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J Am Soc Nephrol 13:1199-1209, 2002
© 2002 American Society of Nephrology

Transcription Factor IRF-1 in Kidney Transplants Mediates Resistance to Graft Necrosis during Rejection

Marjan Afrouzian*, Vido Ramassar*, Joan Urmson*, Lin-Fu Zhu{dagger} and Philip F. Halloran*

*Department of Medicine, Division of Nephrology and Immunology, and {dagger}Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.

Correspondence to: Dr. Philip F. Halloran, Director, Division of Nephrology & Immunology, University of Alberta, 250 Heritage Medical Research Centre, Edmonton, Alberta T6G 2S2, Canada. Phone: 780-407-8880; Fax: 780-407-3417; E-mail: phil.halloran{at}ualberta.ca

ABSTRACT. In many circumstances kidney transplants remain viable despite extensive inflammation, permitting rejection episodes to be reversed. The mechanisms by which the kidney resists host effector mechanisms are not known. In mouse kidney transplants, resistance requires interferon-{gamma} (IFN-{gamma}), which acts on the graft to protect the graft from necrosis during the first days of rejection as well as inducing major histocompatibility complex (MHC) expression. Because some effects of IFN-{gamma} are mediated by transcription factor IRF-1, the role of IRF-1 in the donor tissue early phases of rejection of mouse kidney allografts was studied. H-2b kidneys were transplanted from mice with wild-type IRF-1 genes (WT) or mice with disrupted IRF-1 genes (IRF-1KO) into CBA (H-2k) recipients. At day 5 and day 7, IRF-1KO and WT kidneys were functioning despite typical rejection pathology: interstitial infiltration and tubulitis. However, function deteriorated rapidly in rejecting IRF-1KO allografts, associated with widespread epithelial necrosis, peritubular capillary congestion, glomerulitis, and fibrin thrombi in small veins by day 7. At day 21, WT kidneys were viable despite severe tubulitis and arteritis, whereas IRF-1KO kidneys showed massive necrosis of the epithelium despite patent large vessels. Compared with WT kidneys, rejecting IRF-1KO kidneys showed less induction of donor MHC yet had similar mRNA levels of perforin, granzyme B, and Fas ligand and evoked host alloantibody responses. Thus in rejecting kidney transplants, IRF-1 in the graft mediates MHC induction, but it also mediates resistance to necrosis, an effect that could be crucial to permit success in interventions against rejection.






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