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Primary immune deficiencies (PIDs) comprise more than 250 distinct disorders that affect the immune system’s development, function, and/or homeostasis. Inability to control infections represents a major challenge in several forms of PID, leading to increased incidences of mortality early in life. Furthermore, immune dysregulation, defined as disorders of immune homeostasis presenting with autoimmunity or inflammatory disease, is increasingly being recognized as an important manifestation of various forms of PID and may also affect quality and duration of life. In the majority of cases, PIDs result from genetic defects that are intrinsic to the hematopoietic system. When associated with a poor prognosis, such forms of PID can be treated and cured with allogeneic hematopoietic stem cell transplantation (HCT). However, despite continuous advances in donor selection, development of less toxic chemotherapy preparatory regimens, supportive care, and prevention of transplant-related complications, mortality and late effects continue to affect the outcomes of patients with PIDs treated with HCT. In this chapter, we will review the current status of HCT for PIDs and discuss possible developments in the field.



Stem Cell Sources, Donor Type, and Cell Manipulation

Transplantable hematopoietic stem cells (HSCs) can be retrieved from bone marrow, peripheral blood, or umbilical cord blood (UCB). Bone marrow HSCs are obtained by aspiration along the iliac crests, with the patient under general anesthesia. If the donor and the recipient are mismatched for AB0 blood type, red blood cell depletion of the bone marrow product must be performed prior to intravenous infusion through a central line. Otherwise, no further manipulation is required when the donor and the recipient are matched for human leukocyte antigen (HLA). By contrast, in the case of donor/recipient HLA mismatching (such as when one of the parents serves as a donor), the bone marrow is typically manipulated by depleting ex vivo the mature T cells contained in the graft (which would otherwise cause severe graft-versus-host disease [GVHD]) or by positive selection of CD34+ HSCs. Modern methods of T-cell depletion include use of monoclonal antibodies (mAb) directed against the αβ form of the T-cell receptor (TCRαβ). Often, in addition to TCRαβ T-cell depletion, B cells are depleted from the graft using anti-CD19 mAb. B-cell depletion decreases the risk of development of Epstein-Barr virus (EBV) lymphoproliferative disease after transplantation. As an alternative to ex vivo T-cell depletion, posttransplant administration of cyclophosphamide has been used recently to achieve selective depletion of alloreactive T cells in vivo following T-replete haploidentical HCT.

HSCs can be also obtained from peripheral blood by apheresis upon in vivo treatment of the donor with granulocyte-colony stimulating factor (G-CSF) and/or plerixafor, an antagonist of the chemokine receptor CXCR4, which serves as a retention signal for HSCs in the bone marrow niche.

Finally, UCB is relatively rich in HSCs. Approximately 75 mL of UCB can ...

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