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.
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.
Benda
B
B
Department of Oncology, Radiology, and Clinical Immunology, Uppsala University, Sweden.
Lycke
N
N
Holstad
M
M
Korsgren
O
O
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology; D016207:Cytokines / Q000276:immunology*; D005260:Female; D016332:Fetal Tissue Transplantation / Q000276:immunology / Q000473:pathology; D006084:Graft Rejection / Q000276:immunology*; D006968:Hypersensitivity, Delayed / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000276:immunology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology*; D000096743:Interferon gamma Receptor
D000225:Adenine; D016572:Cyclosporine; D016207:Cytokines; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D017471:Receptors, Interferon; D014409:Tumor Necrosis Factor-alpha; D000096743:Interferon gamma Receptor; C082151:3-(6-amino-9H-purin-9-yl)-cyclopentanol