Wiskott-Aldrich syndrome X-linked hyper-IgM X-linked lymphoproliferative syndromes Cartilage hair hypoplasia Autoimmune lymphoproliferative syndrome (Fas defect) Severe congenital neutropenia Shwachman-Diamond syndrome Immune dysregulation, polyendocrinopathy, enteropathy, X-linked
The principle of HSCT is to replace a patient’s defective bone marrow stem cells with normal stem cells. Hematopoietic stem cells reside in the bone marrow but can also be obtained from peripheral blood or cord blood. Peripheral blood does not contain a significant proportion of stem cells unless the donor’s bone marrow is actively stimulated to generate stem cells. Cord blood is a good source of stem cells and is used for sibling and unrelated HSCT.
Major histocompatibility complex (MHC) compatibilityis crucial in the choice of a stem cell donor to avoid rejection of the donor cells by the host immune system and to prevent graft-versus-host disease (GVHD) caused by contaminating mature T cells. The donor stem cells give rise to T cells that develop in the host thymus and need to interact with donor and host antigen-presenting cells. In cases with MHC mismatched donors, mature T cells need to be removed from the donor to reduce the risk of GVHD; this complication outweighs the disadvantage of a prolonged time of 90 to 120 days before T-cell development. Patients are at risk for developing B-cell lymphoproliferative disease, usually associated with Epstein-Barr virus, when T-cell–depletion techniques are used, likely due to the delay in T-cell engraftment.
The most important factor affecting outcomes in HSCT is the similarity of the donor MHC. The best outcomes are obtained using MHC-identical siblings (25% chance of a matched sibling) as donors, followed by matched unrelated donors. Unlike transplantation for other disorders, MHC haploidentical bone marrow from a parent (preferred) or a sibling can be used to treat severe combined immunodeficiency (SCID), likely the result of these patients lacking functioning T cells. Stem cells from a partially mismatched donor, such as a parent, can give rise to a functioning immune system because the patient shares at least half of the MHC molecules with the donor stem cells.
MHC molecules are highly polymorphic, and typing is currently performed on DNA rather than by serology. Bone marrow and cord blood registries are available worldwide. Searching and identifying a donor can be a lengthy process, especially for some underrepresented ethnic backgrounds. Finding a suitable cord blood donor is faster because the cord blood already has been obtained and stored, whereas bone marrow donors have to be identified, located, and tested. A matched sibling, if available, is the preferred source of hematopoietic stem cells.
Patients with SCID are ideal candidates for HSCT, which is the only option for treatment of SCID at this time. Patients are unlikely to survive beyond 1 to 2 years of age without transplantation, and they have no T-cell function to reject donor cells. Thus they may not need to undergo conditioning with chemotherapy or irradiation before transplantation. The development of transplantation using T-cell–depleted, haploidentical bone marrow from a parent for SCID has provided almost every patient with SCID a potential donor. The mother is the preferred source for haploidentical bone marrow, if she is able to donate, because some transfer of maternal T cells can occur during pregnancy, and these maternal T cells can reject cells obtained from the father. The survival rate after HSCT for SCID is approximately 90% with MHC-identical and 60% with haploidentical bone marrow transplantation. Early transplant before the acquisition of infection improves outcomes. Because newborn screening for SCID is now possible, stem cell transplantation can occur as early as possible when the infants are healthy, providing the best opportunity for a cure.