Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.