Using a murine skin allograft tolerance induction system that consists of intravenous injection of 1 x 10(8) allogeneic spleen cells followed by intraperitoneal (i.p.) injection of 200 mg/kg cyclophosphamide (CP) 2 days later, sensitivity to tolerance induction was examined across various histocompatibility (H) barriers. Although each group of class I, class II or multiminor H antigens was not by itself a prohibitively strong barrier, resistance to tolerance induction increased when the three types of barriers were combined in various ways. When the donor-recipient combinations were disparate at the entire spectrum of both H-2 plus non H-2 antigens (fully allogeneic), profound tolerance to skin allografts was not induced by this method in any of the combinations examined. Based on these results, induction of tolerance across fully allogeneic barriers was attempted in C57BL/10SnJ (B10; H-2b) mice against C3H/HeSnJ (C3H; H-2k) strain by addressing the 11 barriers as two separate challenges. B10 mice were first given B10.BR/SgSnJ (B10.BR; H-2k) spleen cells plus CP to make them tolerant to the H-2k component represented among C3H antigens, and then later were given C3H spleen cells plus CP to establish a tolerant state to the remainder of the disparate antigens of the C3H donors. After these two separate manipulations, C3H skin was accepted in the B10 mice, and normal hair growth was observed in the grafted C3H skin. By contrast, B10 mice given C3H spleen cells plus CP and then again another injection of C3H spleen cells plus CP were not rendered tolerant to C3H skin. In B10 mice, tolerance to C3H induced with B10.BR spleen cells plus CP and then C3H spleen cells plus CP was specific to C3H, and the tolerant B10 mice rejected third-party skin from DBA/2J (DBA; H-2d) strain in a normal fashion. In transfer experiments, the mechanism of tolerance was found to be based largely on reduction of the effector cells rather than on a mechanism involving active suppression. Assays for chimerism revealed that maintaining the tolerant state required persistence of cells of donor origin. These data indicate that in a primary immune response to a certain dose of allogeneic cells (tolerogen), the existence of a relatively large proportion of potentially reactive clones in the host may trigger proliferation of only a part of the population and some of the potentially reactive cells may differentiate rapidly without a prolonged period of proliferation.(ABSTRACT TRUNCATED AT 400 WORDS)