A New Murine Model of Islet Xenograft Rejection

• Published in: Diabetes (New York, N.Y.) Vol. 52; no. 5; pp. 1111 - 1118
• Main Authors: Schmidt, Peter, Krook, Henrik, Maeda, Akira, Korsgren, Olle, Benda, Birgitta
• Format: Journal Article
• Language: English
• Published: American Diabetes Association 01.05.2003
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.52.5.1111

A New Murine Model of Islet Xenograft Rejection Graft Destruction Is Dependent on a Major Histocompatibility–Specific Interaction Between T-Cells and Macrophages Peter Schmidt 1 , Henrik Krook 1 , Akira Maeda 2 , Olle Korsgren 1 and Birgitta Benda 1 1 Division of Clinical Immunology, Uppsala University, Uppsala, Sweden 2 Department of Transplantation Surgery, Karolinska Hospital, Huddinge, Sweden Abstract A new murine model of porcine islet-like cell cluster (ICC) xenograft rejection, avoiding interference of unspecific inflammation, was introduced and used to investigate rejection mechanisms. Athymic ( nu/nu ) mice were transplanted with syngeneic, allogeneic, or xenogeneic islets under the kidney capsule. After the original transplantation, immune cells in porcine ICC xenografts undergoing rejection in native immunocompetent mice were transferred to the peritoneal cavity of the athymic mice. At defined time points after transfer, the primary grafts were evaluated by immunohistochemistry and real-time quantitative RT-PCR to estimate cytokine and chemokine mRNA expression. Transfer of immunocompetent cells enabled athymic ( nu/nu ) mice to reject a previously tolerated ICC xenograft only when donor and recipient were matched for major histocompatibility complex (MHC). In contrast, allogeneic and syngeneic islets were not rejected. The ICC xenograft rejection was mediated by transferred T-cells. The main effector cells, macrophages, were shown to be part of a specific immune response. By day 4 after transplantation, there was an upreglation of both Th1- and Th2-associated cytokine transcripts. The transferred T-cells were xenospecific and required MHC compatibility to induce rejection. Interaction between the TCR of transferred T-cells and MHC on host endothelial cells and/or macrophages seems necessary for inducing ICC xenograft rejection. Footnotes Address correspondence and reprint requests to Peter Schmidt, Division of Clinical Immunology, Uppsala University, Rudbeck Laboratory CII, Dag Hammarskjölds väg 20, SE-75185 Uppsala, Sweden. E-mail: peter.schmidt{at}klinimm.uu.se . Received for publication 7 May 2002 and accepted in revised form 21 January 2003. DTH, delayed-type hypersensitivity; EC, endothelial cell; ICC, islet-like cell cluster; MCP, monocyte chemoattractant protein; MIP, macrophage inflammatory protein; MHC, major histocompatibility complex; RANTES, regulated upon activation in normal T-cells, expressed, probably secreted; TNF-α, tumor necrosis factor-α DIABETES