IFN-γ Prevents Early Perforin-Granzyme-Mediated Destruction of Kidney Allografts by Inducing Donor Class I Products in the Kidney |
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Authors: | B. Sis K. S. Famulski K. L. Allanach L.-F. Zhu P. F. Halloran |
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Affiliation: | Department of Medicine, Division of Nephrology &Transplantation Immunology;, Department of Surgery;, Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada |
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Abstract: | Interferon-γ (Ifng) protects organ allografts: mouse kidney allografts lacking Ifng receptors rapidly fail with massive ischemic necrosis around days 5 to 7, reflecting microcirculation failure. We hypothesized that Ifng protects the graft by preventing perforin-granzyme-mediated cytotoxic damage to the microcirculation by inducing class Ia and/or Ib products. We transplanted kidney allografts lacking Ifng receptors into various knockout hosts. The necrosis/congestion phenotype did not require host B cells or IL-4 and IL-13 receptors, but required the T-cell alloresponse: it did not occur if the hosts were syngeneic or T-cell deficient. However, host perforin-granzyme mechanisms were required: no necrosis developed if hosts lacked either perforin or granzymes A and B. The ability of Ifng to protect the allograft required donor class I products: allografts lacking class I products due to Tap1 or β2 microglobulin deficiency developed a similar necrosis-congestion phenotype at day 7 despite Ifng receptors being present. Thus when host cytotoxic T cells infiltrate organ allografts, Ifng prevents their perforin-granzyme mechanism from compromising the microcirculation by a mechanism requiring donor class Ia or Ib products. We propose that donor class Ia or Ib products are needed to trigger inhibitory receptors on effector T cells. |
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Keywords: | Arginase B cell cytotoxic T cell graft rejection granzyme IL-4 receptor inflammation kidney kidney transplantation knockout mice macrophages macrophage activation necrosis neutrophils perforin transplantation |
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