Regulation of IFN-γ and IL-10 synthesis in vivo, as well as continuous antigen exposure, is associated with tolerance to murine skin allografts

C3H/HEJ mice are rendered hyporesponsive to multiple minor incompatible (B10.BR) skin allografts by pretreatment with irradiated B10.BR lymphoid cells injected via the portal vein, but not the lateral tail vein. As assessed by PCR with lymphocytes taken from grafted mice, or by measuring cytokines in vitro from antigen-restimulated cells, this hyporesponsiveness is associated with decreased mRNA for IFN-γ and IL-2 production, but enhanced mRNA for IL-4 and IL-10 production. In mice given B10.BR cells via the tail vein, but in addition injected every second day with anti-IFN-γ antibody, similar enhanced graft survival (with diminished IFN-γ/IL-2 and enhanced IL-4/IL-10 production) was seen. In a separate study spleen cells from pretreated mice were “parked” in lethally irradiated syngeneic mice for 21 days, along with B10.BR skin grafts to some of the recipients. Only when recipients received this reexposure to B10.BR antigen did adoptively transferred spleen cells show “persistence” of the ability to produce delayed graft rejection and preferential IL-4 production in vitro.