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Biomedical subjects

T Motoji

Publications and source records attributed to T Motoji.

At least 55 records · Page 3Linked to original sources
PubMed1993

Circulating megakaryocyte progenitors in myeloproliferative disorders are hypersensitive to interleukin-3.

Previous studies have reported that megakaryocyte progenitors in myeloproliferative disorders (MPD) formed spontaneous megakaryocyte colonies without the addition of megakaryocyte colony-stimulating factor (Meg-CSF). To determine whether this spontaneous colony formation is due to autocrine proliferation of MPD megakaryocyte progenitors or to hypersensitivity to Meg-CSF that might exist in the culture system, we investigated colony-forming unit-megakaryocytes (CFU-Meg) in the peripheral blood of 11 MPD patients, using serum-free cultures. Spontaneous megakaryocyte colonies were observed in serum-free cultures of nonadherent mononuclear cells (NAdMNC) obtained from MPD patients with thrombocytosis, whereas the NAdMNC of MPD patients without thrombocytosis, that of patients with reactive thrombocytosis and normal subjects never formed spontaneous colonies. However, the spontaneous colonies from MPD patients with thrombocytosis disappeared in cultures using highly purified CD34-positive cells as target cells. To study the hypersensitivity of megakaryocyte progenitors to Meg-CSF, dose-response experiments were performed with interleukin-3 (IL-3). CFU-Meg from MPD patients with thrombocytosis showed maximal growth at the concentrations of IL-3 lower than those for normal subjects. CFU-Meg of MPD patients without thrombocytosis and that of patients with reactive thrombocytosis showed the same colony growth response to IL-3 as that of normal subjects. This result indicates that the CFU-Meg of MPD patients with thrombocytosis are hypersensitive to IL-3. It also suggests that spontaneous colony formation by NAdMNC is not due to the autocrine growth of megakaryocyte progenitors but is due to the hypersensitivity of megakaryocyte progenitors to Meg-CSF, such as IL-3, released by accessory cells. Furthermore, it is possible that such hypersensitivity of CFU-Meg to IL-3 might be a pathogenic factor in MPD with accompanying thrombocytosis.

Adult↗
PubMed1993

Heterogeneity of CD7+ 4- 8- 1- leukemia: usefulness of cytoplasmic antigen detection for subclassification.

We identified CD3 and myeloperoxidase (MPO) antigens in the cytoplasm of leukemic cells from 15 patients with CD7+ 4- 8- 1- leukemia. Seven patients, five of whom had a mediastinal mass, had only cytoplasmic CD3 (cCD3) antigen; these seven were regarded as possibly being of T-lineage type. Six patients, one of whom had a mediastinal mass, showed both cCD3 and MPO; they were considered to have mixed lineage type. Two patients had neither cCD3 nor cytoplasmic myeloid antigens; they were therefore considered to have stem cell type. These two latter types were considered as the subgroups: mixed lineage or stem cell type. Patients with T-lineage type were good responders to L-17M therapy; four out of five who received L-17M therapy achieved complete remission. There were significant differences between the two subgroups in relapse-free survival, patients with T-lineage type exhibiting better prognosis than other types (p < 0.05).

Adult↗
PubMed1992

Granular lymphocyte leukemia with pure red cell aplasia: usefulness of gene analysis in assessing therapeutic effect.

A patient with granular lymphocyte leukemia (GLL) of the CD3+, CD4-, CD8+ phenotype accompanied by pure red cell aplasia (PRCA) is described. Surface marker analysis, nonmajor histocompatibility complex (MHC)-restricted cytotoxicity assay, gene analysis, and in vitro colony assay were performed on the granular lymphocytes before and after treatment. Cyclophosphamide therapy was highly effective, and after remission clonal granular lymphocytes were no longer identified by T-cell antigen receptor (TCR) gene analysis or surface marker analysis. Lymphocytes obtained after remission did not exhibit elevated levels of non-MHC-restricted cytotoxicity, nor did they demonstrate a suppressive effect on erythroid colony formation. TCR gene analysis proved to be a sensitive parameter for evaluating the residual malignant granular lymphocytes. Gene analysis will be useful both for timing the discontinuation of treatment and for the early detection of relapse. Various factors possibly related to the development of PRCA in this patient were investigated and their significance is discussed.

Bone Marrow↗
PubMed1992

Differential expression of non-major histocompatibility complex-restricted cytotoxicity in patients with granular lymphocyte-proliferative disorders associated with or unassociated with severe anemia.

Of 27 patients with granular lymphocyte-proliferative disorders (GLPD), 18 patients had CD3+ T-cell-lineage GLPD (T-GLPD), and 9 patients had CD3-CD16+ natural killer (NK) cell-lineage GLPD (NK-GLPD). In 9 of the 18 patients with T-GLPD, severe anemia of less than or equal to 7.5 g/dl hemoglobin (mean 5.4 g/dl) and erythroid hypoplasia in the bone marrow developed, while the remaining 9 patients with T-GLPD and 9 patients with NK-GLPD exhibited hemoglobin levels of greater than or equal to 10.0 g/dl, and erythroid hypoplasia was not found. The number of leukocytes, neutrophils, lymphocytes or granular lymphocytes in the peripheral blood, or the percentage of lymphocytes in the bone marrow did not differ significantly between the patients with T-GLPD associated with severe anemia and those with T-GLPD not associated with severe anemia, and the immunophenotypes of peripheral blood mononuclear cells (PBMC) were not significantly different either. However, when non-major histocompatibility complex (MHC)-restricted cytotoxicity was assayed with PBMC, T-GLPD patients with severe anemia and NK-GLPD patients exhibited significantly higher levels of non-MHC-restricted cytotoxicity than T-GLPD patients without severe anemia. Because PBMC obtained from T-GLPD patients with severe anemia were shown not to lyse erythroblasts directly, the possibility that patient PBMC lyse erythroblasts in the bone marrow and thus cause anemia seems unlikely. The pathogenesis of anemia in GLPD was discussed.

Anemia↗
PubMed1992

A case of transfusion-associated graft-versus-host disease not prevented by white cell-reduction filters.

A case of transfusion-associated graft-versus-host disease (TA-GVHD) in a patient with non-Hodgkin's lymphoma is reported. The patient, a 67-year-old woman, was diagnosed as having diffuse, mixed type non-Hodgkin's lymphoma, at clinical stage IIIA. She was treated with combination chemotherapy and received multiple blood transfusions for anemia and thrombocytopenia. Although white cells (WBCs) were reduced in the transfused components by WBC-reduction filters, the patient developed TA-GVHD that was confirmed by skin biopsy. It is suggested that the WBC reduction attained with these filters does not prevent TA-GVHD in immunocompromised patients. It is recommended that all blood components should be irradiated before transfusion to such patients.

Aged↗
PubMed1992

Mutations of the p53 tumour suppressor gene in haematologic neoplasms.

Mutations of the p53 tumour suppressor gene have frequently been observed in several types of solid tumours and are believed to be implicated in the development of these tumours. To determine the relevance of p53 mutations in haematologic neoplasms, we performed polymerase chain reaction-single strand conformation polymorphism analysis on the p53 gene in 45 patients with various types of haematologic neoplasms. In exons 5-8 containing highly conserved regions, mobility shifts indicating sequence alterations were detected in four of the 45 patients, and subsequent sequencing was performed. A point mutation resulting in a novel stop codon was detected at codon 213 in one of 23 cases of chronic myelogenous leukaemia (one of five cases of blast crisis). Point mutations causing amino acid substitutions were detected in one of four cases of myelodysplastic syndrome at codon 195, one of three cases of adult T-cell leukaemia at codon 281, and one of eight cases of acute lymphoblastic leukaemia at codon 281, and these missense mutations were accompanied by loss of the wild type allele. Patients harbouring these nonsense and missense mutations were in advanced disease stages. These findings suggest that mutational inactivation of the p53 gene is infrequent but is involved in the tumorigenesis of several types of haematologic neoplasms at least in some cases.

Amino Acid Sequence↗
PubMed1991

Correlation between the proliferative response to granulocyte colony-stimulating factor and the positivity of transferrin receptor in acute myeloblastic leukemia cells.

The use of granulocyte colony-stimulating factor (G-CSF) after chemotherapy for acute myeloblastic leukemia (AML) has been reported. However, there is a drawback in that G-CSF may stimulate the proliferation of AML progenitors. To determine the parameter(s) indicative of responsiveness of AML blasts to G-CSF, various surface phenotypes of blasts were examined in relation to the blast colony formation stimulated by G-CSF in 39 AML patients. A correlation was found only with transferrin receptor positivity among the various phenotypes studied. The population mean of percentages of transferrin receptor-positive blasts in the group responding to G-CSF in vitro was significantly higher than that of blasts in the group not responding to G-CSF. A further correlation was found between transferrin receptor positivity and the number of G-CSF receptors on the blasts; that is, blasts expressing more G-CSF receptors have greater transferrin receptor positivity. In our previous study, we observed that blasts with a large number of G-CSF receptors produce more colonies in response to G-CSF. These results indicated that blasts expressing more transferrin receptors have a larger number of G-CSF receptors and may show more active proliferation in response to G-CSF. Therefore, the proliferative response of blasts to G-CSF can be predicted by examining transferrin receptor positivity. The clinical use of G-CSF in AML patients may be recommended when the patient's blasts have a low level of transferrin receptor expression. The measurement of transferrin receptors on blasts, instead of the rather complicated G-CSF receptor determination, would be a useful indicator for the safer application of G-CSF in AML patients.

Antigens, CD↗
PubMed1991

Effects of interleukins 1-7 on the proliferation of T-lineage acute lymphoblastic leukemia cells.

We investigated the proliferative effects of interleukins 1-7 (IL-1 to -7) on leukemic cells from 10 patients with T-lineage acute lymphoblastic leukemia (T-ALL). Five patients had CD7+4-8-acute leukemia, one had CD5+ acute leukemia, and four had CD1+ acute leukemia. To examine the proliferative effect of each interleukin, 3H-TdR incorporation method was used. In the presence of IL-1, no increase in 3H-TdR incorporation was observed for any of the T-ALL cells. With IL-2, 3H-TdR incorporation increased in cells from 5 out of 10 T-ALL patients, including those with CD7+4-8-, CD5+, and CD1+ acute leukemia. In the presence of IL-3 or IL-6, 3H-TdR incorporation increased in cells from 2 out of 5 patients with CD7+4-8- acute leukemia. However, CD5+ or CD1+ acute leukemia cells were not stimulated by IL-3 or IL-6. With IL-4, 3H-TdR incorporation was increased in the cells from 2 out of 5 patients with CD7+4-8- acute leukemia and in the cells of 2 of those with CD1+ acute leukemia. IL-5 increased the 3H-TdR incorporation by cells from 2 out of 5 patients with CD7+4-8- acute leukemia and 1 patient with CD1+ acute leukemia. IL-7 increased 3H-TdR incorporation in cells from all five CD7+4-8- acute leukemia and 2 of those with CD5+ or CD1+ leukemia. No synergistic effect was found when IL-7 and other cytokines were added to cells from the 3 patients with CD7+4-8- acute leukemia who were tested.

Antigens, CD↗
PubMed1991

Granulocyte colony-stimulating factor (G-CSF) receptors on acute myeloblastic leukaemia cells and their relationship with the proliferative response to G-CSF in clonogenic assay.

The number and the affinity of granulocyte colony-stimulating factor (G-CSF) receptors expressed by blast cells in acute myeloblastic leukaemia (AML) were determined using radiolabelled recombinant human G-CSF (rhG-CSF). Eighteen of 20 patients demonstrated specific binding, and Scatchard analysis revealed a single class of high affinity (Kd 15-130 pM) G-CSF receptors on the AML blasts. The number of G-CSF receptors varied from 55 to 1,200 per cell (mean 278). In the remaining two patients, specific binding was not observed. The number of G-CSF receptors did not differ significantly between various AML subtypes, but the mean receptor number was the highest on type M2 blasts. A chemical cross-linking study revealed that the G-CSF receptor has an approximate molecular weight of 140,000. Autoradiography showed heterogeneity of the distribution of G-CSF receptors on the AML blasts obtained from a single patient. The number of colonies stimulated by the addition of rhG-CSF varied from 0 to 566 per dish, and blast colony formation was observed in eight of 20 patients. The population mean of G-CSF receptor number expressed by blasts that formed colonies on stimulation with rhG-CSF was significantly higher than that on blasts which did not form colonies. These results suggest that a proliferative response of AML blasts to G-CSF may be predicted when the blasts express a large number of G-CSF receptors. Accordingly, it may be safer to restrict the clinical use of G-CSF to AML patients who have blasts with a low G-CSF receptor expression and no response to G-CSF in blast colony assay.

Granulocyte Colony-Stimulating Factor↗
PubMed1990

Flow cytometric analysis of expression of interleukin-2 receptor beta chain (p70-75) on various leukemic cells.

We analyzed the expression of the interleukin-2 receptor (IL-2R) beta chain (p70-75) on various leukemic cells from 44 patients by flow cytometric analysis using the IL-2R beta chain-specific monoclonal antibody (MoAb), designated Mik-beta 1, which has been recently developed. Flow cytometric analysis demonstrated the expression of the IL-2R beta chain on granular lymphocytes (GLs) from all eight patients with granular lymphocyte proliferative disorders (GLPDs), on adult T-cell leukemia (ATL) cells from all three patients with ATL, and on T-cell acute lymphoblastic leukemia (T-ALL) cells from one of three patients with T-ALL. Although GLs from all the GLPD patients expressed the IL-2R beta chain alone and not the IL-2R alpha chain (Tac-antigen: p55), ATL and T-ALL cells expressing the beta chain coexpressed the alpha chain. In two of seven patients with common ALL (cALL) and in both patients with B-cell chronic lymphocytic leukemia, the leukemic cells expressed the alpha chain alone. Neither the alpha chain nor the beta chain was expressed on leukemic cells from the remaining 28 patients, including all 18 patients with acute nonlymphocytic leukemia, five of seven patients with cALL, all three patients with multiple myeloma, and two of three patients with T-ALL. These results indicate that three different forms of IL-2R chain expression exist on leukemic cells: the alpha chain alone; the beta chain alone; and both the alpha and beta chains. To examine whether the results obtained by flow cytometric analysis actually reflect functional aspects of the expressed IL-2Rs, we studied the specific binding of 125I-labeled IL-2 (125I-IL-2) to leukemic cells in 18 of the 44 patients. In addition, we performed 125I-IL-2 crosslinking studies in seven patients. The results of IL-2R expression of both 125I-IL-2 binding assay and crosslinking studies were in agreement with those obtained by flow cytometric analysis. These results indicate that flow cytometric analysis using MoAbs, anti-Tac, and Mik-beta 1 is useful for detecting the expression of the IL-2R chains.

Antibodies, Monoclonal↗
PubMed1990

Successful treatment of refractory anemia with high-dose methylprednisolone.

Five patients with refractory anemia were treated with high-dose methylprednisolone. An immediate and long-lasting hematological improvement without serious side effects was achieved in two of the patients, although chromosomal abnormalities persisted in both. The clinical course and laboratory data of these two patients are described. Restoration of normal hematopoiesis was achieved regardless of the enhancement of colony formation of granulocyte progenitor cells by the simultaneous addition of hydrocortisone in vitro. The same treatment was given to six patients who had refractory anemia with an excess of myeloblasts (RAEB), but no improvement was observed in any of these patients. It appears that high-dose methylprednisolone can be valuable in the treatment of refractory anemia, but is not useful for RAEB.

Adult↗
PubMed1990

Effects of various cytokines on proliferation of acute lymphoblastic leukemia cells.

We investigated the effects of recombinant human interleukins 1 to 6 (rIL-1 to -6) on the proliferation of blast cells from patients with acute lymphoblastic leukemia (ALL). The 3H-TdR incorporation in the presence of various cytokines was examined in cells from 14 patients: 12 with B-lineage ALL, 1 with T-lineage ALL and 1 with biphenotypic leukemia. In B-lineage ALL, a significant increase in 3H-TdR incorporation was observed in 5/12 cases (42%) in the presence of rIL-1 alpha, in 10/12 cases (83%) with rIL-2, in 9/12 cases (75%) with rIL-3, in 3/6 cases (50%) with rIL-4, in 4/6 cases (67%) with rIL-5, and in 4/12 cases (33%) with rIL-6. The mean stimulation index of the cells showing a positive response was 1.74 for rIL-1 alpha, 3.40 for rIL-2, 2.55 for rIL-3, 1.86 for IL-4, 1.56 for rIL-5, and 2.97 for rIL-6. T-lineage ALL cells were stimulated only in the presence of rIL-2, and biphenotypic leukemia cells were not stimulated by any of the cytokines tested.

Antigens, CD↗
PubMed1990

Induction of eosinophilic colonies by interleukin-5 on acute myeloblastic leukaemic cells.

The effect of interleukin-5 (IL-5) on blast colony formation of acute myeloblastic leukaemia (AML) cells was studied. IL-5 showed a weak but significant colony stimulatory effect in one out of six cases studied. IL-5 induced eosinophilic colony growth in this case, and chromosomal and histochemical analyses strongly suggested that these eosinophilic colonies were derived from leukaemic blast progenitor cells. To our knowledge, this is the first report that IL-5 induces eosinophilic colonies on fresh AML cells. A possible induction of differentiation of AML blast cells by IL-5 is suggested.

Adult↗
PubMed1990

Enhanced growth of clonogenic cells from acute myeloblastic leukaemia by erythropoietin.

The effect of erythropoietin (Epo) on colony formation by blast progenitors in acute myeloblastic leukaemia other than erythroleukaemia was studied using a blast colony assay. Epo alone did not induce colony formation, but when it was used together with phytohaemagglutinin-stimulated leucocyte-conditioned medium (PHA-LCM) the number of leukaemic colonies significantly increased in nine out of 12 cases studies. Preincubation of Epo with anti-Epo antibody completely abolished this enhancement, indicating that the increase in colony numbers was caused by Epo itself. Cell surface phenotype analysis of colonies produced by Epo plus PHA-LCM showed no increase in percentages of erythroid and megakaryocyte lineages. The addition of Epo also increased the self-renewal capacity of leukaemic blast cells. Fresh leukaemic cells did not express Epo receptors, but they were induced after incubation with PHA-LCM. The present study thus showed that the proliferative response to Epo is not restricted only to the erythroid lineage, but also extends to AML blast cells other than those in erythroleukaemia in the presence of colony stimulating factors.

Antibodies↗
PubMed1990

A new serum-free culture system for leukemic colony assay.

A new serum-free assay system for leukemic colony formation (leukemic colony-forming units, L-CFU) was established, and, utilizing this system, the colony-promoting activities of recombinant human colony-stimulating factors (rhCSFs) and the effectiveness of CSFs on cellular self-renewal capacity were investigated. The serum-free assay system included deionized bovine serum albumin (1%), cholesterol (7.8 micrograms/ml), and ASF 101 medium. The plating efficiencies obtained by culturing with phytohemagglutinin-stimulated leukocyte-conditioned medium (PHA-LCM) ranged from 0.01% to 1.35% in this system. Spontaneous colonies were observed in 9 out of 13 cases studied. Recombinant human granulocyte CSF (rhG-CSF), rh granulocyte-macrophage CSF (rhGM-CSF), rh interleukin 3 (rhIL-3), and rh interleukin 1 (rhIL-1) stimulated colony formation in 10, 9, and 6 out of 13, and 5 out of 11 cases, respectively. The magnitude of stimulation by each CSF ranged from 6% to 145%, 21% to 200%, 0% to 1229%, and 14% to 182% of PHA-LCM, respectively. In eight cases, blast colony assays in serum-free and serum-containing cultures were simultaneously performed. The magnitudes of responsiveness of each CSF differed in the two assay systems; this indicated some effect of fetal calf serum. The value of self-renewal capacity was also examined and compared with that in serum-containing culture. Self-renewal capacity could be maintained with a serum-free culture system. It showed marked variation from case to case, and there was no correlation between the primary colony formation and the self-renewal capacity in both culture systems. Taken together, the development of a completely serum-free culture system was found to be efficient as evaluated by a L-CFU colony assay.

Blood↗
PubMed1989

Effect of recombinant interferons on hairy cell leukemia progenitors.

The effects of recombinant interferons (rIFNs) on colony formation by progenitor cells from the peripheral blood of patients with hairy cell leukemia (HCL) were examined. Results showed that both rIFN-alpha and -beta inhibited HCL colony formation in a dose-dependent manner, with the inhibitory effect of rIFN-alpha being similar in degree with that of rIFN-beta. The inhibitory effect of rIFN-gamma, however, was not uniform; of four patients, inhibition was observed in cells from two patients, but no effect was found in the cells of the other two. These results indicate that rIFN-alpha and -beta could be effective in the treatment of HCL, whereas rIFN-gamma may be of limited efficacy.

Blast Crisis↗