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Delayed type hypersensitivity‐associated cytokines in islet xenotransplantation: limited efficacy of interleukin‐2‐ and tumor necrosis factor‐α‐blockade in interferon‐γ receptor‐deficient mice
Author(s) -
Benda Birgitta,
Lycke Nils,
Holstad Maria,
Korsgren Olle
Publication year - 2000
Publication title -
xenotransplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.052
H-Index - 61
eISSN - 1399-3089
pISSN - 0908-665X
DOI - 10.1034/j.1399-3089.2000.00055.x
Subject(s) - xenotransplantation , blockade , immunology , medicine , islet , tumor necrosis factor alpha , interferon , interleukin 2 , receptor , cytokine , transplantation , endocrinology , insulin
To investigate the role of interferon (IFN)‐γ and tumor necrosis factor (TNF)‐α 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‐γ receptor gene and wild‐type controls were transplanted with fetal porcine ICCs under the kidney capsule and given post‐transplant treatment with the TNF‐α‐inhibiting agent MDL 201,449A. Some of the MDL 201,449A‐treated IFN‐γ receptor‐deficient mice received additional treatment with cyclosporinee (CsA). Evaluation of the xenografts was performed 7 days after transplantation (all groups), and in IFN‐γ 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‐γ 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‐γ, TNF‐α, 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‐γ, TNF‐α and interleukin‐2.