Untying the Gordian knot: policies, practices, and ethical issues related to banking of umbilical cord blood.
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Since the first successful transplantation of umbilical cord blood in 1988, cord blood has become an important source of hematopoietic stem and progenitor cells for the treatment of blood and genetic disorders. Significant progress has been accompanied by challenges for scientists, ethicists, and health policy makers. With the recent recognition of the need for a national system for the collection, banking, distribution, and use of cord blood and the increasing focus on cord blood as an alternative to embryos as a source of tissue for regenerative medicine, cord blood has garnered significant attention. We review the development of cord blood banking and transplantation and then discuss the scientific and ethical issues influencing both established and investigational practices surrounding cord blood collection, banking, and use. (+info)
Human cord blood--derived cells generate insulin-producing cells in vivo.
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Here we report the capacity of human cord blood (CB)-derived cells to generate insulin-producing cells. To investigate in vivo capacity of human CB-derived cells, T cell-depleted mononuclear cells were intravenously transplanted into nonobese diabetic/severe combined immunodeficient/beta2-microglobulinnull mice within 48 hours of birth. At 1-2 months post-transplantation, immunofluorescence staining for insulin and fluorescence in situ hybridization (FISH) analysis using a human chromosome probe indicated that human CB-derived cells generated insulin-producing cells at a frequency of 0.65%+/-0.64% in xenogeneic hosts. Reverse transcription-polymerase chain reaction analysis confirmed the transcription of human insulin in the pancreatic tissue of the recipient mice. To clarify the mechanism underlying CB-derived insulin-producing cells, double FISH analysis using species-specific probes was performed. Almost equal proportions of human chromosome+ murine chromosome- insulin+ cells and human chromosome+ murine chromosome+ insulin+ cells were present in recipient pancreatic islets. Taken together, human CB contains progenitor cells, which can generate insulin-producing cells in recipient pancreatic tissues across a xenogeneic histocompatibility barrier by fusion-dependent and -independent mechanisms. (+info)
Primary alloproliferative TH1 response induced by immature plasmacytoid dendritic cells in collaboration with myeloid DCs.
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The role played by dendritic cell (DC) subsets in the immune response to alloantigens is not well defined. In vitro experiments have extensively shown that freshly isolated myeloid (M)DCs induce a strong T lymphocyte proliferation whereas plasmacytoid (P)DCs do not, unless activated by CD40 ligation. The aim of these studies was to explore whether the interplay among PDCs, MDCs and T cells modulates alloresponse. Freshly isolated MDCs and PDCs were merged in different proportions and used as antigen presenting cells (APCs) in mixed lymphocyte cultures (MLC). As described, isolated PDCs only induced a mild alloresponse, while MDCs were potent inducers of alloproliferation. Unexpectedly, when PDCs were merged with even low numbers of MDCs (down to 100 cells) and used as APCs, a potent Th1 cell proliferation was detected. Survival and maturation of PDCs was increased in these MLC conditions, which could partially explain the magnitude of the T-cell response. Interestingly, the proportion of IFNgamma-producing cells generated in such cultures was higher compared to MDC-stimulated cultures. These data suggest that the interaction between both DC subsets is determinant to generate a potent Th1 response, at least in an allogeneic situation, and may be relevant to the outcome of allogeneic stem cell transplantation. (+info)
Umbilical cord blood transplantation: a new alternative option.
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Allogeneic hematopoietic stem cell transplantation is a life-saving procedure for hematopoietic malignancies, marrow failure syndromes, and hereditary immunodeficiency disorders. However, wide application of this procedure is limited by availability of suitably HLA-matched adult donors. Umbilical cord blood (UCB) has being increasingly used as an alternative hematopoietic stem cell source for these patients. To date, over 6000 UCB transplant procedures in children and adults have been performed worldwide using UCB donors. Broader use of UCB for adult patients is however limited by the available infused cell dose. This has prompted intensive research on ex vivo expansion of UCB stem cells and UCB graft-engineering including accessory cells able to improve UCB engraftment and reconstitution and for tissue regenerative potential. Recently, two large European and North American retrospective studies demonstrated that UCB is an acceptable alternative source of hematopoietic stem cells for adult recipients who lack HLA-matched adult donors. UCB is anticipated to address needs in both transplantation and regenerative medicine fields. It has advantages of easy procurement, no risk to donors, low risk of transmitting infections, immediate availability and immune tolerance allowing successful transplantation despite HLA disparity. (+info)
Comparable results of umbilical cord blood and HLA-matched sibling donor hematopoietic stem cell transplantation after reduced-intensity preparative regimen for advanced Hodgkin lymphoma.
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We compared the safety and efficacy of allogeneic stem cell transplantation (allo-SCT) after reduced-intensity conditioning using either unrelated umbilical cord blood (UCB) donors or matched-sibling donors (MSDs) for 21 adults at high risk with advanced Hodgkin lymphoma (UCB, n = 9; MSD, n = 12). Both groups were comparable except for younger age in the UCB cohort (median, 28 vs 42 years; P = .02). Neutrophil recovery occurred earlier in the MSD group (median, 7 vs 10 days; P = .02). All patients had sustained donor engraftment by day 60. Cumulative incidence of acute severe graft-versus-host-disease (33% vs 33%; P = .99), chronic graft-versus-host-disease (11% vs 33%; P = .24), and 100-day treatment-related mortality (11% vs 17%; P = .80) were comparable. With median follow-up periods of 17 and 24 months, the 2-year progression-free survival rates were 25% (95% confidence interval [95% CI], 0%-55%) for UCB and 20% (95% CI, 0%-44%) for MSD allo-SCT (P = .67). Our results suggest comparable outcomes for reduced-intensity allo-SCT using UCB or MSD in adults at high risk with advanced Hodgkin lymphoma. (+info)
Maternal transplantation of human umbilical cord blood cells provides prenatal therapy in Sanfilippo type B mouse model.
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Numerous data support passage of maternal cells into the fetus during pregnancy in both human and animal models. However, functional benefits of maternal microchimerism in utero are unknown. The current study attempted to take advantage of this route for prenatal delivery of alpha-N-acetylglucosaminidase (Naglu) enzyme into the enzyme-deficient mouse model of Sanfilippo syndrome type B (MPS III B). Enzymatically sufficient mononuclear cells from human umbilical cord blood (MNC hUCB) were intravenously administered into heterozygote females modeling MPS III B on the 5th day of pregnancy during blastocyst implantation. The major findings were 1) administered MNC hUCB cells transmigrated and diffused into the embryos (E12.5); 2) some transmigrated cells expressed CD34 and CD117 antigens; 3) transmigrated cells were found in both the maternal and embryonic parts of placentas; 4) transmigrated cells corrected Naglu enzyme activity in all embryos; 5) administered MNC hUCB cells were extensively distributed in the organs and the blood of heterozygote mothers at one week after transplantation. Results indicate that prenatal delivery of Naglu enzyme by MNC hUCB cell administration into mothers of enzyme-deficient embryos is possible and may present a significant opportunity for new biotechnologies to treat many inherited disorders. (+info)
Serial transplantations in nonobese diabetic/severe combined immunodeficiency mice of transduced human CD34+ cord blood cells: efficient oncoretroviral gene transfer and ex vivo expansion under serum-free conditions.
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Stable oncoretroviral gene transfer into hematopoietic stem cells (HSCs) provides permanent genetic disease correction. It is crucial to transplant enough transduced HSCs to compete with and replace the defective host hemopoiesis. To increase the number of transduced cells, the role of ex vivo expansion was investigated. For a possible clinical application, all experiments were carried out in serum-free media. A low-affinity nerve growth factor receptor (LNGFR) pseudotyped murine retroviral vector was used to transduce cord blood CD34(+) cells, which were then expanded ex vivo. These cells engrafted up to three generations of serially transplanted nonobese diabetic/severe combined immunodeficiency mice: 54.26% +/- 5.59%, 19.05% +/- 2.01%, and 6.15% +/- 5.16% CD45(+) cells from primary, secondary, and tertiary recipient bone marrow, respectively, were LNGFR(+). Repopulation in secondary and tertiary recipients indicates stability of transgene expression and long-term self-renewal potential of transduced HSCs, suggesting that retroviral gene transfer into HSCs, followed by ex vivo expansion, could facilitate long-term engraftment of genetically modified HSCs. (+info)
Unrelated cord blood transplants in adults with hematologic malignancies.
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BACKGROUND AND OBJECTIVES: We analyzed outcomes and risk factors after unrelated cord blood transplantation (CBT) in adults with hematologic malignancies. DESIGN AND METHODS: One hundred and seventy-one patients were transplanted after 1997. Their median age was 29 years (15-55), and the median follow-up time was 18 months (1-71). Most patients had acute or chronic leukemia (n=142, 83%), 91 (53%) were transplanted in advanced phase and an autologous transplant had failed in 32 (19%). Most patients (87%) received an HLA-mismatched cord blood unit with 1-2 HLA disparities. At infusion, the median number of nucleated cells and CD34(+) cells was 2.1x10(7)/kg and 1x10(5)/kg, respectively RESULTS: The cumulative incidence of neutrophil recovery at day 60 was 72+/-3% with a median of 28 days (11-57). A higher neutrophil count and use of hematopoietic growth factors were independently associated with faster neutrophil recovery. The cumulative incidence of grade II-IV acute graft-versus-host disease was 32+/-4% and this complication was not associated with the number of HLA mismatches. The 2-year cumulative incidence of chronic graft-versus-host disease, transplant related-mortality and relapse were 36+/-10%, 51+/-4% and 22+/-4%, respectively. At 2-years, disease-free-survival for patients transplanted in early, intermediate and advanced phases of disease was 41+/-9%, 34+/-10% and 18+/-4%, respectively. In multivariate analyses, advanced disease status was an adverse factor for relapse and disease-free survival. INTERPRETATION AND CONCLUSIONS: Unrelated CBT is a clear alternative for adults with hematological malignancies lacking an HLA-matched related or unrelated donor. The choice of units containing a higher neutrophil count and a policy of earlier transplantation are likely to provide better results. (+info)