IFN-gamma prevents early perforin-granzyme-mediated destruction of kidney allografts by inducing donor class I products in the kidney.
Interferon-gamma (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 beta2 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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Department of Medicine, Division of Nephrology & Transplantation Immunology, University of Alberta, Edmonton, Alberta, Canada.
Famulski
K S
KS
Allanach
K L
KL
Zhu
L-F
LF
Halloran
P F
PF
D000818:Animals; D053804:Granzymes / Q000235:genetics*; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis*; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008819:Mice, Nude; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014184:Transplantation, Homologous / Q000276:immunology / Q000473:pathology
D015395:Histocompatibility Antigens Class I; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D007371:Interferon-gamma; D053804:Granzymes