title: Novel sphingosine-1-phosphate receptor modulator KRP203 combined with locally delivered regulatory T cells induces permanent acceptance of pancreatic islet allografts.
abstract: BACKGROUND
  KRP203, a structural FTY720 analogue, has 5-fold greater selectivity for binding to sphingosine-1-phosphate receptor (S1PR) 1 (S1PR(1)) versus S1PR3 and 100-fold greater selectivity over S1PR(2) and S1PR(5). 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 CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) to induce islet allograft tolerance.
  
  
  METHODS
  BALB/c (H-2(d)) mice received transplants of fresh C57BL/10 (H-2(b)) 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 (9200 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 x 10(5) - 7 x 10(5) Tregssurvived 83.6 ± 67.2 days, addition of transient 3 mg/kg KRP203 therapy induced prolonged drug-free graft survival (9200 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.
authors.affiliation: Department of Medical Microbiology and Immunology, University of Toledo Medical College, Toledo, OH 43614, USA.
authors.forename: Mithun
authors.initials: M
authors.lastname: Khattar
authors.forename: Ronghai
authors.initials: R
authors.lastname: Deng
authors.forename: Barry D
authors.initials: BD
authors.lastname: Kahan
authors.forename: Paul M
authors.initials: PM
authors.lastname: Schroder
authors.forename: Tammy
authors.initials: T
authors.lastname: Phan
authors.forename: Lynne P
authors.initials: LP
authors.lastname: Rutzky
authors.forename: Stanislaw M
authors.initials: SM
authors.lastname: Stepkowski
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D016381:Islets of Langerhans Transplantation / Q000009:adverse effects / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D049349:Receptors, Lysosphingolipid / Q000187:drug effects* / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000637:transplantation*; D013997:Time Factors; D023001:Transplantation Tolerance / Q000187:drug effects
chemical_list: D015415:Biomarkers; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C508018:Il2ra protein, mouse; D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit; C501899:KRP-203; D049349:Receptors, Lysosphingolipid; C556330:S1pr1 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; D013438:Sulfhydryl Compounds; D049452:Green Fluorescent Proteins
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