Cord blood from unrelated donors appears to be an excellent source of stem cells for transplantation in patients with Hurler's syndrome. Sustained engraftment can be achieved without total-body irradiation. Cord-blood transplantation favorably altered the natural history of Hurler's syndrome and thus may be important to consider in young children with this form of the disease.
UCBT was performed in seven children with SCD and stroke (HLA match 4/6 n=5; 5/6 n=2). Four received myeloablative regimens (BU, CY, ATG plus FLU in one patient). One had primary graft failure, three had sustained engraftment, two with grade III-IV GVHD (one died, one developed chronic GVHD), one with stable mixed chimerism. Three patients treated with reduced-intensity regimens (FLU, BU or CY, ATG, TLI) failed to engraft; one engrafted after second UCBT (HU, TT, RXA, ALZ, TBI). Four patients (57%) developed viral infections. Engraftment, GVHD, and infection remain challenges.
Chemokines are critical for the movement of leukocytes. Chemotaxis is deficient in neonates, particularly those delivered prematurely, and this likely contributes to their increased vulnerability to sepsis. The concentrations of circulating chemokines in neonates have not been reported, nor is it known whether low chemokine concentrations contribute to their defective chemotaxis. We hypothesized that serum concentrations of chemokines 1) would be lower in preterm than term neonates, and 2) would be lower in preterm and term neonates than adults. Samples were obtained from preterm and term neonates with normal neutrophil and eosinophil counts, umbilical cord blood samples from pregnancies without clinical evidence of intra-amniotic infection, and healthy adult volunteers. The concentrations of epithelial neutrophil activating peptide-78, growth-related oncogene-␣, eotaxin, RANTES (regulated upon activation, normal T cell expressed and secreted), and macrophage inflammatory protein-1␣ were measured using specific ELISA. Serum concentrations from preterm infants were either similar to or higher than those measured in term neonates and adults. We conclude that the chemotactic defect observed in premature neonates is not the result of diminished circulating concentrations of any of the specific chemokines we measured. Neonatal sepsis is a life-threatening event affecting 3-5 neonates per 1000 live births (1). The susceptibility of neonates to serious bacterial and fungal infections is related, in part, to quantitative and qualitative neutrophil deficiencies (2). Neutrophil migration, or chemotaxis, involves the recruitment of neutrophils from the circulation, their adherence to vascular endothelial cells, and their migration through the vessel wall to the site of microbial invasion (3). Important elements in this process are the chemotactic cytokines collectively known as chemokines. These are members of a family of homologous proteins with molecular weights in the range of 8 -12 kD (4, 5).IL-8 is the most extensively studied chemokine in neonates (6), but no information exists regarding the circulating concentrations of other leukocyte-specific chemokines during the neonatal period. Because preliminary in vitro studies suggest that perturbations in the concentration of chemokines are, in part, responsible for deficiencies in leukocyte chemotaxis (7), we quantified the circulating concentrations of specific leukocyte chemokines in cord blood sera/plasma and in the sera/ plasma of uninfected preterm and term neonates. On the basis of the chemotactic deficiencies of neonates, we hypothesized that the serum concentrations of leukocyte chemokines would 1) be lower in preterm neonates than in term neonates and 2) be lower in term neonates than in adults. Using specific ELISA, we measured the concentrations of neutrophil-specific ␣-chemokines-ENA-78 and GRO-␣-as well as eosinophil-, basophil-, and monocyte-specific -chemokines-RANTES, eotaxin, and MIP-1␣. MATERIALS AND METHODS SubjectsPreterm (n ϭ 50) and term neonates (n...
Human milk contains proteins that survive digestion in the neonatal gastrointestinal tract. Our group and others have reported that granulocyte colony-stimulating factor (G-CSF), a hematopoietic cytokine that influences neutrophil proliferation and differentiation, is present in human milk. We also reported that specific receptors for G-CSF are expressed on the villous enterocytes of neonates. However, the physiologic role of milk-borne G-CSF is not known. Thus, we sought to evaluate the capacity of human milk to protect G-CSF against proteolytic degradation after exposure to gastric secretions obtained from preterm (PT) and term (T) neonates at pH concentrations of 3.2, 5.8, and 7.4. Specifically, we examined degradation of 1) endogenous G-CSF in PT (n = 15) and T (n = 15) human milk; 2) recombinant human G-CSF (rhG-CSF) added to a protein-free buffer (n = 10, 5 PT and 5 T); and 3) rhG-CSF added to human milk (n = 12, 6 PT and 6 T), various commercially prepared infant formulas (n = 15), and cow's milk (n = 5). Endogenous G-CSF and rhG-CSF added to human milk resisted degradation at 1 and 2 h. However, when rhG-CSF was added to commercial formulas, >95% was degraded at 1 and 2 h at each pH level. Similarly, approximately 60% of rhG-CSF added to cow's milk was degraded at I and 2 h. We conclude that 1) endogenous G-CSF and rhG-CSF added to human milk are protected from degradation after exposure to gastric secretions at physiologic pH levels, 2) rhG-CSF added to infant formulas is not protected from degradation, and 3) it is likely that the G-CSF present in human milk is biologically available to the neonate.
Delayed platelet engraftment is a major complication of umbilical cord blood (CB) transplantation. Megakaryocytes derived from CB in vitro are smaller than megakaryocytes derived from bone marrow (BM) or mobilized peripheral blood from adults. Small megakaryocyte size may contribute to delayed platelet engraftment. To test whether small size persists after transplantation, we measured megakaryocyte size, concentration, and maturational stage in BM biopsy specimens obtained after transplantation in archived BM samples from patients receiving CB (CB group, n = 10) versus mobilized peripheral blood or BM transplantation (BM group, n = 9). Megakaryocytes in the postengraftment BM samples were significantly smaller in the CB group than in the BM group (median diameter, 16.7 vs 22.0 microm). There were no significant differences in megakaryocyte concentration or maturational stage between the CB and BM groups. For the first time, we demonstrate that the attainment of adult size in CB-derived megakaryocytes is delayed after human CB transplantation.
Cord blood has become an important alternative unrelated donor allogeneic hematopoietic stem cell source. The NMDP has developed a comprehensive coordinated network of CB banks, search coordinating center and transplant programs with prospective collection of outcome data coordinated by the NMDP (now CIBMTR). Critical to CBT has been limited cell dose with resultant prolonged engraftment time. The NMDP cord blood inventory has both total nucleated cell count (TNC) and CD34+ quantification on the units, allowing a comparison of the relative utility of either measure in identifying units that would result in rapid engraftment. We report a retrospective review of the NMDP CBT experience, analyzing the impact of graft characteristics with engraftment and survival. Between 03/2000 and 03/2004, 12 NMDP banks (total inventory 31,976 units) released CB units to 144 patients at 44 NMDP transplant programs included in this analysis (median f/u 217 days, 26–1204 days). The median recipient age was 8.2 years (0.2–63.1 years, 38 were ≥ 15 years) and median weight was 27 kg (3–158 kg: 26% > 57 kg). Transplant indications included malignancy in 113 (ALL 36, AML 43, MDS 13, other 21), metabolic disorders (8) immune disorders (9) histiocytic disorders (3), erythrocytic abnormalities (6), platelet abnormality (1), SAA (3) and other nonmalignant disease (1). Most malignancy patients had advanced disease (60 patients (53%) were beyond CR2 or in relapse). The median prefreeze TNC was 4.4 x 107/kg (0.3–433 x 107/kg) and CD34+ cells 7.9 x 105/kg (1.1–68.5 x 105/kg) in units selected for transplantation. Thus the median CB TNC was 142 x 107 cells (54–396 x 107 cells); only 12 units under 80 x 107 cells were used. 114 patients engrafted by day +42 post CBT with median time to neutrophil recovery > 500/mm3 of 21 days (8–62 days) and platelet count > 20,000 x 109/L of 64 days (12–473) respectively. 1-year survival and DFS were 39% ± 9% and 38% ± 9% respectively. Relapse rate was 16% ± 8% in this high risk population. The 100-day TRM rate was 26% ± 7%. For patients > 15 yrs, TRM was 42% ± 16% vs. 21% ± 8% for patients < 15 years. Higher cell dose was associated with faster neutrophil and platelet engraftment. Units with both high TNC/kg and high CD34+/kg were associated with more rapid engraftment vs. those with only high TNC or high CD34+ or neither (p<0.0001). In multivariate analysis, recipient age > 15 years led to poorer survival (RR 3.4 (1.7, 6.7)) and DFS (RR 2.8 (1.5, 5.2)) compared to younger children, especially those < 3 years (p<0.0001). Male grafts into females yielded poorer survival than other gender combinations. These data confirm that CB is a valuable alternative unrelated donor histocompatible stem cell source. Since transplantation using CB units containing both high TNC and CD34+ content resulted in more rapid engraftment, optimal CB inventory should strive for both high cell count (> 80 x 107 cells) and high CD34+ cell content.
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