Roles of islet Toll-like receptors in pig to mouse islet xenotransplantation.
Although innate immunity plays important roles in xenograft rejection, there have been few studies on the role of toll-like receptors (TLRs) in xenotransplantation. Furthermore, most studies focused on the recipient's TLRs. Therefore, we investigated whether TLRs in porcine islets can contribute to islet xenograft rejection. Adult porcine islets were isolated and stimulated by polyinosinic/polycytidylic acid (poly I:C) or lipopolysaccharide (LPS). Both poly I:C and LPS stimulation in porcine islets induced expression of chemokines (RANTES, MCP-1, IP-10, and IL-8), cytokines (IL-6 and type I interferons), and adhesion molecules (VCAM-1 and ICAM-1). Porcine islet supernatants stimulated by TLR agonists induced chemotaxis of human leukocytes. They also induced procoagulant activation (tissue factor and fgl-2). However, TLR stimulation did not influence insulin secretion. When porcine MyD88 was knocked down using shRNA lentivirus, TLR-mediated induction of proinflammatory mediators and procoagulants was attenuated. When LPS was injected to MyD88 or TLR4 knockout mice after porcine islet transplantation, LPS stimulation on donor islets interfered with islet xenograft tolerance induction by anti-CD154 antibodies. Inflammatory cell infiltration and expression of proinflammatory chemokines and cytokines in islet xenografts also increased. In conclusion, TLR activation in porcine islets induced both a proinflammatory and procoagulant response and thereby contributed to xenograft rejection.
Transplantation Center, Seoul National University Hospital, Seoul, Republic of Korea.
Han
H
Ro
Eun Won
EW
Lee
Joo Ho
JH
Hong
Kyu Hyun
KH
Han
Hye-Jung
HJ
Yeom
Hwa Jung
HJ
Kim
Myung-Gyu
MG
Kim
Hye Seung
HS
Jung
Kook-Hwan
KH
Oh
Kyong Soo
KS
Park
Curie
C
Ahn
Jaeseok
J
Yang
D000328:Adult; D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D016381:Islets of Langerhans Transplantation / Q000276:immunology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism; D013552:Swine; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D014183:Transplantation, Heterologous / Q000379:methods*
D016207:Cytokines; D007328:Insulin; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors