DEVELOPMENT OF TOLERANCE AFTER HAPLOCOMPATIBLE T-DEPLETED BONE-MARROWTRANSPLANTATION

We evaluated proliferative responses in mixed lymphocyte cultures (MLC ) following bone marrow transplantation (BMT) in 14 recipients of T ce ll-depleted haplocompatible parental marrow: 11 for the treatment of s evere combined immunodeficiency (SCID), 2 for leukemia and 1 for Wisko tt-Aldrich syndrome (WAS). We compared the results obtained in 9 SCID patients and 1 WAS patient with split chimerism (T cells of donor orig in, B cells and monocytes of recipient origin) to 4 patients (2 SCID a nd 2 leukemias) who were full chimeras (T, B and monocytes of donor or igin). In the full chimeras, as with the fresh donor PBMC, fresh donor T cells did not proliferate in the MLC to recipient non-T cells (E-). In this group there were no differences (p > 0.2) between the respons es of engrafted T and fresh donor T to recipient E- cells. We found to lerance of engrafted donor T celts to residual mismatched T cell-deple ted (E-) recipient cells in the split chimera group. In this group the engrafted T cells had low or no responses in MLC to HLA mismatched E- host cells compared with fresh donor cells (p < 0.001). In 3 of 8 spl it chimera patients that we tested the addition of small numbers (5000 -10 000) of freshly isolated donor T cells, irradiated or not, resulte d in a two fold increase in the engrafted T cell response to recipient E- cells. In contrast, in 3 of 3 full chimeras tested, the addition o f fresh donor T cells had no demonstrable effect on the response of en grafted T cells to recipient E-. The proportion of T cell subsets in t he responding cell populations was similar to that seen in normal cont rol MLC. Finally, in one patient there was no evidence for a suppressi on mechanism of tolerance. These results are consistent with either de letion of a T cell subpopulation responsive to recipient alloantigens and/or an anergy model in which engrafted T cells do not respond to cl ass II MHC antigens because they fail to produce a necessary cytokine.