Untreated BALB/c mice acutely rejected C57BL/10 islet allografts at a mean survival time of 13.8±2.7 days (n=5). A 7-day dosing of 0.3 or 1.0 mg/kg KRP203 produced long-term islet allograft survival (>200 days) in one of five and two of seven recipients, respectively. A 3 mg/kg KRP203 dose resulted in islet graft survival for more than 200 days in 5 of 12 recipients. Whereas recipients that received 500 allogeneic islets admixed with 5×10-7×10 Tregs survived 83.6±67.2 days, addition of transient 3 mg/kg KRP203 therapy induced prolonged drug-free graft survival (>200 days) in all recipients. CONCLUSIONS: A brief treatment with KRP203 significantly prolonged islet allograft survival, whereas additional intragraft delivery of Tregs induced tolerogenic effects selective to islet alloantigens.