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It is generally assumed that IFNγ plays a central role in acute allograft rejection. To test this hypothesis, we transplanted fully allogeneic (MHC class I and II incompatible) C3H/HeJ (H2k) murine hearts to IFNγ-/- (IFNγ gene-knockout) and IFNγ+/+ BALB/c (H2d) mice. The phenotype of IFNγ-/- mice was confirmed by demonstrating absent IFNγ protein production by Con A stimulated IFNγ-/- splenocytes. Both IFNγ-/- and IFNγ+/+ strains rejected transplanted hearts acutely: graft survival (mean ± SD) was 5.2±0.4 and 6.0±0.0 days, respectively. Histologic examination revealed similar patterns of acute cellular rejection in both mouse groups. IFNγ mRNA was present in hearts rejected by IFNγ+/+ mice but was absent in those rejected by IFNγ-/- mice. IL-2, IL-4, IL-10, and TNFα mRNA expression, on the other hand, was similar in grafts rejected by either strain. We also observed that hapten-induced delayed-type hypersensitivity(DTH) response was significantly reduced but not absent in IFNγ-/- mice. Our results demonstrate that IFNγ is not required for acute cellular rejection of fully allogeneic murine hearts. We propose that non-DTH mechanisms of allograft destruction could be enhanced in the absence of IFNγ and thus lead to robust acute rejection.