Activation of peripheral organs following explosive brain death may be caused by various interrelated events, including the effects of massive acute central injury, hypotension, and circulating factors. Almost complete suppression of these changes could be produced by biological agents. Such interventions, if reproducible in humans, could improve the quality of organs from "marginal" donors, broadening the criteria for donor acceptance.
We have hypothesized that T cell cytokines participate in the pathogenesis of graft arterial disease (GAD). This study tested the consequences of IFN-␥ deficiency on arterial and parenchymal pathology in murine cardiac allografts. Hearts from C-H-2 bm12 KhEg (bm12, H-2 bm12 ) were transplanted into C57/B6 (B6, H-2 b ), wild-type, or B6 IFN-␥ -deficient (GKO) recipients after immunosuppression by treatment with anti-CD4 and anti-CD8 mAbs. In wild-type recipients, myocardial rejection peaked at 4 wk, (grade 2.1 Ϯ 0.3 out of 4, mean Ϯ SEM, n ϭ 9), and by 8-12 wk evolved coronary arteriopathy. At 12 wk, the GAD score was 1.4 Ϯ 0.3, and the parenchymal rejection grade was 1.2 Ϯ 0.3 ( n ϭ 8). In GKO recipients of bm12 allografts, myocardial rejection persisted at 12 wk (grade 2.5 Ϯ 0.3, n ϭ 6), but no GAD developed (score: 0.0 Ϯ 0.0, n ϭ 6, P Ͻ 0.01 vs. wild-type). Mice treated with anti-IFN-␥ mAbs showed similar results. Isografts generally showed no arterial changes. In wild-type recipients, arterial and parenchymal cells showed increased MHC class II molecules, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 compared to normal or isografted hearts. The allografts in GKO recipients showed attenuated expression of these molecules ( n ϭ 6). Thus, development of GAD, but not parenchymal rejection, requires IFN-␥ . Reduced expression of MHC antigens and leukocyte adhesion molecules may contribute to the lack of coronary arteriopathy in hearts allografted into GKO mice. ( J. Clin. Invest. 1997. 100:550-557.)
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