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PubMed1995

Differential effect of type I interferons on hematopoietic progenitor cells: failure of interferons to inhibit IL-3-stimulated normal and CML myeloid progenitors.

We observed a differential effect of type I interferons (IFNs) in inhibiting the proliferation of various hematopoietic progenitor cell types. Upon stimulation with interleukin-3 (IL-3), IFN-alpha and IFN-beta failed to inhibit colony formation of myeloid progenitors (day-14 colony-forming units-granulocyte/macrophage [CFU-GM]) obtained from peripheral blood (PB) and bone marrow (BM) of untreated chronic myelogenous leukemia (CML) patients in chronic phase even at IFN doses as high as 10,000 U/mL. In contrast, day-7 CFU-GM stimulated with granulocyte colony-stimulating factor (G-CSF) and burst-forming units-erythroid (BFU-E) were readily inhibited by moderate doses of IFNs. IFN-resistant myeloid progenitor cells were also detected in normal BM but not in normal PB cells. When suboptimal doses of IL-3 were used in clonal progenitor cell assays, day-14 CFU-GM were not protected from the inhibitory action of IFN. The failure of IFN to inhibit immature myeloid progenitors was confirmed in normal and CML cells highly enriched in CD34-expressing cells. Combinations of growth factors were required for sufficient colony formation in these cells, whereas IL-3 alone provided only an inadequate stimulation, which was further inhibited by IFN. In purified CD34+ cells, day-14 CFU-GM were protected from IFN-mediated inhibition only upon stimulation with stem cell factor (SCF) in combination with IL-3 or G-CSF.

Antigens, CD34↗

PubMed1996

Phenotypic, molecular, and functional characterization of human peripheral blood CD34+/THY1+ cells.

A subset of mobilized CD34+ cells present in patient aphereses expresses Thy1 (CDw90). This population contains most long-term culture initiating cells, as assayed with a murine stromal cell line. It also contains a significant proportion of colony-forming unit granulocyte macrophage, but very few burst-forming unit erythroid. The limited differentiation towards the erythroid lineage is further confirmed by the absence of GATA-1 mRNA in the CD34+/Thy1+ subset, and by the low level of c-kit expression. The CD34+/Thy1+ subset appears phenotypically and functionally heterogeneous, a finding consistent with its high representation, compared to phenotypes such as CD34+/CD38-. Therefore, while at least some of CD34+/Thy1+ cells may be infectable by retroviral vectors, as shown by the presence of a transcript for the receptor for murine amphotropic retroviruses, the use of this selection strategy to specifically target human stem cells appears questionable.

Antigens, CD34↗

PubMed1997

Animal serum-free culture of purified human CD34+ cells: amplification of progenitors from G-CSF and GM-CSF-mobilized peripheral blood.

The isolation and culture of human CD34+ cells could have broad clinical application for hematologic support following high-dose chemotherapy or bone marrow transplantation. The need for reproducible, animal product-free conditions for the culture of progenitors is crucial to the widespread clinical implementation of ex vivo cell therapies. In these studies, we explored the use of animal serum-free (ASF) medium for the culture of isolated human bone marrow and peripheral blood CD34+ cells. In this ASF system, isolated CD34+ cells were cultured using a variety of different growth factor combinations. Such ASF culture conditions yielded equivalent to superior cell and progenitor growth when directly compared with culture containing 10% fetal calf serum (FCS). In cultures containing IL-1, IL-3, and stem cell factor, total cell numbers increased, on average, 33-fold over the first 2 weeks. On phenotypic analysis, the ASF cultures demonstrated sustained proliferation of CD33+ myeloid cells throughout the culture period. CD34+ cell numbers increased during the first 7-10 days of culture, with a mean 3.4-fold expansion. Concomitant with the CD34+ cell expansion was an average 8.2-fold expansion of colony-forming unit-granulocyte-macrophage (CFU-GM) and a 102.0-fold increase in burst-forming units-erythrocytes (BFU-E). Likewise, a mean 4929-fold expansion of CD41a+ megakaryocyte progenitors was observed in these CD34+ cultures. Different combinations of growth factors affected the fold increase in cell and progenitor number. When CD34+ cell cultures from normal healthy volunteers mobilized with either G-CSF or GM-CSF were compared, similar expansions of total cell and progenitor cells resulted. However, CD41+ cells expansions were greater in those samples from G-CSF-mobilized volunteers in every case tested. These studies established the feasibility of this ASF CD34+ cell culture system to generate a population of maturing progenitors for potential use in transfusion support during cytopenic periods following high-dose chemotherapy or bone marrow transplantation.

Animals↗

PubMed1990

Purification of peripheral blood hematopoietic cells using Campath-1M monoclonal antibody.

The purpose of this study was to develop a method for exhaustive depletion of T cells in preparation for allogeneic peripheral blood (PB) hematopoietic stem cell (HSC) transplantation. Our goal was to achieve 4 logs of T-cell reduction while minimizing the loss of colony-forming progenitor cells. Campath-1M, a rat IgM cytolytic to T cells, B cells, and monocytes in the presence of human complement, was chosen for the investigation. To determine the best target population for Campath treatment, three different PB mononuclear cell (MNC) populations were examined: 1) total MNC isolated with Ficoll-sodium diatrizoate; 2) MNC after T-cell depletion by sheep red blood cell rosetting and high capacity Percoll density gradient fractionation (E-MNC); and 3) B/Null cells, a population of E-MNC obtained by lysing monocytes with L-phenylalanine methyl ester (PME). Of the three target MNC populations, Campath-treated B/Null cells had the highest cloning efficiencies (CE) for granulocyte-macrophage colony-forming units (CFU-GM) and erythroid burst-forming units (BFUe) (56.7 and 38.5 colonies per 5 x 10(3) cells, respectively) and the highest enrichments for CFU-GM (108.2-fold, range 18- to 440-fold) and BFUe (178.5-fold, range 78- to 314-fold). Recoveries of progenitor cells were comparable for Campath-treated MNC (49.7% and 84.5%, respectively, for CFU-GM and BFUe) and Campath-treated B/Null (44.8% and 76.1%), and significantly higher than those from Campath-treated E-MNC (19.5% and 34.3%). The T-cell content in the Campath-treated B/Null cells were reduced by 5.0 logs from the starting MNC, as determined by limiting dilution analysis (LDA). We conclude that Campath-1M can be used for T-cell depletion of PB HSC. The best results were obtained when T cells and monocytes were removed prior to Campath treatment. This cell population is highly enriched for hematopoietic cells and may prove useful for in vitro studies as well allogeneic transplantation.

Antibodies, Monoclonal↗

PubMed1990

Inhibition of human bone marrow progenitors by the synthetic tetrapeptide AcSDKP.

The purpose of this work was to study the effects of a tetrapeptide, acetyl-N-Ser-Asp-Lys-Pro (AcSDKP), an inhibitor of spleen colony-forming unit (CFU-S) entry into DNA synthesis, on human progenitor cells. Normal human mononuclear cells were incubated with concentrations of the synthetic tetrapeptide ranging from 10(-12) to 10(-7) M for 1.5 and 24 h and then plated in methylcellulose in the presence of human placenta-conditioned medium and recombinant human erythropoietin. The proportion of progenitors in DNA synthesis was determined by the thymidine suicide assay. Incubation with AcSDKP for 24 h leads to a significant inhibition of granulocyte-macrophage colony-forming unit (CFU-GM) and erythroid burst-forming unit (BFU-E) growth and in some cases of erythroid colony-forming unit (CFU-E) growth. The inhibition, which was never greater than 50%, was obtained with 10(-10)-10(-9) M AcSDKP, whereas no effect was seen at higher concentrations. The percentage of CFU-GM, BFU-E, and CFU-E in DNA synthesis was significantly reduced in five consecutive patients after incubation of cells for 24 h with inhibitory doses of the peptide, indicating that it is active on cycling cells. Therefore, these studies provide the first evidence that the tetrapeptide AcSDKP, originally obtained from bovine marrow and now chemically synthesized, is able to inhibit the in vitro growth of human progenitors and to decrease their proportion in cell cycle.

Amino Acid Sequence↗

PubMed2006

Evaluation of CD7 and terminal deoxynucleotidyl transferase (TdT) expression in CD34+ myeloblasts from patients with myelodysplastic syndrome.

There is an emerging use of flow cytometry to evaluate patients with myelodysplastic syndrome (MDS). We have studied CD7 and TdT expression in the CD34+ myeloid blast cell population in 55 bone marrow samples of patients with MDS. CD7 and/or TdT were detected in 38 out of 55 patients (69%). CD7 expression was not related to other bad prognosis data but conversely, we found an association between TdT+ CD34 myeloblasts and high-risk MDS patients according to the International Prognostic Scoring System. Therefore, CD7 and TdT may help to establish the diagnosis of MDS and, TdT expression also seems to be a useful marker in distinguishing risk groups.

Adult↗

PubMed2004

Influence of dosing schedule on toxicity and antitumor effects of a combination of adriamycin and docetaxel in mice.

PURPOSE: Although the combination of Adriamycin (ADR) and docetaxel (DOC) showed a better cure rate against metastatic breast cancer in a clinical study, severe myelosuppression and cardiotoxicity were dose-limiting factors. The purpose of this study was to establish the most suitable dosing schedule to relieve severe adverse effects and improve the antitumor effects. EXPERIMENTAL DESIGN: Both ADR and DOC were administered simultaneously in the simultaneous-dosing group (ADR/DOC), whereas in the intermittent-dosing groups (ADR-DOC and DOC-ADR), the second drug was administered 12 h after the first drug. Leukocyte counts and survival were measured to estimate adverse effects. After administration, ADR and DOC concentrations in blood, myelocyte cells, and heart were determined. To clarify the antitumor effect, tumor growth was measured in Ehrlich-cell-bearing mice after the initiation of drug injections. RESULTS: The simultaneous-dosing group showed severe leukopenia compared with the saline-treated group. However, the toxicity was reduced in the intermittent-dosing groups. The DOC-ADR group showed the best survival rate in the dosing groups. In the pharmacokinetic study, ADR and DOC concentrations in plasma, myelocyte cells, and the heart were markedly higher in the simultaneous-dosing group than the intermittent-dosing groups. These results indicate that pharmacokinetic interactions may contribute to the change in leukopenia induced by concurrent administration of ADR and DOC. The antitumor effect in the DOC-ADR group was the highest in the dosing groups. CONCLUSIONS: In the present study, the findings suggest that ADR administered 12 h after DOC injection (DOC-ADR group) not only inhibits tumor growth more strongly but also significantly reduces leukopenia compared with results for the simultaneous-dosing (ADR/DOC) group and significantly reduced the number of toxic deaths compared with the other groups.

Animals↗

PubMed1993

In vitro sensitivity of human hematopoietic progenitor cells to 4-hydroperoxycyclophosphamide.

Protracted engraftment and prolonged thrombocytopenia remain problems when marrow purged with 4-hydroperoxy-cyclophosphamide (4-HC) is employed for autotransplants. Toxic effects of 4-HC on early progenitor and stem cells might play an important causative role. Surprisingly, few investigations have examined the effects of 4-HC on progenitor cells other than colony-forming units-granulocyte/macrophage (CFU-GM) and burst-forming units-erythroid (BFU-E), and only one study could be found where 4-HC exposure was carried out on cells purified beyond the buffy coat stage. Since the cellular milieu, and in particular the red blood cell count, can ameliorate 4-HC toxicity, the suppressive effect of this agent on marrow stem cells might be underestimated. We therefore investigated the relative 4-HC sensitivity of different human bone marrow progenitor cells in vitro using partially purified adherent cell- and T lymphocyte-depleted bone marrow mononuclear cells (A-T-MNC). Cells were exposed to increasing doses (10 to 200 micrograms/mL) of 4-HC using a standard purging protocol established for bone marrow buffy coat cells. Effects on mixed (CFU-Mix), erythroid (CFU-E and BFU-E), granulocyte-macrophage (CFU-GM), and stromal cell (CFU-F) progenitors were determined. In addition, we examined the 4-HC sensitivity of megakaryocyte progenitors (CFU-Meg) since, to our knowledge, this has not been reported before. As expected, increasing doses of 4-HC led to progressive inhibition of hematopoietic colony formation. CFU-F, CFU-Mix, and CFU-Meg appeared most resistant to 4-HC exposure, while CFU-E, BFU-E, and CFU-GM appeared most sensitive. At doses over 100 micrograms/mL, the usual concentration recommended for purging of buffy coat cells, hematopoietic colony formation was completely inhibited. These data suggest that if more highly purified marrow cells are employed for purging, lower 4-HC doses may need to be used. They also suggest that the thrombocytopenia that frequently accompanies 4-HC purging is not likely due to loss of CFU-Meg.

Bone Marrow Cells↗

PubMed2006

Recommendation of the use of myeloblast percentage among non-erythroid cells instead of percentage among total nucleated cells for therapeutic response assessment in acute erythroid leukemia.

The diagnostic criteria of acute erythroid leukemias (AEL) has been revised by WHO in 2001. The National Cancer Institute (NCI) published a set of standardized diagnostic and response criteria for acute myeloid leukemia in 1990, which was revised in 2003. The aim of the present study was to establish the best criteria for therapeutic response assessment in the newly classified AEL and evaluate patient outcomes. Fifty-two patients with AEL as defined by the new WHO criteria were evaluated in this study. The following seven indices for therapeutic response assessment were evaluated: (i) NCI criteria (myeloblast percentage among total nucleated cells (TNC) and cellularity); (ii) myeloblast percentage among non-erythroid cells (NEC) and cellularity; (iii) erythroid series percentage among TNC; (iv) pronormoblast percentage among erythroid cells; (v) ratio of pronormoblasts and blasts; (vi) maturation arrest index; and (vii) disappearance of erythroid dysplasia. Complete remission (CR) patients with <5% of myeloblast/NEC (NEC-CR) showed significantly longer overall survival periods (mean 55.8 months) compared to CR patients with >5% myeloblast/NEC (mean 11.7 months, P = 0.006). NEC-CR patients also had longer event-free survival (median 16.4 months) compared to patients with >5% and <20% of myeloblast/NEC (median 6.2 months) (P = 0.044). The other indices for therapeutic response assessment are not significant for predictability of relapse and outcomes. Therefore, we recommend that the myeloblast percentage among NEC be used instead of myeloblast percentage among TNC for therapeutic response assessment in AEL.

Adolescent↗

PubMed1996

Differential effects of nitric oxide on erythroid and myeloid colony growth from CD34+ human bone marrow cells.

Nitric oxide (NO) is a reactive molecule with numerous physiologic and pathophysiologic roles affecting the nervous, cardiovascular, and immune systems. In previous work, we have demonstrated that NO inhibits the growth and induces the monocytic differentiation of cells of the HL-60 cell line. We have also demonstrated that NO inhibits the growth of acute nonlymphocytic leukemia cells freshly isolated from untreated patients and increases monocytic differentiation antigens in some. In the present work, we studied the effect of NO on the growth and differentiation of normal human bone marrow cells in vitro. Mononuclear cells isolated from human bone marrow were cultured in semisolid media and treated with the NO-donating agents sodium nitroprusside (SNP) or S-nitroso-acetyl penicillamine (SNAP) (0.25 to 1 mmol/L). Both agents decreased colony-forming unit-erythroid (CFU-E) and colony-forming unit-granulocyte macrophage (CFU-GM) formation by 34% to 100%. When CD34+ cells were examined, we noted that these cells responded to SNP and SNAP differently than did the mononuclear cells. At a concentration range of 0.25 to 1 mmol/L, SNP inhibited the growth of CFU-E by 30% to 75%. However, at the same concentration range, SNP increased the number of CFU-GM by up to 94%. At concentrations of 0.25 to 1 mmol/L, SNAP inhibited the growth of CFU-E by 33% to 100%. At a concentration of 0.25 mmol/L, SNAP did not affect CFU-GM. At higher concentrations, SNAP inhibited the growth of CFU-GM. Although SNP increased intracellular levels of cGMP in bone marrow cells, increasing cGMP in cells by addition of 8-Br-cGMP (a membrane permeable cGMP analogue) did not reproduce the observed NO effects on bone marrow colonies. These results demonstrate that NO can influence the growth and differentiation of normal human bone marrow cells. NO (generated in the bone marrow microenvironment) may play an important role modulating the growth and differentiation of bone marrow cells in vivo.

Antigens, CD34↗

PubMed1991

Effect of recombinant human transforming growth factor beta and tumor necrosis factor alpha on bone marrow progenitor cells of HIV-infected persons.

With progressive disease, the majority of patients with human immunodeficiency virus (HIV) infection develop bone marrow failure with anemia, leukopenia, and thrombocytopenia, the cause of which has not yet been clarified. Besides direct infection of bone marrow progenitor cells and immune-mediated cytolysis, the action of inhibitory cytokines, like transforming growth factor beta (TGF-beta) and tumor necrosis factor alpha (TNF-alpha), has to be discussed with regard to their pathophysiological role in HIV-induced bone marrow failure. Therefore, the influence of recombinant human TGF-beta and TNF-alpha on colony growth of pluripotent (CFU-GEMM), erythroid (BFU-E), and granulocyte-macrophage (CFU-GM) progenitor cells from the bone marrow of HIV-1-infected persons and normal controls was assessed in methylcellulose cultures. Both cytokines inhibited the colony formation of hematopoietic progenitor cells from HIV-positive persons. When added to unseparated bone marrow cells from HIV-infected persons and normal controls, the 50% inhibition (ID50) of BFU-E by TGF-beta occurred at 1.3 ng/ml and 3.7 ng/ml, respectively, while the ID50 of CFU-GM occurred at 15.5 ng/ml and 142.7 ng/ml. Concentrations of TNF-alpha, causing 50% inhibition of colony formation by bone marrow cells from HIV-infected or noninfected individuals were 6.3 U/ml and 17.0 U/ml for BFU-E, and 24.4 U/ml and greater than 3,000 U/ml for CFU-GM, respectively. The ID50 of the CFU-GEMM growth was below the lowest concentration of both cytokines tested. The suppressive effects were specifically abolished by antibodies against TGF-beta and TNF-alpha, thus confirming that the inhibitory activities were due to the cytokine preparation used.

Adult↗

PubMed1989

Differential effect of natural killer cells on modulating CFU-Meg and BFU-E proliferation in situ.

As a result of the striking discrepancy between the substantial amount of information on the role of natural killer (NK) cells derived from in vitro experimentation and the corresponding lack of data demonstrating their physiologic relevance, we have examined the importance of NK cells for the steady state production of hematopoietic stem and progenitor cells in situ. B6D2F1 mice received two 0.2-ml injections of ascites containing anti-NK 1.1 monoclonal antibody (anti-NK) directed to murine NK cells. Another group was treated similarly but received "control" ascites (CA) that was induced solely by injection of a mouse myeloma cell similar to the fusion partner of the NK 1.1 hybridoma. Two days after the last injection, we determined the number and cycling fraction (i.e., percentage of cells in S-phase determined by in vivo hydroxyurea suicide) of femoral stem cells (spleen colony-forming units; CFU-S) and committed granulocyte-macrophage (granulocyte-macrophage colony-forming units; CFU-GM), megakaryocytic (megakaryocyte colony-forming units; CFU-Meg), and erythroid (erythroid burst-forming units; BFU-E and erythroid colony-forming units; CFU-E) progenitor cells. The striking finding was the almost complete abolishment of the proliferation of CFU-Meg in the anti-NK group, resulting in a statistically significant (p less than 0.02) decrease in number to 37% of the CA control. In contrast, the cycling fraction of BFU-E was significantly (p less than 0.05) increased to 205% of the CA control with no increase in number. The number and cycling fraction of CFU-S, CFU-GM, and CFU-E in the anti-NK group were not significantly different from values in the control group. These findings add a novel aspect to the understanding of hematopoietic regulation by providing the first evidence for a differential effect of NK cells on the steady-state proliferation of CFU-Meg and BFU-E in situ.

Animals↗

PubMed1990

Role of heme metabolism in AZT-induced bone marrow toxicity.

We studied the effects of azidothymidine (AZT) on rat bone marrow heme metabolism and colony growth as determined by assays of granulocyte-macrophage (CFU-GM), erythroid (CFU-E), burst-forming erythroid (BFU-E), and alpha-aminolevulinic acid synthase (ALAS), the first enzyme in the heme pathway. In all cases, AZT (1-0.01 microM) was found to be toxic to bone marrow colony growth. When AZT was included in colony assays, 1 microM resulted in 98-100% inhibition, whereas lower concentrations (0.01 microM) inhibited growth by 58-76%. In addition, cultures from AZT-treated animals had a marked reduction in colony growth as compared with sham controls. In most cases, hemin (10(-5) M) was found to overcome some of the colony inhibitory effects of AZT. Analysis of heme metabolism indicated that ALAS activity was reduced by 71% in bone marrow cells from treated animals. ALAS activity for control was 204 +/- 33 pM ALA formed/4 X 10(6) cells/hr, whereas ALAS activity from AZT-treated animals was only 60 +/- 3 pM ALA formed/4 x 10(6) cells/hr. It is considered that AZT toxicity may be due to a depression in the pool of available heme, which is required for adequate hematopoiesis.

5-Aminolevulinate Synthetase↗

PubMed1994

Myelosuppressive effects in vivo with very low dosages of monomeric recombinant murine macrophage inflammatory protein-1 alpha.

Macrophage inflammatory protein (MIP)-1 alpha has myelosuppressive/myeloprotective effects in vivo in mice. We recently reported that > 99.7% of recombinant murine (rm) MIP-1 alpha polymerizes rapidly at relatively high concentrations in physiological salt solution, and it is the monomeric form of MIP-1 alpha that is active in vitro as a myelosuppressive factor. Polymerized MIP-1 alpha is inactive in this effect and does not block the myelosuppressive action of monomeric MIP-1 alpha. MIP-1 alpha could be maintained in monomeric form in physiological saline if diluted to low concentrations. This led us to reevaluate the actual amounts of MIP-1 alpha necessary for myelosuppression in vivo. C3H/HeJ mice were injected intravenously (i.v.) with monomeric rmMIP-1 alpha or control diluent and effects were evaluated on progenitor cells--multipotent colony-forming units (CFU-GEMM), burst-forming units-erythroid (BFU-E), and colony-forming units-granulocyte/macrophage (CFU-GM)--as described in previous studies in which MIP-1 alpha concentrations were used that we now know to have been mainly in polymerized form. Monomeric MIP-1 alpha rapidly decreased cycling rates and absolute numbers of myeloid progenitor cells in marrow and spleen. These effects, which occurred with about 1000-fold less MIP-1 alpha than we previously reported, were dose-dependent, time-related, and reversible. Suppressive effects were noted within 3 hours for cell cycling and within 24 hours for absolute numbers of progenitor cells in marrow and spleen and were lost by 48 hours. Decreased circulating neutrophils were noted at 48 hours. Column-separated polymerized rmMIP-1 alpha was inactive in vivo. These results demonstrate the potency of low doses of monomeric MIP-1 alpha in vivo. Since clinical administration of large amounts of an agent that is mainly in an inactive form may result in severe pharmacological side effects, the information presented here is of relevance for potential clinical trials using MIP-1 alpha as a myelosuppressive/myeloprotective agent.

Animals↗

PubMed2002

In vitro myelotoxicity of propanil and 3,4-dichloroaniline on murine and human CFU-E/BFU-E progenitors.

Because of the wide use of pesticides for domestic and industrial purposes, the evaluation of their potential effects is of major concern for public health. The myelotoxicity of the herbicide propanil (3,4-dichloroproprioanilide) and its metabolite 3,4-dichloroaniline (DCA) is well documented in mice, but evidence that pesticides may severely compromise hematopoiesis in humans is lacking. In this study, an interspecies comparison of in vitro toxicity of these two compounds on murine and human burst- and colony-forming unit-erythrocyte (BFU-E, CFU-E) and colony-forming unit-granulocyte/macrophage (CFU-GM) progenitors, has been carried out. Murine bone marrow progenitors and human cord blood cells were exposed to propanil or DCA in doses ranging from 10 micro M to 1000 micro M, and the toxic effect was detected by a clonogenic assay with continuous exposure to the compounds. The results on murine cells indicate that the erythrocytic lineage is the most sensitive target for propanil and DCA. On the other hand, human progenitors seem to be less sensitive to the toxic effects of both compounds than murine progenitors at the same concentrations (IC(50) values are 305.2 +/- 22.6 micro M [total erythroid colonies] and >500 micro M [CFU-GM] for propanil). Propanil was significantly more toxic to human erythroid progenitors than to human CFU-GM progenitors, as was found for the murine cells, emphasizing the role of the heme pathway as the target for propanil. These data confirm the evidence that the compounds investigated interfere with erythroid colony formation at different stages of the differentiation pathway and have different effects according to the dose.

Aniline Compounds↗

PubMed1996

The effect of IL-1 receptor antagonist on the proliferation of hematopoietic progenitor cells in regenerating bone marrow.

To evaluate the involvement of IL-1 on bone marrow granulocyte-macrophage (CFU-GM) and erythroid (BFU-E and CFU-E) progenitor cell regeneration during the recovery of hematopoiesis after sublethal irradiation of CBA mice, we examined the effects of IL-1 receptor blockade by recombinant human IL-1 receptor antagonist (rhIL-1ra). The actual number of progenitors and proportion of these cells in S phase of the cell cycle were determined in regenerating bone marrow cells obtained 3 days after 2 Gy irradiation both following the in vivo administration of rhIL-1ra, as well as after the in vitro preincubation with increasing amounts of rhIL-1ra. The results revealed that rhIL-1ra decreased the number and the proportion of CFU-GM in the S phase in regenerating bone marrow. As concerning erythroid progenitors, rhIL-1ra treatment suppressed BFU-E and enhanced CFU-E-derived colony growth, indicating that the biological effects of IL-1 might be different depending on the stage of differentiation. The observed effects pointed to the importance of the basal levels of IL-1, as well as IL-1 receptor expression during the recovery of hematopoiesis.

Animals↗

PubMed1994

The optimal dose of glycosylated recombinant human granulocyte colony stimulating factor for use in clinical practice: a review.

In pharmacokinetic studies, higher maximum plasma concentrations of granulocyte colony stimulating factor (G-CSF) were achieved after intravenous administration of lenograstim than after subcutaneous administration of the same dose. However, subcutaneous administration resulted in a longer elimination half life, and a greater and more sustained neutrophil response. The safety of lenograstim at doses up to 40 micrograms/kg/day has been demonstrated in Phase I studies involving 21 healthy volunteers and 37 cancer patients. In controlled Phase II dose-ranging studies which included 66 solid tumour and 121 bone marrow transplantation (BMT) patients, doses from 2 micrograms/kg/day were shown to effectively restore neutrophil counts. A dose of 5 micrograms/kg/day was chosen for further clinical trials. Phase III double-blind randomised studies in a further 439 patients with solid tumours or postBMT confirmed the clinical efficacy of the recommended therapeutic dose of lenograstim of 150 micrograms/m2/day which is equivalent in efficacy to 5 micrograms/kg/day. At this unique dose, one 263-microgram vial of lenograstim is sufficient to effectively treat the average adult patient in solid tumour or bone marrow transplantation settings.

Drug Administration Schedule↗

PubMed1993

Large-scale expansion of human stem and progenitor cells from bone marrow mononuclear cells in continuous perfusion cultures.

There is a growing consensus that clinical practice in the areas of bone marrow (BM) transplantation and gene therapy will rely on the ex vivo expansion of hematopoietic cells. We report here on the development of continuously perfused culture systems (bioreactor systems) that expand human stem and progenitor cells from BM mononuclear cell (MNC) populations obtained without cell enrichment. In three separate experiments, 10 bioreactors were each inoculated with 3 x 10(7) BM MNC from patients undergoing marrow harvest for autologous transplantation. At various times thereafter (between days 6 and 16), duplicate bioreactors were harvested and cells were analyzed. The bioreactors contained three cell populations that were analyzed separately: nonadherent cells; cells that were loosely adherent to the endogenously formed stromal layer; and an adherent cell layer that required trypsinization for removal. Total cell numbers increased continuously to give an overall 10-fold (range, 8- to 11-fold) expansion by day 14. The adherent stromal layer significantly expanded to more than 2 x 10(7) cells, but remained less than 6% of the total cell population. Colony-forming unit-granulocyte-macrophage (CFU-GM) numbers expanded 21-fold (range, 12- to 34-fold) by day 14 and, because this expansion was greater than that for total cells, CFU-GM were enriched by as much as fourfold by day 14. Burst-forming unit-erythroid (BFU-E) numbers peaked earlier than did CFU-GM numbers, with a 12-fold (range, 6- to 18-fold) expansion obtained on day 8. In contrast to CFU-GM, which were predominantly nonadherent, BFU-E were more evenly distributed between the three cell populations. Stem cell activity was measured by the long-term culture-initiating cell (LTC-IC) limiting dilution assay. The number of LTC-IC per reactor consistently increased with time in all cultures, resulting in a 7.5-fold (range, 3.4- to 9.8-fold) expansion. In summary, more than 3 billion cells, containing 12 million CFU-GM, were reproducibly generated from the equivalent of a 10 to 15 ml BM aspirate. These data indicate that small numbers of BM MNC can be readily expanded ex vivo in continuous perfusion cultures, and that such ex vivo expansion may have direct applications in clinical and experimental BM transplantation.

Bone Marrow Cells↗