LONG-TERM SURVIVAL OF HAMSTER-TO-RAT CARDIAC XENOGRAFTS IN THE ABSENCE OF A TH2 SHIFT

Background. In hamster-to-rat cardiac xenografts, long-term survival ( LTS) is obtained in 60% of recipients if vascular rejection is overcom e by cobra venom factor and cyclosporine (CsA), It has been suggested that this accommodation state could be due to the Th2 response. Method s. We examined the infiltrate by using immunostaining and the accumula tion of cytokine mRNA (interferon-gamma [IFN-gamma], interleukin [IL]- 4, IL-10, IL-13, and transforming growth factor-beta 1 [TGF-beta 1]) b y using competitive reverse transcriptase polymerase chain reaction, i n hamster hearts grafted into LEW.1A rat. Results. Hearts from untreat ed and treated (cobra venom factor and CsA) but rejecting recipients p resented a rapid and severe vascular rejection. In contrast, hearts fr om long-surviving treated animals had subnormal cardiac muscle with a mild infiltrate, principally macrophages, which peaked on day 15, T ly mphocytes were also maximal on day 15 (12% of the infiltrate). Rejecte d grafts from untreated recipients showed accumulation of IFN-gamma mR NA 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-re gulated (P<0,001), while IFN-gamma mRNA decreased (P<0.001). In both g roups, 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 m ajor infiltrating cells (60%), Lastly, LTS is induced in the absence o f IL-4, which suggests that the high IL-4 production could simply be c orrelated with LTS without being a condition for it.