An immunological approach to the treatment of inherited life-threatening bone marrow defects

The evidence that the human fetus at 15-22 weeks gestation is still immunoincompetent when judged by the generation of cytotoxic T cell responses is briefly reviewed. It suggests that it might be possible to induce immunological tolerance in the human fetus by the inoculation of allogeneic cells, thus offering a potential treatment for fetuses that have been shown to suffer from life-threatening inherited bone marrow disorders. Adult bone marrow or fetal liver thus transplanted could be expected to establish cellular chimerism and ameliorate the symptoms of the disease. Graft-versus-host disease (GVHD), brought about by mature lymphocytes present in adult bone marrow, poses the main threat. Rodent experiments have shown that GVHD can be avoided if T cell-depleted bone marrow is used in the induction of tolerance. This report summarises experiments in cynomolgus monkeys designed to test this approach rigorously by the inoculation of T-depleted paternal bone marrow cells into fetuses of different ages. Although it has become clear that tolerance can be induced there have been many in utero deaths, at least some of them from GVHD. Those fetuses that went to term were not chimeric. The possible reasons for these disappointing results are discussed.