HEART-TRANSPLANTS IN INTERFERON-GAMMA, INTERLEUKIN-4, AND INTERLEUKIN-10 KNOCKOUT MICE - RECIPIENT ENVIRONMENT ALTERS GRAFT-REJECTION

To study the role of cytokines in long-term cardiac allografts we have used recipient mice with targeted gene deletions (-/-) in IFN-gamma, IL-4, or IL-10, In wild-type and IL-4 -/- recipients immunosuppressed with a 30-d course of anti-CD4 and anti-CD8, graft survival was > 87 d , This time was significantly reduced in IFN-gamma -/- (62 +/- 19 d, P < 0.05) and IL-10 -/- recipients (55 +/- 4 d, P < 0.0001). Histology showed mononuclear cell infiltration, patchy necrosis, fibrosis, and v ascular thickening in all groups, Intragraft transcript levels measure d by P-32-reverse transcriptase PCR showed different inflammatory patt erns, IFN-gamma -/- recipients had higher IL-2 transcripts and selecti ve alteration in macrophage activation that may have contributed to de creased graft survival. Decreased graft survival in IL-10 -/- recipien ts was associated with increases in iNOS and IFN-gamma-driven response s, Finally, in grafts from IL-4 -/- recipients, there were increases i n CD3 transcripts concurrent with TNF-alpha levels, This increase sugg ests that IL-4 may regulate T cell infiltration through TNF-alpha-medi ated inflammatory cell recruitment, Concurrent evaluation of these thr ee isolated cytokine deletions has shown that the recipient environmen t caused distinct graft modifications.