Delayed type hypersensitivity-associated cytokines in islet xenotransplantation: limited efficacy of interleukin-2- and tumor necrosis factor-alpha-blockade in interferon-gamma receptor-deficient mice.

Abstract

To investigate the role of interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha and their potential to replace each other in the process of fetal porcine islet-like cell cluster (ICC) xenograft rejection, mice with a targeted disruption of the IFN-gamma receptor gene and wild-type controls were transplanted with fetal porcine ICCs under the kidney capsule and given post-transplant treatment with the TNF-alpha-inhibiting agent MDL 201,449A. Some of the MDL 201,449A-treated IFN-gamma receptor-deficient mice received additional treatment with cyclosporinee (CsA). Evaluation of the xenografts was performed 7 days after transplantation (all groups), and in IFN-gamma receptor-deficient mice treated with MDL 201 449 A, also 10 and 13 days after transplantation. On day 7 after transplantation, a few CD3+ cells were seen accumulated peripherally in the ICC xenograft. Moderate to abundant numbers of F4/80+ and Mac-1+ cells surrounded a few remaining ICCs present within the xenograft. Histochemical visualization of cyanide-resistant endogenous peroxidase activity for detection of eosinophils demonstrated only small numbers of eosinophils present within the xenograft by day 7 after transplantation. An increased amount of eosinophilic granulocytes was not found until day 10 after transplantation, i.e. at a time when ICC xenograft rejection has already been completed. However, two out of six IFN-gamma receptor-deficient mice given post-transplant treatment with CsA and MDL 201,449A exhibited intact ICC xenografts with ICCs arranged in chords and duct-like structures on day 7 after transplantation. Taken together, findings in this study indicate that, in the pig-to-mouse model, IFN-gamma, TNF-alpha, and interleukin-2 seem to be of importance to fetal porcine ICC xenograft rejection. Nevertheless, in a majority of animals, other cytokines eventually substitute for the lack of IFN-gamma, TNF-alpha and interleukin-2.

• Authors: B Benda, N Lycke, M Holstad, O Korsgren
• Journal: Xenotransplantation (Xenotransplantation) Vol. 7 Issue 3 Pg. 206-13 (Aug 2000) ISSN: 0908-665X [Print] Denmark
• PMID: 11021666 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-(6-amino-9H-purin-9-yl)-cyclopentanol
• Cytokines
• Immunosuppressive Agents
• Interleukin-2
• Receptors, Interferon
• Tumor Necrosis Factor-alpha
• interferon gamma receptor
• Cyclosporine
• Adenine

Topics

• Adenine (analogs & derivatives, pharmacology)
• Animals
• Cyclosporine (pharmacology)
• Cytokines (immunology)
• Female
• Fetal Tissue Transplantation (immunology, pathology)
• Graft Rejection (immunology)
• Hypersensitivity, Delayed (immunology)
• Immunosuppressive Agents (pharmacology)
• Interleukin-2 (antagonists & inhibitors, immunology)
• Islets of Langerhans Transplantation (immunology, pathology)
• Lymphocytes (immunology, pathology)
• Mice
• Mice, Inbred Strains
• Mice, Knockout
• Receptors, Interferon (deficiency, genetics, immunology)
• Swine
• Transplantation, Heterologous (immunology, pathology)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, immunology)