Premium
IFN‐γ Prevents Early Perforin‐Granzyme‐Mediated Destruction of Kidney Allografts by Inducing Donor Class I Products in the Kidney
Author(s) -
Sis B.,
Famulski K. S.,
Allanach K. L.,
Zhu L.F.,
Halloran P. F.
Publication year - 2007
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/j.1600-6143.2007.01947.x
Subject(s) - granzyme b , perforin , cytotoxic t cell , granzyme , immunology , medicine , kidney , receptor , cancer research , immune system , biology , cd8 , biochemistry , in vitro
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.