S-Space College of Medicine/School of Medicine (의과대학/대학원) Internal Medicine (내과학전공) Journal Papers (저널논문_내과학전공)
Roles of Toll-like Receptors on Islets in Xenogenic Islet Transplantation
- Ro, Han; Yang, Jaeseok; Lee, Eun W.; Han, Kyu H.; Yeom, Hye J.; Lee, Han K.; Hwang, Young-H.; Ahn, Curie; Oh, Kook-H.; Bang, Kitae; Kim, Hwa J.; Cho, Bumrae
- Issue Date
- WILEY-BLACKWELL PUBLISHING, INC
- XENOTRANSPLANTATION; Vol.16 5; 387-387
- Background: Stimulation of innate immunity through toll-like receptors
(TLRs) interfered with tolerance induction in allogeneic transplantation.
Recently, roles of TLRs have been reported in parenchymal cells such as
renal tubular epithelial cells beyond antigen presenting cells. Here, we tried
to elucidate the roles of TLRs on porcine islets in xenogeneic islet
Methods: After isolation, adult porcine islets were stimulated by poly I:C,
lipopolysaccharide (LPS) and CpG. Induction of cytokines and chemokines
in islets in response to TLR stimulation was assessed using RT-PCR and
ELISA. Transmigration assays were performed in order to measure the chemotactic activity of islet culture supernatant. Impacts of TLR stimulation
on both apoptosis and insulin secretion of islets were assessed using
Annexin-V/7-AAD staining and glucose-induced insulin stimulation test,
respectively. Procoagulant induction was also assessed using RT-PCR and
tissue factor assay. Porcine islets were transplanted to renal subcapsular
space of MyD88 knockout, TLR4 knockout and wild type C57BL6/J mice.
TLR agonists (LPS, Poly I:C) were injected together with anti-CD154
antibodies (MR-1) after pig to mouse islet transplantation.
Results: Porcine islets expressed TLRs at resting status. In vitro TLR
stimulation upregulated expression of both cytokines (IL-6, type I
interferon) and chemokines (MCP-1, RANTES, IP-10, IL-8). Islet culture
supernatant after stimulation by TLR agonists induced transmigration of
THP-1 and human peripheral blood mononuclear cells across the species
barrier. However, TLR stimulation influenced neither apoptosis nor insulin
secretion. Both expression and functional activity of tissue factor in islets
were increased by TLR stimulation. Poly I:C treatment decreased graft
survival in pig to wild type mouse islet transplantation. Moreover, LPS
interfered with long-term graft survival induced by MR-1 in pig to TLR4
knockout or MyD88 knockout mouse islet transplantation.
Conclusion: Stimulation of TLRs on porcine islets induced both proinflammatory
and procoagulant responses and thereby interfered with
long-term graft survival in xenogeneic islet transplantation.
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