Interleukin-2 and interferon-γ double knockout mice reject heterotopic cardiac allografts

Background. Several studies suggest that MHC-mismatched allografts reject with a Th1 or Th2 immune response, but these models all have low-level expression of the Th1 cytokines interleukin (IL)-2 and interferon-γ (IFN-γ). Methods. We interbred mice with single targeted gene disruptions for IL-2 and IFN-γ to establish IL-2 + IFN-γ double knockout (DKO) mice. Heterotopic cardiac allografts from DBA/2j (H2(d)) donors were transplanted WT, IL-2 knockout (KO), IFN-γ KO, and DKO recipients (C57BL/6x129; H2^b). Cytokine transcripts from allografts and DKO splenocytes were analyzed by reverse transcription polymerase chain reaction. Results. DKO mice had a cytokine profile and IgG1/IgG2a isotype ratio characteristic of Th2 deviation. DKO recipients rejected heterotopic cardiac allografts faster than IL-2 KO mice, but significantly slower than WT and IFN-γ KO mice (P<0.01). Analysis of the rejecting DKO recipients showed intragraft Th2 cytokine expression. Conclusion. The combined absence of IL-2 and IFN-γ in the setting of Th2 deviation does not prevent allograft rejection.