Stem cells from bone marrow, umbilical cord blood and peripheral blood for clinical application: current status and future application

Bone marrow transplantation (BMT) has progressed rapidly during the past two decades to that of a treatment of choice as a therapeutically effective modality for the treatment of selected patients with malignant disease and non-malignant hematological disorders. However, its use is limited by availability of human leukocyte antigens (HLA)-matched donor cells, engraftment and graft-versus-host disease (GVHD). Prevention of GVHD, improvement in the speed and quality of marrow reconstitution, and screening of new immunomodulating agents which improve engraftment and augment hemopoiesis are intense areas of investigation. To this end there has clearly been progress in purification and characterization of human stem cells from different tissue sources. Discussed in this review are: (a) stem cell purification, characterization and ex vivo expansion; (b) bone marrow stem cell transplantation; (c) cord blood stem cell transplantation; (d) peripheral blood stem cell transplantation; (e) fetal liver stem cell transplantation; (f) in utero stem cell transplantation; and (g) evaluation of the capacity of stem cells to serve as targets for gene therapy.     

Candidate hematopoietic stem cells from fetal tissues, umbilical cord blood vs. adult bone marrow and mobilized peripheral blood

BACKGROUND: The eosinophil granulocyte is an inflammatory cell that plays an active part in diseases such as asthma and rhinitis. This study aimed to investigate oxidative metabolism by blood eosinophils taken from allergic rhinitis patients, asthmatics, and nonallergic controls before and during the birch-pollen season. METHODS: Twenty patients with allergy to birch pollen and seasonal symptoms of rhinitis, some of whom were also asthmatic, were followed before and during the birch-pollen season in Sweden. The cells were purified using a Percoll gradient and the MACS system. Eosinophil purity in all samples was > 95%. Oxidative metabolism was measured by a chemiluminescence (CL) assay, with luminol and lucigenin acting as enhancers, and PMA, serum-treated zymosan (STZ), interleukin (IL)-5, or RANTES as stimuli. RESULTS: The allergic subjects showed reduced luminol CL when activated before the season with PMA (P = 0.040) or STZ (P = 0.0055). This was not seen during pollen exposure. STZ-activated lucigenin CL was also reduced before the season (P = 0.0027). The reduction was most evident in the group with asymptomatic rhinitis. In terms of eosinophil stimulation, IL-5 and RANTES were equally effective in allergic and nonallergic subjects, both before and during the pollen season. CONCLUSIONS: Blood eosinophils from asymptomatic allergics may have a lower capacity to produce oxygen-free radicals than eosinophils from nonallergics.     

Comparison of retroviral-mediated gene transfer into cultured human CD34+ hematopoietic progenitor cells derived from peripheral blood, bone marrow, and fetal umbilical cord blood

Genetic alteration of stem cells ex vivo followed by bone marrow transplantation could potentially be used in the treatment of numerous diseases and malignancies. However, there are many unanswered questions as to the best source of hematopoietic cells for long-term reengraftment and the most effective way to introduce foreign genes into this target cell. We have compared retroviral-mediated gene transfer into CD34+-enriched cells derived from peripheral blood (PB), bone marrow (BM), or fetal umbilical cord blood (CB). Cells from all three sources that had been expanded ex vivo in the presence of stem cell factor (SCF), interleukin-3 (IL-3), IL-6, and granulocyte colony-stimulating factor (G-CSF) showed transduction efficiencies ranging from 5-45%, as measured by acquisition of G418 resistance. The average efficiencies of gene transfer from multiple experiments for PB, BM, and CB were not statistically different. To determine the effect of ex vivo expansion on gene transfer into CB CD34+ cells, we compared the transduction efficiencies of cells exposed to virus immediately after harvest and CD34 selection or after 6 days of culture CD34+ CB cells were more effectively transduced after expansion in culture, showing gene transfer efficiencies 3- to 5-fold higher on day 6 compared with day 0. Last, we examined retroviral transduction via spinoculation of CB CD34+ cells and found it to be approximately as effective as our standard transduction with no significant loss of cell viability as measured by colony formation in semi-solid medium.     

NK cells differentiated from bone marrow, cord blood and peripheral blood stem cells exhibit similar phenotype and functions

In the present study, we investigated the differentiation of human NK cells from bone marrow, cord blood and mobilized peripheral blood purified CD34+ stem cells using a potent culture system. Elutriated CD34+ stem cells were grown for several weeks in medium supplemented with stem cell factor (SCF) and IL-15 in the presence or absence of a murine stromal cell line (MS-5). Our data indicate that IL-15 induced the proliferation and maturation of highly positive CD56+ NK cells in both types of culture, although murine stromal cells slightly increased the proliferation of NK cells. NK cells differentiated in the presence of MS-5 were mostly CD56+ CD7 and a small subset expressed CD16. These in vitro differentiated CD56+ NK cells displayed cytolytic activity against the HLA class I- target K562. The CD56+ CD16+ subset also lysed NK-resistant Daudi cells. Neither of these NK subsets were shown to express Fas ligand. Total CD56+ cells expressed high amounts of transforming growth factor-beta and granulocyte-macrophage colony-stimulating factor, but no IFN-gamma. Investigation of NK receptor expression showed that most CD56+ cells expressed membrane CD94 and NKG2-A mRNA. PCR analysis revealed that p58 was also expressed in these cells. The role of CD94 in NK cell-mediated cytotoxicity was assessed on human HLA-B7-transfected murine L cells. While a low cytotoxic activity towards HLA-B7 cells was observed, the HLA-DR4 control cells were killed with high efficiency. These studies demonstrate that cytolytic and cytokine-producing NK cells may be derived from adult and fetal precursors by IL-15 and that these cells express a CD94 receptor which may influence their lytic potential.     

Flow cytometric analysis of peripheral blood and bone marrow for tumor cells in patients with neuroblastoma

PURPOSE: To report initial clinical experience with a novel high-precision stereotactic radiotherapy system. METHODS AND MATERIALS: Sixty patients ranging in age from 2 to 82 years received a total of 1426 treatments with the University of Florida frameless stereotactic radiotherapy system. Of the total, 39 (65%) were treated with stereotactic radiotherapy (SRT) alone, and 21 (35%) received SRT as a component of radiotherapy. Pathologic diagnoses included meningiomas (15 patients), low-grade astrocytomas (11 patients), germinomas (9 patients), and craniopharyngiomas (5 patients). The technique was used as means of dose escalation in 11 patients (18%) with aggressive tumors. Treatment reproducibility was measured by comparing bite plate positioning registered by infrared light-emitting diodes (IRLEDs) with the stereotactic radiosurgery reference system, and with measurements from each treatment arc for the 1426 daily treatments (5808 positions). We chose 0.3 mm vector translation error and 0.3 degrees rotation about each axis as the maximum tolerated misalignment before treating each arc. RESULTS: With a mean follow-up of 11 months, 3 patients had recurrence of malignant disease. Acute side effects were minimal. Of 11 patients with low grade astrocytomas, 4 (36%) had cerebral edema and increased enhancement on MR scans in the first year, and 2 required steroids. All had resolution and marked tumor involution on follow-up imaging. Bite plate reproducibility was as follows. Translational errors: anterior-posterior, 0.01 +/- 0.10; lateral, 0.02 +/- 0.07; axial, 0.01 +/- 0.10. Rotational errors (degrees): anterior-posterior, 0.00 +/- 0.03; lateral, 0.00 +/- 0.06; axial, 0.01 +/- 0.04. No patient treatment was delivered beyond the maximum tolerated misalignment. Daily treatment was delivered in approximately 15 min per patient. CONCLUSION: Our initial experience with stereotactic radiotherapy using the infrared camera guidance system was good. Patient selection and treatment strategies are evolving rapidly. Treatment accuracy was the best reported, and the treatment approach was practical.     

Relative sedimentation of hematopoietic progenitors in human cord blood, peripheral blood, and bone marrow as determined by counterflow centrifugal elutriation

OBJECTIVE: Although there have been many studies of the outcome of anorexia nervosa, methodological weaknesses limit their interpretation. The authors used a case-control design to try to improve knowledge about the outcome of anorexia nervosa. METHOD: All new female patients referred to an eating disorders service between Jan. 1, 1981, and Dec. 31, 1984, who had probable or definite anorexia nervosa were eligible for inclusion. Of these women, 86.4% (N = 70) were located and agreed to participate. The comparison group (N = 98) was a random community sample. All subjects were interviewed with a structured diagnostic instrument. RESULTS: A minority of the patients (10%) continued to meet the criteria for anorexia nervosa a mean of 12 years after initial referral. Even among those who no longer met these criteria, relatively low body weight and cognitive features characteristic of anorexia nervosa (perfectionism and cognitive restraint) persisted. The rates of lifetime comorbid major depression, alcohol dependence, and a number of anxiety disorders were very high. CONCLUSIONS: In the managed care/brief treatment era, therapeutic approaches with an excessive focus on weight gain that neglect the detection and treatment of associated psychological features and comorbidity may be inappropriate. Anorexia nervosa is a serious psychiatric disorder with substantial morbidity.     

Generation and functional characterization of human dendritic cells derived from CD34 cells mobilized into peripheral blood: comparison with bone marrow CD34+ cells

Dendritic cells (DCs) are the most powerful professional antigen-presenting cells (APC), specializing in capturing antigens and stimulating T-cell-dependent immunity. In this study we report the generation and characterization of functional DCs derived from both steady-state bone marrow (BM) and circulating haemopoietic CD34+ cells from 14 individuals undergoing granulocyte colony-stimulating factor (G-CSF) treatment for peripheral blood stem cells (PBSC) mobilization and transplantation. Clonogenic assays in methylcellulose showed an increased frequency and proliferation of colony-forming unit-dendritic cells (CFU-DC) in circulating CD34+ cells, compared to that of BM CD34+ precursors in response to GM-CSF and TNF-alpha with or without SCF and FLT-3L. Moreover, peripheral blood (PB) CD34+ cells generated a significantly higher number of fully functional DCs, as determined by conventional mixed lymphocyte reactions (MLR), than their BM counterparts upon different culture conditions. DCs derived from mobilized stem cells were also capable of processing and presenting soluble antigens to autologous T cells for both primary and secondary immune response. Replacement of the early-acting growth factors SCF and FLT-3L with IL-4 at day 7 of culture of PB CD34+ cells enhanced both the percentage of total CD1a+ cells and CD1a+ CD14- cells and the yield of DCs after 14 d of incubation. In addition, the alloreactivity of IL-4-stimulated DCs was significantly higher than those generated in the absence of IL-4. Furthermore, autologous serum collected during G-CSF treatment was more efficient than fetal calf serum (FCS) or two different serum-free media for large-scale production of DCs. Thus, our comparative studies indicate that G-CSF mobilizes CD34+ DC precursors into PB and circulating CD34+ cells represent the optimal source for the massive generation of DCs. The sequential use of early-acting and intermediatelate-acting colony-stimulating factors (CSFs) as well as the use of autologous serum greatly enhanced the growth of DCs. These data may provide new insights for manipulating immunocompetent cells for cancer therapy.     

Biologic and phenotypic analysis of early hematopoietic progenitor cells in umbilical cord blood

Umbilical cord blood (UCB) is an attractive potential alternative to bone marrow (BM) as a source of hematopoietic progenitor cells since the number of progenitors in UCB is similar or even greater than that in normal BM. It was the aim of the present study to analyze the degree of immaturity of UCB progenitor cells. UCB mononuclear (MNC) and/or CD34+ cells were tested for surface antigen phenotype, expression of cytokines receptor, effect of stem cell factor (SCF) on colony growth, resistance to mafosfamide and replating potential. We have found that 34.9 +/- 3.4% and 77.9 +/- 2.6% of UCB CD34+ cells did not express CD38 and CD45RA antigens, respectively, suggesting that UCB contains a high proportion of immature progenitor cells. By means of three-color analysis, the receptor for SCF was detected on the majority of the CD34+ HLA-DR+ subpopulation; in fact, 81.8% +/- 4.3% of CD34+ HLA-DR+ cells were defined as SCF(low) and 8.1 +/- 1.5% as SCF(high). Colony growth of MNC and CD34+ cells was enhanced by the addition of SCF to methylcellulose mixture, resulting in a statistically significant increase in CFU-GM and CFU-GEMM but not in BFU-E numbers. UCB progenitor cells showed a higher resistance to mafosfamide treatment, in comparison to BM; the addition of SCF to the culture medium resulted in a statistically significant increase in mafosfamide concentration required to inhibit 95% of colony growth (P < or = 0.05). Moreover, as shown by single colony transfer assays, the presence of SCF in primary cultures promoted a significantly higher replating potential for both untreated (42 +/- 3.3% vs 21 +/- 4.6%, P < or = 0.018) and mafosfamide-treated samples (62 +/- 5.6% vs 44 +/- 6.1%, P < or = 0.018). In conclusion, UCB is a source of progenitor cells with immature characteristics in terms of surface antigen expression, distribution of SCF receptor, resistance to mafosfamide and replating potential. Therefore, UCB progenitor cells represent an ideal candidate population for experimental programs involving gene transfer and ex vivo stem cell expansion.     

Allogeneic peripheral blood progenitor cells for treatment of relapse after bone marrow transplantation

Donor leukocyte infusions (DLI) are an effective therapy for patients who relapse with leukemia after bone marrow transplantation (BMT). Severe graft-versus-host disease and prolonged periods of pancytopenia compromise the success of this treatment in a substantial number of patients. We used filgrastim-mobilized peripheral blood progenitor cells (PBPCs), in some cases preceded by cytoreductive therapy, to circumvent some of the problems associated with DLI. Eleven patients (median age 41 years) received a total of 20 donor cell infusions. Their diagnosis was CML in hematological (two patients) or cytogenetic relapse (two patients), six patients suffered from acute myeloid leukemia (AM; n = 5) or Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL Ph+). One patient had multiple myeloma (MM). All six patients with acute leukemias received cytoreductive therapy prior to PBPC infusions; three patients with CML were pretreated with IFN alpha. Four of four patients with CML responded to PBPC infusions and currently are in complete clinical and molecular remission for time periods between 1 and 12 months. Six of six patients with acute leukemias achieved a complete remission. All of them relapsed after a median remission duration of 24 weeks (range 11-49 weeks). Three patients relapsed at extramedullary sites (CNS, testes, skin). Four of six acute leukemia patients received further cytoreductive therapy. All patients responded again and are in complete remission for time periods between 14 and 615 days. Two patients with acute leukemias have died due to dissemination of the disease. The patient with MM did not respond and is alive with disease. Severe (grade III) acute GVHD developed in two of 11 patients, three patients developed grade II disease, six patients did not show any signs of GVHD. Extensive chronic GVHD has developed in two cases to date. Patients with chemotherapy prior to PBPC infusion developed neutropenia and thrombocytopenia with a maximum duration of 20 and 14 days, respectively; prolonged periods of neutropenia did not occur. Two patients developed long-lasting thrombocytopenia in spite of PBPC infusion, in one case followed by leukemic relapse. Repeated courses of chemotherapy and PBPC infusion were generally tolerated well; no early deaths due to treatment-related toxicity or GVHD were observed. We conclude that the use of allogeneic PBPC instead of DLI in patients with relapse after BMT is technically feasible and safe. The efficacy of PBPC infusions seems comparable to DLI in patients with CML. Patients with acute leukemias also achieved complete albeit transient remissions. Aggressive chemotherapy followed by PBPC infusions resulted in only limited duration of cytopenia. The usage of PBPC infusion instead of non G-CSF-mobilized donor cells for treatment of relapse after BMT may reduce pancytopenia-related complications and merits further investigation.     

Blastogenic response of activated human umbilical cord blood T-lymphocytes

Donor T-lymphocytes are thought to play a crucial role in both acute and chronic graft-versus-host disease (GvHD), pathological conditions that frequently complicate allogeneic bone marrow transplantation. These diseases are described as occurring with a lower incidence and lesser severity when human umbilical cord blood (HUCB) cells, which have recently emerged as a potential source of hematopoietic progenitors, are used for transplantation. This condition is probably related to the immaturity of neonatal HUCB T cells. Lymphocyte blastogenic response to phytohemagglutinin (PHA), evaluated by means of flow cytometry, is a useful tool for testing the functional ability of T-cells to display an immune response against allo-antigens, reproducing in vitro the in vivo mechanism of activation. This study was designed to verify whether an impairment in HUCB T-cell ability to undergo an in vitro blastogenic response to mitogens could explain their reduced in vivo ability to induce GvHD.     

Allogeneic cell therapy with donor peripheral blood cells and recombinant human interleukin-2 to treat leukemia relapse after allogeneic bone marrow transplantation

Allogeneic bone marrow transplantation (BMT) is the only effective treatment for hematologic malignancies resistant to conventional chemotherapy. Until recently, no cure existed for patients who relapsed post-BMT. We present our long-term observations on remission induction, after relapse post-BMT, by allogeneic cell therapy (allo-CT) and the feasibility of remission induction in allo-CT-resistant patients by activation of antileukemia effector cells with recombinant human interleukin-2 (rhIL-2) in vitro and in vivo. The longest observation of successful allo-CT (event-free survival, greater than 8 years) was made in a patient with resistant pre-B lymphoblastic leukemia who received infusions with graded increments of donor (female) peripheral blood lymphocytes (PBL) as soon as bulky hematologic and extramedullary relapse was noticed early post-BMT. The patient is currently without evidence of residual host (male) cells as determined by polymerase chain reaction (PCR). Of 17 patients with acute and chronic leukemia in relapse after BMT, 10 were reinduced into complete remission. Four patients with cytogenetic relapse responded to allo-CT alone, while five of six patients with overt hematologic relapse responded only after additional activation of donor with rhIL-2. Allo-CT can, therefore, successfully reverse chemoradiotherapy-resistant relapse of both acute and chronic leukemia. Moreover, in patients resistant to donor lymphocyte infusion, remission can be accomplished by additionally activating donor PBL in vitro and/or in vivo with rhIL-2. Based on our observations, after BMT, allo-CT should be considered the treatment of choice for patients with hematologic malignancies resistant to conventional anticancer modalities. Allogeneic activated cell therapy (allo ACT) should be considered for patients with tumor cells resistant to allo-CT. Although allo-CT, followed if indicated by allo-ACT, can be effective for patients with overt hematologic relapse, reversal of persistent minimal residual disease or documented molecular/cytogenetic relapse early after BMT may also be considered as a possible indication for allo-CT.     

Cost comparative study of autologous peripheral blood progenitor cells (PBPC) and bone marrow (ABM) transplantations for non-Hodgkin's lymphoma patients

Intensive high-dose chemotherapy with autologous stem-cell support has become a common treatment strategy for non-Hodgkin's lymphomas. A cost-identification analysis was conducted comparing 10 patients autografted with PBSC to 10 others autografted with BM. The analysis included harvest and graft until graft day +100 and was carried out from the point of view of the hospital setting. Resources used, logistic and direct medical costs per patient were identified, and sensitivity analyses performed. The cost distribution was different. Stem cell harvest was more expensive for PBPC ($9030) and BM ($4745); on the other hand, hospitalization from graft to discharge from hospital cost savings with PBSC were about $10666. After discharge from hospital, costs were similar and cheaper in both groups. For the overall study the PBPC procedure was less expensive than ABMT, $35381 and $41759 respectively, with cost savings of $6378. The number of days spent in hospital and blood bank costs were the major cost factors. This study was based on a single pathology, non-Hodgkin's lymphoma, and the actual hospital records for each patient situation as opposed to a clinical trial, and our results were consistent with different previous studies carried out in different health care systems.     

Study on the collecting method of human umbilical cord blood

Anemia is responsible for an estimated 20% of maternal deaths in West Africa and contributes to still more deaths through obstetric hemorrhage. Anemia during pregnancy has been linked to iron and folate dietary deficiencies, the secondary effects of malaria and hookworm infestations, infections such as human immunodeficiency virus, and hemoglobinopathies. Parasitic infestations interfere with the normal increase (given a balanced diet) in iron absorption during pregnancy. An understanding of locally salient etiologic factors should form the basis of public health programs aimed at addressing anemia during pregnancy. There is a need for basic prevalence statistics, especially from West Africa's rural areas. Finally, reliable laboratory parameters that can be used in the assessment of iron and folate status and the degree of anemia attributable to malaria must be established. Although there is emerging evidence that serum transferrin receptor concentration is not affected by chronic disease or the physiological changes of pregnancy, further studies are needed to validate this measure.     

Distribution of hematopoietic stem cells in the mononuclear fraction of human umbilical cord blood]

Specific features of intrathoracic tuberculosis course, outcomes and treatment are outlined for 109 children. In 59 of them tuberculosis was associated with nonspecific respiratory diseases (NRD). 28.8%, 25.4%, 18.6, 27.2% of patients had cystic hypoplasia, chronic hypoplasia, recurrent pneumonia, recurrent bronchitis, respectively. Complicated course of tuberculosis occurred 2 times more frequently in its combination with NRD (71.2%). Destruction and discharge of bacteria were recorded in 49.2 and 47.5% of patients, respectively. Undulating running was 3.4 and side effects 1.6 times more frequent. Tuberculous children with NRD need longer antituberculous therapy using wide-spectrum antibiotics, symptomatic and exercise treatment, massage, surgical intervention if necessary. Complete resolution of lung lesions in NRD children were seen 4.8 times less frequently. In case of late diagnosis 54% of them retained residual changes in the form of lung tissues fibrosis, calcified foci in the lungs and lymph nodes.     

Separation of parental genomes in human blood and bone marrow cells and its implications

The linear order of genes is apparently interrupted at chromosomal ends. Our observations on human blood and bone marrow cells indicate that the chromosomes of each of the two parental sets maintain coherence, perhaps in tandem, forming a ring. Two such rings in a diploid cell join building a larger ring, which folds up to form the interphase nucleus. The linear order of genes thus extends beyond the chromosomal ends. These observations become especially significant when seen in the light of cell biologic findings on interaction of chromosomes or chromatin and centrioles in different cell cycle phases, in polymorphonuclear cells and during the zygotic developments. They may explain how the genomic order and the sequential continuity of the genes are maintained and why such order remains often cryptic.     

The effects of Flk-2/flt3 ligand as compared with c-kit ligand on short-term and long-term proliferation of CD34+ hematopoietic progenitors elicited from human fetal liver, umbilical cord blood, bone marrow, and mobilized peripheral blood

The Flk-2/flt3 ligand (FL) was evaluated and compared with c-kit ligand (KL) for its in vitro proliferative effects on CD34+ cells from human fetal liver, umbilical cord blood, bone marrow, and mobilized peripheral blood. Using a 7-day liquid culture system, FL in combination with interleukin-3 (IL-3), interleukin-6 (IL-6), and granulocyte colony-stimulating factor (G-CSF) was comparable with KL in combination with IL-3, IL-6, and G-CSF for the expansion of hematopoietic progenitors. When FL-containing cultures were assayed after 21 or 28 days, a greater number of progenitors were generated as compared with KL-containing cultures. Using bone marrow microvascular endothelial cells as support stroma, cultures supplemented with FL generated a greater number of progenitors in both the nonadherent and adherent layers at day 35. These data suggest that FL ligand, in combination with other cytokines, can be used for short-term ex vivo expansion of hematopoietic progenitors and facilitates the preservation and possible expansion of primitive cells capable of long-term generation of progenitors.     

Umbilical cord blood transplantation: acceptance of umbilical cord blood donation by pregnant patients

BACKGROUND/OBJECTIVE: Umbilical cord blood is an alternative source for allogeneic transplantation of hematopoietic stem cells from related and unrelated donors. It can easily be collected, cryopreserved and stored in cord blood banks for later use. In Switzerland, cord blood banks for related and unrelated stem cell transplantation are being established. The aim of the study was to evaluate previous knowledge of the possible medical use of cord blood and acceptance of cord blood banking in pregnant women. METHODS: We performed a prospective open study using a structured, anonymous questionnaire at the University of Basel Women's Hospital pregnancy outpatient clinic. After concise information on the use of cord blood for transplantation, questions were asked concerning previous knowledge of the use of placenta and cord blood in general, concerning the attitude to donation of cord blood for transplantation, and the respondent's willingness to donate cord blood of her own child. Women of different ethnic background were compared. RESULTS: From 300 questionnaires handed out to pregnant women of different ethnic background attending our outpatient clinic, 250 (83%) were returned, and 245 could be evaluated for final analysis. Only 40% indicated that they did know what usually happens to the placenta after birth. In contrast, the vast majority (95%) supported the idea of umbilical cord blood for banking and later use for stem cell transplantation. Similarly, 93% stated that they would agree to donate the cord blood from their own child for this purpose, while no statistically significant differences could be identified either between women with or without previous knowledge or of different ethnic background. CONCLUSIONS: This study shows the high acceptance of umbilical cord blood donation for banking and stem cell transplantation purposes in pregnant women, irrespective of previous knowledge. As there are no major differences between women of different ethnic background, a high degree of diversity of HLA-types of donated cord blood samples can be expected and may offset the underrepresentation of ethnic minorities in bone marrow donor registries.     

Cytokine receptors, growth factors and cell cycle in human bone marrow and peripheral blood hematopoietic progenitors

BACKGROUND AND OBJECTIVE: An increasing number of growth factors have been shown to be responsible for the proliferation, survival and enhanced function of many cell types within the hemopoietic system. The action of these hemopoietic growth factors in stimulating cell growth and survival applies both to cells within the progenitor compartment and mature cells. Whether a specific cytokine influences in vivo hematopoietic progenitor cell proliferation or survival depends on cytokine-mediated modulation or target cell cytokine receptors, cell proliferation, and cell death regulator genes and other pathways. To address these issues, particularly in view of the current and future clinical use of hemopoietic growth factors, the Italian Society of Experimental Hematology organized a Meeting in Florence on July 4th, 1996. INFORMATION SOURCES: The material examined in the present review includes full papers and abstracts published in journals covered by the Science Citation Index and Medline. All the participants to the Meeting in Florence have been actively working in the field of biology and clinical application of hemopoietic growth factors. Summaries of their oral presentations at the Florence Meeting are reported in the Appendix to this article. STATE OF ART AND PERSPECTIVES: Myelopoietic growth factors particularly granulocyte (G-) colony-stimulating factor (CSF) and granulocyte-macrophage (GM)-CSF, have been available for clinical use for only a few years but they have already markedly changed the management of chemotherapy-induced neutropenia, the use of dose-intensive chemotherapy regimens and the practice and safety of autologous stem cell transplantation. While these growth factors have been rapidly introduced as routine agents in the management of cancer patients, they have continued to generate a considerable amount of fundamental research into the biology of hematopoiesis as well as the growth regulation of normal and cancer cells. For instance, one goal of cancer treatment is to protect hematopoietic stem and progenitor cells from the damaging effects of chemotherapy, while maintaining their anticancer action. Any means of preferentially and reversibly suppressing the proliferation of normal hematopoietic stem and progenitor cells while leaving the proliferation of tumor cells and their susceptibility to chemotherapy unmodified, could potentially optimize treatment efficacy. In this field, the possibility of using colony-stimulating factors as myeloprotective agents in dose-intensive chemotherapy to enhance anticancer activity could be an attractive goal of current anti-cancer treatment modalities.