Recent evidence indicates that MHC peptides play an important role in T-cell recognition of alloantigen. We studied the tolerogenicity of orally administered synthetic MHC allopeptides in the rat model. Initially, we demonstrated that oral administration of synthetic class II MHC allopeptides significantly inhibited the DTH response to the peptides as well as to donor-derived cells. The tolerogenic effect was antigen specific and was induced by immunogenic, but not by nonimmunogenic, allopeptides. Immunohistological studies of DTH skin lesions showed that oral tolerance is associated with a state of "immune deviation" to a predominance of Th2 cell function in the lesions. We recently extended the above observations and examined the tolerogenic effect of orally administered synthetic MHC allopeptides on MLR and CTL generation. We found that oral administration of the class II allopeptides effected significant reduction of MLR proliferation and CTL generation, which was antigen specific. In addition, similar to the DTH results when we compared the tolerogenicity of the immunogenic versus the nonimmunogenic peptides, MLR and CTL suppression was significantly higher with the immunogenic peptides. The gut immune system play an important role in oral tolerance by MHC peptides. Initial experiments showed that intestinal epithelial cells pulsed in vitro with immunogenic MHC allopeptides, or in vivo by oral administration of immunogenic peptides, were capable of presenting these peptides to primed T cells in vitro. Whether such presentation by intestinal epithelial cells or other gut antigen-presenting cells leads to preferential activation of Th2 regulatory cells, which ultimately suppress Th1 alloimmune responses, remains to be determined.