Islet allograft rejection is independent of toll-like receptor signaling in mice.
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.
Hutton
Meredith J H
MJ
Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia, Child and Family Research Institute, Vancouver, BC, Canada.
Westwell-Roper
Clara
C
Soukhatcheva
Galina
G
Plesner
Annette
A
Dutz
Jan P
JP
Verchere
C Bruce
CB
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D017931:DNA Primers; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000601:surgery*; D003922:Diabetes Mellitus, Type 1 / Q000601:surgery; D007108:Immune Tolerance; D007113:Immunity, Innate; D016381:Islets of Langerhans Transplantation / Q000276:immunology / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D014184:Transplantation, Homologous / Q000473:pathology
D001786:Blood Glucose; D017931:DNA Primers; D051193:Toll-Like Receptors; D012313:RNA