Novel sphingosine-1-phosphate receptor modulator KRP203 combined with locally delivered regulatory T cells induces permanent acceptance of pancreatic islet allografts.
Novel sphingosine-1-phosphate receptor modulator KRP203 combined with locally delivered regulatory T cells induces permanent acceptance of pancreatic islet allografts.
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DOI：
10.1097/tp.0b013e3182842396
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发表时间：
2013-04-15
期刊：
影响因子：
6.2
通讯作者：
Stepkowski SM
中科院分区：
文献类型：
--
作者：
Khattar M;Deng R;Kahan BD;Schroder PM;Phan T;Rutzky LP;Stepkowski SM
KRP 203是一种结构FTY 720类似物，与S1 PR 3相比，对鞘氨醇-1-磷酸受体1（S1 PR 1）的结合选择性高5倍，对S1 PR 2和S1 PR 5的选择性高100倍。虽然FTY 720的免疫调节作用已在临床和实验研究中得到验证，但KRP 203在同种异体移植模型中的治疗效果仍然难以捉摸。在这项研究中，我们研究了KRP 203单独和与移植物内注射CD 4 + CD 25 + FoxP 3+调节性T细胞（TCRs）联合诱导胰岛移植物耐受的潜力。Balb/c（H-2d）小鼠在肾包膜下接受新鲜C57 BL/10（H-2b）胰岛同种异体移植物的移植，并且用单独的0.3、1.0或3.0mg/kg KRP 203或与移植物内输注的THP组合处理7天。未处理的Balb/c小鼠急性排斥C57 BL/10胰岛同种异体移植物，平均存活时间（MST）为13.8 ± 2.7天（n=5）。0.3或1.0 mg/kg KRP 203的7天给药分别在5名接受者中的1名和7名接受者中的2名中产生长期胰岛移植物存活（>200天）。3 mg/kg KRP 203剂量导致12个受体中的5个中的胰岛移植物存活超过200天。虽然接受500个与5-7 × 105 TdR混合的同种异体胰岛的受体存活了83.6 ± 67.2天，但在所有受体中，加入短暂的3 mg/kg KRP 203治疗诱导了延长的无药物移植物存活（>200天）。用KRP 203的短暂治疗显著延长了胰岛同种异体移植物存活，而额外的移植物内递送TGFAP诱导了对胰岛同种异体抗原的选择性致耐受作用。
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 over S1PR2 and S1PR5. Although the immune regulatory 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 intra-graft injection of CD4+CD25+FoxP3+ regulatory T cells (Tregs) to induce islet allograft tolerance. 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-infused Tregs. 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 produced long-term islet allograft survival (>200 days) in 1 out of 5 and 2 out of 7 recipients, respectively. A 3 mg/kg KRP203 dose resulted in islet graft survival for greater than 200 days in 5 out of 12 recipients. While recipients that received 500 allogeneic islets admixed with 5–7 × 105 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. A brief treatment with KRP203 significantly prolonged islet allograft survival, while additional intragraft delivery of Tregs induced tolerogenic effects selective to islet allo-antigens.