Mechanisms of tolerance of the Ia antigen disparate skin allografts.

Transplantation tolerance was induced in A.TL mice to donors having disparity in the Ia antigens and identity at the H-2K, H-2D and non-H-2 antigens. After neonatal injection of 12 X 10(6) semiallogeneic lymphoid cells, permanent survival of A.TH skin allografts was observed in more than 90% of the recipients. Adoptive transfer of 50 X 10(6) lymphoid cells from normal A.TL donors to tolerant mice resulted in rejection of the tolerated grafts only in half of the animals. When cells from tolerant mice were tested in MLC and GVH assays, they reacted positively as did cells from normal mice. After sensitization in vitro, cells from tolerant mice were cytotoxic to A.TH antigens. Serum from tolerant mice did not inhibit cell proliferation in MLC assay nor blocked cytotoxic reaction in vitro and also did not enhance survival of A.TH skin grafts in normal A.TL mice. When the enhancing effect of this serum was tested in the recipients treated with ALS, prolonged survival of allografts was observed. Attempts to prolong survival of A.TH skin allografts by transfer of spleen cells from tolerant donors failed in normal A.TL recipients, while they were successful in the recipients treated with ALS. Long-term tolerated A.TH allografts, when transferred to normal A.TL recipients, were rejected. The findings show that loss of antigenicity of the tolerated skin allografts is not the mechanism of tolerance in this model and that cells capable of recognizing antigens of the tolerated allografts and reacting against them are still present in tolerant animals. Tolerance of skin allografts disparate only in Ia antigens, as has been shown at least for the strain combination tested, is probably mediated by the positive serum and cell suppressor mechanisms that block in vivo the effector phase of allotransplantation reaction.