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354 Part V: Therapeutic Principles Chapter 23: Hematopoietic Cell Transplantation 355

appeared favorable compared to historical controls. Cotransplantation SOURCES OF HEMATOPOIETIC CELLS
34
of antigen-specific mature T cells is being investigated as an approach to
address the T-cell–specific immunodeficiency seen in patients receiving In humans, HSCs for transplantation can be collected from several
purified HSC autografts. 35 sources, including directly from the marrow; from the blood after
mobilization; and from umbilical cord blood (UCB) obtained at the
time of delivery.
TRAFFICKING AND HOMING OF
HEMATOPOIETIC STEM CELLS MARROW

The ability of HSCs to migrate from marrow to blood and back has been Marrow has historically been the traditional source of HSCs for allo-
conserved throughout evolution. Although the biologic role and phys- geneic and autologous transplantation. Marrow for transplantation is
iologic significance of constitutive HSC circulation remains unclear, typically aspirated by repeated placement of large-bore needles into
this capacity to traffic leads to hematopoietic cell reconstitution and is both sides of the posterior iliac crest, generally involving 50 to 100 aspi-
essential for the success of HCT in the treatment of hematologic and rations per side, with the patient under regional or general anesthesia.
nonhematologic diseases. The lowest cell dose which ensures stable long-term engraftment has
The restoration of adequate hematopoiesis after transplantation not been defined with certainty; typical collections contain at least 2 ×
8
requires a series of balanced interactions between the infused HSCs and 10 total nucleated marrow cells per kg of recipient body weight. Cur-
the complex supporting marrow microenvironment (Chap. 5). Initially, rent guidelines indicate that collection of up to 20 mL/kg of donor body
infused HSCs must adhere to the marrow endothelium with sufficient weight is considered safe.
strength to overcome the shear forces of blood flow. Adhesion and Marrow harvesting is considered a very safe procedure, and
36
arrest of HSCs are mediated primarily by the selectin ligand P-selectin serious side effects are rare. A review of almost 10,000 healthy adult
glycoprotein ligand-1 (PSGL-1) and by the hematopoietic cell L- and volunteer unrelated donors by the National Marrow Donor Program
E-selectin ligands, which interact principally with endothelial E-selectin. 37,38 (NMDP) found that the risk of serious adverse events was 2.38 percent,
Other HSC surface adhesion molecules that mediate adherence to the most of which were mechanical or anesthesia-related and self-limited.
marrow endothelium include members of the integrin superfamily, Unexpected, life-threatening, or chronic complications occurred in
53
principally very late antigen-4, integrin α4β7 and lymphocyte function 0.99 percent of donors. Evaluation of pediatric marrow donor safety
antigen-1, that interact with endothelial immunoglobulin (Ig) super- is more limited, but a safety review of 453 pediatric donors by the Euro-
family receptors (e.g., vascular cell adhesion molecule [VCAM]-1), and pean Group for Blood & Marrow Transplantation (EBMT) found no
the hyaluronate receptor CD44. 39,40 HSCs that are null for the β integrins serious adverse events; pain was the most common complaint but lasted
54
cannot migrate to their marrow niche even though they proliferate and a median of only 1 day after donation. A survey of pediatric transplan-
41
differentiate in the fetal liver. Following firm adherence, the transen- tation hematologists confirmed that 90 percent of centers were willing
dothelial movement and intraparenchymal homing to hematopoietic to perform a marrow harvest on children, even on those younger than
niches within the inner endosteal surface of the bone are predominantly 6 months old. 55
regulated by a gradient of extracellular-matrix-bound stromal cell–derived
factor-1 (also known as CXCL12). Mice deficient in CXCR4 develop fetal
12
liver hematopoiesis but die prenatally as a consequence of the lack of mar- BLOOD
42
row hematopoiesis. The requirement for CXCR4 expression on HSCs for HSCs are normally present in the blood at very low levels. However,
homing and engraftment is well-documented, and has led to the devel- a number of different stimuli, including chemotherapy, hematopoi-
43
opment of CXCR4 antagonists such as plerixafor, which help mobilize etic growth factors, and inhibitors of certain chemokine receptors,
marrow stem cells for clinical use. 44 result in the mobilization of HSC from marrow to blood. Once mobi-
Following successful homing, the initial adhesion of HSC within lized, HSC can be collected by apheresis; this product has been termed
the hematopoietic niche appears to be regulated at least in part by “peripheral blood progenitor cells (PBPCs)” to differentiate it from
annexin II. The marrow niche is a complex biologic unit that includes “blood stem cells,” a term that should be reserved for instances where
45
potentially self-renewing mesenchymal stromal cells (MSCs), regula- the HSC population itself has been isolated. Agents used to mobilize
tory T cells (T ), and cells with the defined phenotype of parathyroid- HSCs include G-CSF, granulocyte-monocyte colony-stimulating factor
reg
hormone-receptor-bearing osteoblasts. 46,47 MSCs promote engraftment (GM-CSF), interleukin (IL)-3, thrombopoietin, and the CXCR4 antag-
48
when cotransplanted with HSCs. Osteoblasts, possibly in conjunction onist plerixafor. 44,56,57
with sinusoidal endothelial cells, also appear to play a pivotal role in the Autologous PBPCs are most commonly mobilized with G-CSF,
regulation of HSC engraftment by producing a number of molecules, with or without additional chemotherapy. In contrast, PBPCs for allo-
such as annexin II, VCAM-1, intercellular adhesion molecule-1, CD44, geneic HCT are typically mobilized with G-CSF alone, so as to avoid
CD164, and osteopontin, which promote engraftment. 49,50 Stimulation of exposing healthy donors to chemotherapy. PBPC mobilization and
osteoblasts with parathyroid hormone results in expansion and mobili- collection is very safe; a review of nearly 7000 healthy unrelated PBPC
51
zation of the HSC pool in animals, although a clinical trial in human donors performed by the NMDP found that the rate of serious adverse
52
cord-blood recipients did not demonstrate a benefit. In addition to events was 0.56 percent, making PBPC donation significantly safer than
the regulators of HSC adhesion and homing, the function of HSCs is marrow donation. The most common side effect of PBPC mobilization
53
further regulated by intrinsic genetic programs for quiescence, self-re- and collection is bone pain as a result of G-CSF administration. More
newal, proliferation, differentiation, and apoptosis that are dependent serious side effects, such as splenic rupture or intracranial hemorrhage,
on communication with a network of interacting cells in the marrow have been described in case reports but are extremely rare. 58,59
microenvironment, including various T-cell subpopulations, adipocytes, Theoretical concern exists about the potential of short-term
and fibroblasts. Given the complexity of HSC trafficking and control, it growth factor therapy to increase the risk of leukemia in normal donors.
is surprising that clinical HCT has a relatively low rate of graft failure. However, long-term followup of healthy adult PBPC donors has shown

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