Neonatal injection of semiallogeneic spleen cells induces a state of specific tolerance to the parental alloantigens, but also the development of an autoimmune syndrome known as host-versus-graft disease (HVGD). The autoimmune features are a consequence of the allogeneic cooperation between persisting alloreactive host T helper type 2 (TH2) cells and donor semiallogeneic B cells. It has been established that I-A alloantigens play a central role in the triggering of this HVGD. Here it was investigated if I-E antigens, which have shown functional differences, regarding autoimmunity and alloreactivity, with respect to I-A antigens, are also able to trigger this autoimmune syndrome. The injection of spleen cells from [B10.A(4R) x B10.A(2R)]F1 (I-E+) hybrid mice into newborn B10.A(4R) (I-E-) mice was accompanied by the establishment of chimerism and also by the development of a characteristic, but moderated, HVGD. The weak intensity of this HVGD is likely due to the moderation of the alloreactive responses induced against I-E molecules. Moreover, the marked increase in the levels of IgE and in the titers of anti-DNA IgG1 antibodies strongly suggest that alloreactive TH2 cells play also a main role in the autoimmune syndrome following tolerization to I-E antigens. Therefore, it is concluded that the I-E and I-A isotypes are functionally similar with respect to the allogeneic cellular interactions that account for the HVGD.