Long-term survival of hamster-to-rat cardiac xenografts in the absence of a Th2 shift.

Abstract

In hamster-to-rat cardiac xenografts, long-term survival (LTS) is obtained in 60% of recipients if vascular rejection is overcome by cobra venom factor and cyclosporine (CsA). It has been suggested that this accommodation state could be due to the Th2 response. We examined the infiltrate by using immunostaining and the accumulation of cytokine mRNA (interferon-gamma [IFN-gamma], interleukin [IL]-4, IL-10, IL-13, and transforming growth factor-betal [TGF-beta1]) by using competitive reverse transcriptase polymerase chain reaction, in hamster hearts grafted into LEW.1A rat. Hearts from untreated and treated (cobra venom factor and CsA) but rejecting recipients presented a rapid and severe vascular rejection. In contrast, hearts from long-surviving treated animals had subnormal cardiac muscle with a mild infiltrate, principally macrophages, which peaked on day 15. T lymphocytes were also maximal on day 15 (12% of the infiltrate). Rejected grafts from untreated recipients showed accumulation of IFN-gamma mRNA but low levels of IL-10, TGF-beta, and IL-13. In hearts rejected by treated recipients, IFN-gamma mRNA did not increase and TGF-beta mRNA was higher. In LTS, IL-10, TGF-beta, and IL-13 transcripts were up-regulated (P<0.001), while IFN-gamma mRNA decreased (P<0.001). In both groups, IL-4 expression remained at a nonsignificant level. The profile of cytokine mRNAs in LTS could result in part from CsA, known to up-regulate TGF-beta and to down-regulate IFN-gamma. Moreover, CsA does not inhibit IL-10 production by monocyte/macrophages, the major infiltrating cells (60%). Lastly, LTS is induced in the absence of IL-4, which suggests that the high IL-4 production could simply be correlated with LTS without being a condition for it.