Document Detail


Novel sphingosine-1-phosphate receptor modulator KRP203 combined with locally delivered regulatory T cells induces permanent acceptance of pancreatic islet allografts.
MedLine Citation:
PMID:  23545505     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Mithun Khattar; Ronghai Deng; Barry D Kahan; Paul M Schroder; Tammy Phan; Lynne P Rutzky; Stanislaw M Stepkowski
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Transplantation     Volume:  95     ISSN:  1534-6080     ISO Abbreviation:  Transplantation     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-04-02     Completed Date:  2013-07-08     Revised Date:  2014-04-16    
Medline Journal Info:
Nlm Unique ID:  0132144     Medline TA:  Transplantation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  919-27     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adoptive Transfer*
Animals
Biological Markers / metabolism
Cells, Cultured
Combined Modality Therapy
Dose-Response Relationship, Drug
Forkhead Transcription Factors / genetics,  metabolism
Graft Rejection / immunology,  metabolism,  prevention & control*
Graft Survival / drug effects*
Green Fluorescent Proteins / genetics,  metabolism
Immunosuppressive Agents / pharmacology*
Interleukin-2 Receptor alpha Subunit / metabolism
Islets of Langerhans Transplantation / adverse effects,  immunology*
Mice
Mice, Inbred BALB C
Mice, Inbred C3H
Mice, Inbred C57BL
Mice, Transgenic
Receptors, Lysosphingolipid / drug effects*,  metabolism
Sulfhydryl Compounds / pharmacology*
T-Lymphocytes, Regulatory / immunology,  transplantation*
Time Factors
Transplantation Tolerance / drug effects
Grant Support
ID/Acronym/Agency:
HL69723/HL/NHLBI NIH HHS; R01 AI061052/AI/NIAID NIH HHS; R21 HL069723/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Biological Markers; 0/Forkhead Transcription Factors; 0/Foxp3 protein, mouse; 0/Il2ra protein, mouse; 0/Immunosuppressive Agents; 0/Interleukin-2 Receptor alpha Subunit; 0/KRP-203; 0/Receptors, Lysosphingolipid; 0/S1pr1 protein, mouse; 0/Sulfhydryl Compounds; 147336-22-9/Green Fluorescent Proteins
Comments/Corrections

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