On the feasibility of inducing tolerance in man: a study in the cynomolgus monkey

Our previous work on the in vitro generation of cytotoxic T lymphocytes from the blood of 15-22-week-old fetuses, and on the induction of immunological tolerane in both radiation chimeras and neonatal mice, using T lymphocyte-depleted allogeneic bone marrow cells, has led us to believe that it should be possible to establish red cell chimerism in human fetuses by the infusion of allogeneic adult bone marrow cells. The essential prerequisite appears to be the removal of immunocompetent T lymphocytes from the bone marrow transplant, for new T cells generated from donor stem cells become tolerant to the histocompatibility antigens of the host's thymus and cannot, therefore, cause graft-versus-host disease (GVHD). Such an approach could be used in the treatment of fetuses diagnosed at an early stage as suffering from life-threatening inherited blood disorders. The experiments described here were designed to test this hypothesis in a sub-human primate species, Macaca fascicularis. Twenty-two cynomolgus monkeys received infusions of haploidentical (paternal) bone marrow between days 51 and 95 of gestation. There was no evidence of chimerism in animals inoculated after day 75 from mating. Eight out of 14 fetuses inoculated before day 70 were late intra-uterine deaths, four were hydropic and in one, histological confirmation of GVHD was obtained, indicating that tolerance can be induced at this time, as GVHD can occur only if donor cells survive. The T cell-depletion technique used here did not appear to prevent GVHD.