FUNCTIONAL CLONAL DELETION VERSUS ACTIVE SUPPRESSION IN TRANSPLANTATION TOLERANCE INDUCED BY TOTAL-LYMPHOID IRRADIATION

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Abstract
Transplantation tolerance andstable chimerism were established in adult mice conditioned with a short course of total lymphoid irradiation (TLI) followed by infusion of 30 x 106 allogeneic bone marrow cells. Spleen cells of tolerant mice could not exert a proliferative or cytotoxic response against host-type cells in vitro and were unable to induce graft-vs.-host reaction in secondary host type recipients. The degree of suppression assessed by coculturing tolerant splenocytes in vitro in the 1-way mixed lymphocyte reaction was quite variable, and, in some cases, was not at all demonstrable, although tolerance was clearly maintained. Suppression, when apparent, could not be ascribed to T lymphocytes. Suppressor cells to binded soybean agglutinin and could be separated from the nonsuppressive cells by means of this lectin. Dissociation of the suppressive population (SBA+ cells) from that which is normally alloreactive (SBA-cells) resulted in a suppressor cell depleted fraction that was still unable to respond to host type cells but regained reactivity to unrelated cells. Limiting dilution analysis of chimeric splenocytes revealed markedly reduced frequencies of cytotoxic T lymphocyte precursors (CTL-P) directed against host-type cells, as compared with normal splenocytes reacting against the same target cells. This difference was accentuated when these cells were sensitized to host type target cells prior in limitingdilution cultures. In 1:1 mixing experiments of normal and chilmeric splenocytes, there was no in vitro suppressive activity to accound for hyporeactivity of chimeric cells against host-type cells. Thus, maintenance of TLI-induced seemed not to be mediated primarily through an active suppressor cell mechanism.