Background: KRP203, a structural FTY720 analog, has 5-fold greater selectivity for binding to sphingosine-1-phosphate receptor 1 (S1PR1) versus S1PR3 and 100-fold greater selectivity versus S1PR2 and S1PR5. In this study, we investigated the potential of KRP203 alone and in combination with intra-graft injection of CD4+CD25+FoxP3+ Helioshigh regulatory T cells (Tregs) to induce islet allograft tolerance.
Methods: Streptozotocin-induced diabetic Balb/c (H-2d) mice received transplants of fresh C57BL/10 (H-2b) 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-infusion of Tregs.
Results: Untreated Balb/c mice acutely rejected C57BL/10 islet allografts at a mean survival time (MST) of 13.8 ± 2.7 days (n=5). A 7-day dosing of 0.3 or 1.0 mg/kg KRP203 resulted in long-term islet allograft survival (>200 days) in 1 out of 5 and 2 out of 7, respectively. A 3 mg/kg KRP203 dose led to long-term graft survival (>200 days) in 7 out of 12 recipients. While recipients that received 500 allogeneic islets admixed with 5-7 x 105 Tregs survived 83.6 ± 67.2 days, addition of transient 3 mg/kg KRP203 therapy induced long-term drug-free graft acceptance of islet allografts (>200 days) in all recipients. This effect was dependent on Tregs, as local delivery of CD4+CD25 cells failed to produce a similar effect (32 ± 4.6 days; n=3). The tolerance effect was alloantigen specific, as adoptive transfer of splenocytes from long-term KRP203/Treg-treated hosts to Balb/cSCID mice protected donor-type C57BL/6 islets (>100 days; n=3) but not third-party C3H (14 ± 4 days; n=2) islet allografts. In vitro splenocyte cultures with 100 ng/ml KRP203 and anti-CD3 mAb for 3 days followed by 3 days with 10 IU IL-2 enhanced Tregs (from 12% to 40%), suggesting that KRP203 promotes Tregs.
Conclusions: Local delivery of intra-graft Tregs combined with a brief treatment with KRP203 induced donor-specific tolerance to islet allografts. In addition, KRP203 alone significantly prolonged islet allograft survival and enhanced the Treg population.
To cite this abstract in AMA style:Baum C, Khattar M, Deng R, Kahan B, Schroder P, Phan T, Rutzky L, Stepkowski S. Locally-Delivered CD4+CD25highFoxp3+ Regulatory T Cells Combined with Systemic KRP203 Therapy Induces Tolerance to Islet Allografts [abstract]. Am J Transplant. 2013; 13 (suppl 5). http://atcmeetingabstracts.com/abstract/locally-delivered-cd4cd25highfoxp3-regulatory-t-cells-combined-with-systemic-krp203-therapy-induces-tolerance-to-islet-allografts/. Accessed September 23, 2017.
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