Roles of Islet Toll-Like Receptors in Pig to Mouse Islet Xenotransplantation

• Published in: Cell transplantation Vol. 22; no. 9; pp. 1709 - 1722
• Main Authors: Ro, Han, Lee, Eun Won, Hong, Joo Ho, Han, Kyu Hyun, Yeom, Hye-Jung, Kim, Hwa Jung, Kim, Myung-Gyu, Jung, Hye Seung, Oh, Kook-Hwan, Park, Kyong Soo, Ahn, Curie, Yang, Jaeseok
• Format: Journal Article
• Language: English
• Published: Los Angeles, CA SAGE Publications 01.09.2013; SAGE Publishing
• Subjects: Adult; Animals; Cytokines - genetics; Cytokines - immunology; Cytokines - metabolism; Female; Humans; Insulin - metabolism; Insulin Secretion; Islets of Langerhans - metabolism; Islets of Langerhans Transplantation - immunology; Islets of Langerhans Transplantation - physiology; Male; Mice; Mice, Inbred C57BL; Myeloid Differentiation Factor 88 - immunology; Myeloid Differentiation Factor 88 - metabolism; Swine; Toll-Like Receptors - immunology; Toll-Like Receptors - metabolism; Toll-Like Receptors - physiology; Transplantation, Heterologous - methods; Rejection; Islet transplantation; Toll-like receptors (TLRs); Xenotransplantation
• ISSN: 0963-6897; 1555-3892
• DOI: 10.3727/096368912X657684

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.