Principles and Clinical Indications of Hematopoietic Stem Cell Transplantation

Allogeneic (from a donor) or autologous (from the same individual) hematopoietic stem cells have been used to cure both malignant and nonmalignant disorders. Autologous transplantation is employed as a rescue strategy after delivering otherwise lethal doses of chemotherapy with or without radiotherapy in children with hematologic malignancies such as relapsed lymphoma or selected solid tumors (e.g., neuroblastoma, brain tumors). Allogeneic transplantation is used to treat children with genetic diseases of blood cells, such as hemoglobinopathies, primary immunodeficiency diseases, various inherited metabolic diseases, and bone marrow failure. Allogeneic transplant is also used as treatment for hematologic malignancies, such as leukemia and myelodysplastic syndromes. Bone marrow had represented the only source of hematopoietic progenitors employed. Growth factor (granulocyte colony-stimulating factor)–mobilized peripheral blood hematopoietic stem cells and umbilical cord blood hematopoietic progenitors have now also been regularly used in clinical practice to perform hematopoietic stem cell transplantation ( HSCT ).

An HLA-matched sibling was once the only type of donor employed. Currently, matched unrelated volunteers, full-haplotype mismatched family members, and unrelated cord blood donors have been largely employed to transplant patients lacking an HLA-identical relative.

Protocols for allogeneic HSCT consist of 2 parts: the preparative regimen and transplantation itself. During the preparative conditioning regimen , chemotherapy, at times associated with irradiation, is administered to destroy the patient's hematopoietic system and to suppress the immune system, especially T cells, so that graft rejection is prevented. In patients with malignancies, the preparative regimen also serves to significantly reduce the tumor burden. The patient then receives an intravenous infusion of hematopoietic cells from the donor. Less aggressive conditioning regimens, known as reduced-intensity conditioning regimens , are also used in pediatric patients. These regimens are mainly immunosuppressive and aim at inducing a state of reduced immune competence of the recipient to avoid the rejection of donor cells.

The immunology of HSCT is distinct from that of other types of transplant because, in addition to stem cells, the graft contains mature blood cells of donor origin, including T cells, B cells, natural killer cells, and dendritic cells. These cells repopulate the recipient's lymphohematopoietic system and give rise to a new immune system, which helps eliminate residual leukemia cells that survive the conditioning regimen. This effect is known as the graft-versus-leukemia (GVL) effect.

The donor immune system exerts its T-cell–mediated GVL effect through alloreactions directed against histocompatibility antigens displayed on recipient leukemia cells. Because some of these histocompatibility antigens are also displayed on tissues, however, unwanted T-cell–mediated alloreactions may ensue. Specifically, donor alloreactive cytotoxic CD8 ⁺ effector T cells may attack recipient tissues, particularly the skin, gastrointestinal (GI) tract, and liver, causing acute graft-versus-host disease (GVHD) , a condition of varying severity that in some cases can be life threatening or even fatal (see Chapter 163 ).

The success of allogeneic HSCT is undermined by diversity between donors and recipients in major and minor histocompatibility antigens. The human leukocyte antigens (HLA) , including HLA-A, HLA-B, and HLA-C major histocompatibility complex (MHC) class I molecules, present peptides to CD8 ⁺ T cells, whereas the HLA-DR, HLA-DQ, and HLA-DP MHC class II molecules present peptides to CD4 ⁺ T cells. There are 100s of variant forms of each class I and class II molecule, and even small differences can elicit alloreactive T-cell responses that mediate graft rejection and/or GVHD. Disparities for HLA-A, -B, -C, or -DRB1 alleles in the donor-recipient pair are independent risk factors for both acute and chronic GVHD. There is also increasing evidence that HLA-DQ and HLA-DP may play a role, prompting some transplant centers to also explore matching at these alleles.

Minor histocompatibility antigens derive from differences between the HLA-matched recipient and donor in peptides that are presented by the same HLA allotype. These antigens result from polymorphisms of non-HLA proteins, differences in the level of expression of proteins, or genetic differences between males and females. An example of the latter is represented by the H-Y antigens encoded by the Y chromosome, which can stimulate GVHD when a female donor is employed to transplant an HLA-identical male recipient. Thus, from this evidence, it is clear that GVHD may occur even when the donor and recipient are HLA identical.

The preferred donor for any patient undergoing HSCT is an HLA-identical sibling. Because polymorphic HLA genes are closely linked and usually constitute a single genetic locus , any pair of siblings has a 25% chance of being HLA identical . Thus, also in view of the limited family size in the developed countries, <25–30% of patients in need of an allograft can receive their transplant from an HLA-identical sibling. This percentage is even lower in patients with inherited disorders since affected siblings will not be considered donor candidates.