Document Detail

Islet allograft rejection is independent of toll-like receptor signaling in mice.
MedLine Citation:
PMID:  19898202     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Islet transplantation is a promising therapy for type 1 diabetes; however, most islet grafts fail within 5 years. Innate immunity has been suggested to play a role in islet allograft rejection, potentially mediated by toll-like receptors (TLRs), a class of innate immune receptors. Lack of TLR4, in particular, has been reported to improve allograft survival. Therefore, we hypothesized that TLRs may be involved in islet allograft rejection, and that deletion of TLR4 may improve islet graft survival. METHODS: Islets were isolated from C57BL/10ScNJ (Tlr4(-/-)) and C57BL/10 (wild-type [WT]) animals and transplanted into Balb/cJ recipients with streptozotocin-induced diabetes. Blood glucose levels were used to determine graft viability and immunostaining to assess graft morphology and immune cell infiltration. The roles of the TLR4 adaptor molecules MyD88 and TLR adaptor molecule 1 (Ticam-1) were assessed using islets isolated from mice lacking MyD88 (MyD88(-/-)), Ticam-1 (Ticam-1(-/-)), or the combined double knockout (MyD88(-/-)/Ticam-1(-/-)). RESULTS: Contrary to our hypothesis, Tlr4(-/-) and WT islet allografts had similar failure rates; grafts failed at 23.2+/-1.2 and 24.5+/-1.5 days posttransplant, respectively (P=NS). Syngeneic grafts of Tlr4(-/-) and WT islets maintained normoglycemia for up to 10 weeks posttransplant, indicating that failure of Tlr4(-/-) islet allografts could not be attributed to an intrinsic defect in Tlr4(-/-) islets. Similarly, islet allotransplants from MyD88(-/-), Ticam-1(-/-), and MyD88(-/-)/Ticam-1(-/-) donors did not have improved allograft survival compared with WT controls. CONCLUSIONS: These findings indicate that islet allograft rejection in mice is independent of TLR4 and the TLR adaptor molecules MyD88 and Ticam-1, speaking against an essential role for TLR signaling in islet allograft rejection.
Meredith J H Hutton; Clara Westwell-Roper; Galina Soukhatcheva; Annette Plesner; Jan P Dutz; C Bruce Verchere
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Transplantation     Volume:  88     ISSN:  1534-6080     ISO Abbreviation:  Transplantation     Publication Date:  2009 Nov 
Date Detail:
Created Date:  2009-11-09     Completed Date:  2010-01-06     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0132144     Medline TA:  Transplantation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1075-80     Citation Subset:  IM    
Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia, Child and Family Research Institute, Vancouver, BC, Canada.
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MeSH Terms
Blood Glucose / metabolism
CD8-Positive T-Lymphocytes / immunology
DNA Primers
Diabetes Mellitus, Experimental / blood,  surgery*
Diabetes Mellitus, Type 1 / surgery
Immune Tolerance
Immunity, Innate
Islets of Langerhans Transplantation / immunology,  pathology*
Mice, Inbred BALB C
Mice, Inbred C57BL
RNA / genetics,  isolation & purification
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / physiology*
Toll-Like Receptors / genetics,  immunology,  physiology*
Transplantation, Homologous / pathology
Grant Support
MOP-64427//Canadian Institutes of Health Research
Reg. No./Substance:
0/Blood Glucose; 0/DNA Primers; 0/Toll-Like Receptors; 63231-63-0/RNA

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