TRANSPLANTATION OF HEMATOPOIETIC STEM-CELLS IN-UTERO

Hematopoietic stem cell (HSC) transplantation in children and adults w ith congenital lymphohematopoietic disorders is limited by donor avail ability, graft failure, graft-versus-host disease (GVHD) and delayed i mmunological reconstitution, These problems may be circumvented by tra nsplanting the patient before birth. Prenatal cellular therapy for the treatment of congenital diseases has tremendous theoretical appeal. P otential advantages of prenatal transplantation include: A) fetal immu nologic immaturity and the potential for induction of donor-specific t olerance; B) available space in the developing bone marrow for engraft ment of donor cells; C) the sterile, protective, fetal environment whi ch provides isolation from environmental pathogens, and D) prevention of clinical manifestations of the disease. Normal hematopoietic and im munologic development during ontogeny creates a ''window of opportunit y'' during which events favor the engraftment of transplanted allogene ic (and xenogeneic) HSC and their proliferation, This is a period in w hich the fetus is immunologically naive and thus incapable of rejectin g the foreign HSC, and the expanding bone marrow spaces allow homing a nd engraftment of HSC without the need for myeloablation. Experiments in sheep have established the optimal age of the recipient, route of d onor cell administration, sources of HSC, and other parameters necessa ry for the successful engraftment and long-term expression of donor HS C, In preclinical studies, transplantation of CD34-enriched or highly purified populations of human adult bone marrow cells in utero resulte d in the long-term engraftment and expression of donor HSC without gra ft failure and GVHD, The strategies developed in allogeneic and xenoge neic fetal sheep models were used to successfully treat human fetuses with X-linked recessive severe combined immunodeficiency.