CYTOKINE MESSENGER-RNA PROFILES IN MOUSE ORTHOTOPIC LIVER-TRANSPLANTATION - GRAFT-REJECTION IS ASSOCIATED WITH AUGMENTED TH1 FUNCTION

Although mouse liver allografts are spontaneously accepted without imm unosuppression in many strain combinations, rejection can be induced b y presensitization with a donor skin graft two weeks prior to transpla ntation. In this study, the semiquantitative reverse transcription pol ymerase chain reaction (RT-PCR) was used to assess the involvement of T helper (TH) cell subsets in liver allograft acceptance by determinin g cytokine mRNA in the graft and spleen of recipients with (A) spontan eously accepting allografts (B) rejecting liver allografts after previ ous skin sensitization, and (C) syngeneic controls. Spontaneously acce pted liver allografts showed upregulation of TH1 (IL-2, IFN-gamma) and TH2 (IL-4, IL-10) intragraft cytokine mRNA, which peaked at day 6 and tapered off thereafter, when compared with levels in syngeneic grafts , but both IFN-gamma and IL-10 mRNA persisted up to day 30. This cytok ine mRNA profile correlated with the transient intragraft inflammation associated with spontaneously resolving rejection. Presensitized reci pients that rejected their grafts revealed marked upregulation of TH1 (IL-2 and IFN-gamma) and TH2 (IL-4, IL-6) intragraft cytokine mRNAs co mpared with spontaneously accepting recipients, although IL-10 mRNA le vels showed no differences between the two groups, The most striking d ifference was seen in IFN-gamma levels, which correlated well with the preferential deposition of IgG2a antibody isotype in the rejecting co mpared with the spontaneously accepting liver allograft recipients, Th ese results suggested an association between liver allograft rejection and enhanced TH1 cytokine immune response. The ability to reject live r allografts by the adoptive transfer of splenocytes, but not serum, f rom a sensitized mouse ruled out preformed antibodies alone as a cause of rejection, However, spleen cytokine mRNA profiles showed no differ ences or trends in TH1 or TH2 expression in spontaneously accepting ve rsus rejecting recipients, which suggested that the spleen is not a ma jor site of alloreactive immune expansion. These data suggest that spo ntaneous acceptance of mouse liver allografts is associated with an in sufficient intragraft TH1 cytokine response, the cause of which is cur rently under investigation.