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Biomedical subjects

M Teramura

Publications and source records attributed to M Teramura.

At least 19 recordsLinked to original sources
PubMed1997

Mechanism of action of antithymocyte globulin in the treatment of aplastic anaemia: in vitro evidence for the presence of immunosuppressive mechanism.

Antithymocyte globulin (ATG) is one of the effective drugs used in the treatment of aplastic anaemia (AA). Although it has been speculated that the mechanism of action of ATG is mediated by its immunosuppressive effect on lymphocytes which might have an inhibitory effect on haemopoietic stem and progenitor cells, no definite evidence of the presence of such a mechanism has been demonstrated. In this study we investigated whether such a mechanism is truly operating in ATG therapy for AA. In five patients who responded to ATG, bone marrow cells were obtained after haematological recovery and CD34-positive cells were separated by immunobeads. Autologous CD34-positive cells were mixed with autologous peripheral CD4- or CD8-positive cells obtained before ATG therapy and after haematological recovery, liquid-cultured for 12h, and then cultured in methylcellulose for 14d in the presence of haemopoietic growth factors. In all five cases studied, only the CD8 cells obtained before ATG therapy suppressed the colony forming unit-granulocyte-macrophage (CFU-GM)- and burst forming unit-erythroid (BFU-E)-derived colony formation. This result is definite evidence that one of the mechanisms of action of ATG in AA is an inhibitory effect on CD8-positive cells which have suppressive activity for the growth of haemopoietic progenitor cells.

Adult↗
PubMed1996

Effect of interleukin 11 on normal and pathological thrombopoiesis.

Interleukin 11 (IL-11) is a stromal cell-derived cytokine that has multiple effects on hematopoietic and nonhematopoietic systems. In vitro, it enhances the growth of early progenitors and promotes megakaryocytopoiesis and erythropoiesis. In healthy animals, IL-11 administration stimulates megakaryocyte maturation and increases peripheral platelet counts. IL-11 accelerates the recovery of peripheral neutrophil, erythrocyte, and platelet counts in mice that have undergone cytoablative treatment. Therefore, IL-11 may be useful clinically as an agent promoting recovery from hematopoiesis. However, its clinical use in patients with hematological malignancies may be restricted because IL-11 has been reported to stimulate some leukemia and myeloma cells. In the United States, phase I trials have shown that IL-11 accelerates recovery from chemotherapy-induced or bone-marrow transplantation (BMT)-induced thrombocytopenia. In Japan, phase II trials studying the thrombopoietic effect of IL-11 in patients with solid tumors postchemotherapy, in patients undergoing BMT, and in patients with aplastic or refractory anemia are now under way. Recently, thrombopoietin (TPO) has been cloned, and its thrombopoietic effect and accelerating effect on platelet count recovery in thrombopoietic states have been demonstrated in animal models. The physiological effect of TPO is restricted to hematopoiesis; therefore, it may have fewer side effects than IL-11. However, in addition to its hematopoietic effect, IL-11 administration to mice that have undergone cytoablative therapy significantly decreases morbidity and mortality due to chemotherapy-related endogenous infections caused by gut microorganisms. Therefore, IL-11 can be used in patients postchemotherapy and post-BMT not only to promote platelet recovery but also to prevent life-threatening infections. The use of in-vitro-expanded hematopoietic stem cells for BMT or as target cells for gene therapy is one of the most exciting areas in the field of medicine. Since IL-11 can expand hematopoietic progenitor-cell populations when used in combination with other cytokines, it may be useful as an ex vivo hematopoietic progenitor-cell-amplifying agent.

Anemia, Aplastic↗
PubMed1996

[Acute myelogenous leukemia with ins(21;8) expressing AML-1-MTG8 fusion transcript].

Here we report a case of acute myelogenous leukemia (M2, FAB classification) presenting with cytogenetic abnormalities of ins(21;8), +del(8) without t(8;21). A 8;21 chromosome translocation is frequently found in acute myelogenous leukemia, especially in the M2 subtype. The translocation results in a fusion transcript between AML1 and MTG8 (ETO), assigned on chromosomes 21 and 8, respectively. Among patients with a t(8;21) abnormality, solid leukemic tumor deposits outside the marrow or good response to chemotherapy are observed frequently. Decrease in neutrophil alkaline phosphatase score and positive rate, and eosinophilia in bone marrow or the blast cells with Auer rods expressing CD19, CD56 antigens occur at a relatively high rate. Although our case lacked these clinical, cytological and cytochemical features, expression of chimeric AML1-MTG8 mRNA was detected. AML1-MTG8 fusion transcript may play a critical role in leukemogenesis of AML M2. Studies on this case may help to reveal the oncogenic function of the AML1-MTG8 fusion gene in AML M2.

Adult↗
PubMed1994

Interleukin-11.

Interleukin-11 (IL-11), a stromal cell-derived cytokine, has been known to act widely in hematopoietic and non-hematopoietic systems. IL-11 supports the growth of certain types of plasmacytoma and hybridoma cells, acts with interleukin-3 (IL-3) in shortening the Go period of early progenitors. IL-11 supports megakaryocyte colony formation and maturation, and acts as an autocrine growth factor in megakaryoblastic cell lines. In addition, IL-11 stimulates erythrocytopoiesis, enhances antigen-specific antibody responses, induces the synthesis of acute phase proteins, inhibits lipoprotein lipase activity and adipocyte differentiation, and promotes neuronal development. Administration of rhIL-11 to mice resulted in an increase of neutrophils and platelets. The human IL-11 gene is localized at 19q13.3-13.4, and codes 199 amino acids and 23 kDa with no N glycosylation. Its receptor and signal transduction share partially those of interleukin-6 (IL-6). Further analysis of its role in normal and pathological state is necessary to determine the exact function and its application for clinical uses.

Acute-Phase Proteins↗
PubMed1994

Combination of interleukin-2-stimulated lymphocytes and bispecific antibodies that efficiently lyse leukemic cells does not affect bone marrow CD34-positive stem cell function in vitro.

We have recently reported that a combination of lymphokine-activated killer (LAK) cells and bispecific antibodies (BsAb) efficiently lysed autologous and allogeneic leukemic blasts that had surface antigens reactive with the BsAb. The effector cells used in that experiment were peripheral blood mononuclear cells stimulated with interleukin-2 (IL-2) for 2 weeks, with the initial addition of anti-CD3 moAb; these were termed T3-LAK effector cells. In this study, we examined the effects of T3-LAK cells and BsAb on autologous normal CD34+ BM cells in both cytotoxicity and colony formation assays. When T3-LAK cells were incubated with CD34+ BM cells, low levels of cytotoxicity were induced against the CD34+ BM cells and the cytotoxicity was enhanced by the addition of anti-CD3 Fab' x anti-CD 13 Fab' BsAb but not by the addition of anti-CD3 Fab' x anti-CD10 Fab' BsAb. This enhancement appeared to be due to the lysis of CD34+CD13+ BM cells. When T3-LAK cells were preincubated with CD34+ BM cells in the presence or absence of the BsAb and plated for colony assay, neither the T3-LAK cells nor the BsAb affected granulocyte-macrophage or mixed-cell colony formation by CD34+ BM cells. Taken together with our previous finding that T3-LAK cells used in combination with the BsAb markedly inhibited colony formation by leukemic progenitor cells, these results indicate that this combination provides a potential new strategy for CD34+ BM cell purging in autologous BMT.

Antibodies, Bispecific↗
PubMed1994

[Cyclic thrombocytopenia associated with erythroid hypoplasia--a case].

We report the case of a 75-year-old woman with cyclic thrombocytopenia associated with erythroid hypoplasia. One platelet cycle lasted for about 28-30 days, with the platelet count fluctuating from 1.0 x 10(4)/microliter to 56.0 x 10(4)/microliter. Megakaryocyte count increased in the phase during which platelet count increased, and decreased in the phase during which platelet count decreased. Bone marrow colony formation was observed in serum-free agar, and megakaryocyte colony count was correlated with the platelet cycle. Platelet-associated immunoglobulin was in the normal range when platelet count increased, but increased when platelet count decreased. These findings suggest that the observed platelet count fluctuation was related to the production and destruction of platelet. Our patient also had erythroid hypoplasia, but her erythrocyte count did not fluctuate. This is the first reported case of cyclic thrombocytopenia and erythroid hypoplasia.

Aged↗
PubMed1993

A bispecific antibody enhances cytokine-induced killer-mediated cytolysis of autologous acute myeloid leukemia cells.

An anti-CD3 Fab' x anti-CD13 Fab' bispecific antibody (BsAb) was generated. This BsAb reacted with both CD3+ T cells and CD13+ acute myeloid leukemia (AML) cells. We investigated whether cytokine-stimulated peripheral blood mononuclear cells (PBMC) could lyse patient AML cells after addition of the BsAb. When interleukin-2 (IL-2)-stimulated PBMC were assayed for their cytotoxicity against 51Cr-labeled allogeneic and autologous CD13+ AML cells, their activity was markedly enhanced by the addition of the BsAb. PBMC stimulated with IL-2 plus anti-CD3 monoclonal antibody (MoAb) showed higher proliferative ability and higher cytotoxicity if this was expressed as lytic units per culture. IL-7-stimulated PBMC also exhibited enhanced cytotoxicity against CD13+ AML cells after addition of the BsAb. Ultrastructurally, CD13+ AML cells incubated with IL-2 plus anti-CD3 MoAb-stimulated PBMC and the BsAb showed apoptotic morphologic changes. A colony assay for AML blast progenitors showed that the colony formation of CD13+ AML cells was inhibited by the addition of autologous IL-2 plus anti-CD3 MoAb-stimulated PBMC, and that this inhibition was further enhanced by the addition of the BsAb. A colony assay for normal bone marrow progenitor cells showed that the addition of autologous IL-2 plus anti-CD3 MoAb-stimulated PBMC and the BsAb inhibited the formation of granulocyte-macrophage colonies and mixed-cell colonies. However, the degree of inhibition was smaller than that for the AML blast colonies. Taken together, these findings suggest that this BsAb may be useful for ex vivo purging of CD13+ AML cells in autologous bone marrow transplantation.

Antibodies, Monoclonal↗
PubMed1993

Interleukin-11 acts as an autocrine growth factor for human megakaryoblastic cell lines.

The cytokine interleukin-11 (IL-11) promotes normal human megakaryocytopoiesis in vitro. However, its role in abnormal megakaryocytopoiesis is not well known. Accordingly, we studied its effects on human megakaryoblastic cell lines CMK and Meg-J. IL-11 stimulated the proliferation of CMK and Meg-J in a dose-dependent manner with maximal growth being achieved at the concentration of 50 and 500 ng/mL, respectively. The growth of the cells was inhibited by anti-IL-11 antibody and IL-11 antisense oligonucleotides. IL-11 transcripts were detected in these two cell lines using a reverse transcriptase-polymerase chain reaction assay. These findings indicate that IL-11 might be an autocrine growth factor for megakaryoblastic cells. IL-11 transcripts also existed in other leukemia cell lines: HL-60, U937, and K562. However, the growth of these cells was not stimulated by IL-11, and was not inhibited by IL-11 antisense oligonucleotides. These results suggested that IL-11 might regulate malignant cells of the megakaryocytic lineage, in part by an autocrine loop.

Base Sequence↗
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

[Mechanism of immunosuppressive therapy for aplastic anemia].

The mechanism of therapeutic effect of anti-lymphocyte globulin (ALG) and cyclosporin A (CyA) on patients with aplastic anemia was studied. When peripheral CD8 positive cells obtained before therapy were cocultured with bone marrow CD34 positive cells obtained after hematological recovery, the number of colony forming unit granulocyte-macrophage (CFU-GM) and burst forming unit erythroid (BFU-E) were decreased. This result indicates that ALG and CyA inhibits CD8 positive cells which suppress the growth of progenitor cells, resulting in the recovery of hematopoiesis. Next we investigated the plasma concentrations of cytokines including G-CSF, GM-CSF, IL-6, IL-1 alpha and IL-1 beta after ALG treatment. Although the elevation of plasma concentrations of G-CSF and GM-CSF after ALG treatment were found in 11 of 13 patients and in 2 of 13 patients respectively, cytokine production by ALG appeared to be unrelated to the therapeutic effect of ALG for aplastic anemia.

Adult↗
PubMed1993

[Study of uneven pulmonary ventilation by sequential bolus method].

We report a new method of measuring the sequential ventilation associated with the primary mechanism for ventilation inhomogeneity. Four types of sequential curves were examined using simultaneous washouts of multiple tracer boluses inhaled from residual volume (RV) and at volumes above RV. The factors that affected the classification of curves were analyzed by the theory of quantification from the statistical data of blood gases, lung function tests, X-ray and clinical diagnosis. This method was applied to evaluate the ventilation distribution in 100 patients with pulmonary disease. It provided clinical information on certain types of disease which cannot be detected by traditional lung function tests. Sequential bolus method may permit determination of whether the disease has predominantly intra or inter-regional inhomogeneity.

Evaluation Studies as Topic↗
PubMed1992

Interleukin-11 enhances human megakaryocytopoiesis in vitro.

We investigated the effect of recombinant human interleukin-11 (rhIL-11) on human megakaryocytopoiesis. Nonadherent and T-cell-depleted human bone marrow (BM) mononuclear cells were cultured in a serum-free agar culture system. rhIL-11 alone did not stimulate the growth of human megakaryocyte colonies. However, when rhIL-11 was combined with optimal or suboptimal doses of rhIL-3, the number and size of the megakaryocyte colonies increased. The same results were obtained when highly purified BM CD34-positive cells were used as target cells. Next, we investigated the effect of rhIL-11 on the ploidy of megakaryocytes. The ploidy distribution of individual cells in megakaryocyte colonies obtained by rhIL-11 in combination with rhIL-3 was significantly shifted towards higher values. Furthermore, when highly purified CD41-positive BM cells were cultured in the presence of rhIL-11, the ploidy distribution was shifted towards higher values. This effect was not suppressed by anti-IL-6 antibody. These results suggest that rhIL-11 acts directly as a megakaryocyte potentiator and may play a role in regulating human megakaryocytopoiesis.

Antigens, CD↗
PubMed1992

Stimulatory effect of tumor necrosis factor-alpha on the growth of CMK, a human megakaryoblastic leukemia cell line.

Recombinant human tumor necrosis factor-alpha (TNF-alpha) was found to stimulate the growth of CMK, a human megakaryoblastic leukemia cell line. This stimulatory effect of TNF-alpha was blocked by anti-TNF-alpha antibody, but antibodies to recombinant human interleukin 3, granulocyte-macrophage colony-stimulating factor and interleukin 6 (all growth factors for CMK cells) did not reduce the stimulatory effect of TNF-alpha. Scatchard analysis showed that CMK cells expressed TNF-alpha receptors on the cell surface. The growth of CMK cells was also stimulated by lymphotoxin, which shares the same receptor as TNF-alpha. These results suggest that TNF-alpha stimulated the growth of CMK cells directly via its specific receptor.

Antibodies↗
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

Activation via the CD3 and CD16 pathway mediates interleukin-2-dependent autocrine proliferation of granular lymphocytes in patients with granular lymphocyte proliferative disorders.

Granular lymphocytes (GLs) in patients with GL-proliferative disorders (GLPDs) are known to express the interleukin-2 receptor (IL-2R) beta chain (p70-75) constitutively and to proliferate in response to stimulation with IL-2 via the beta chain. In this report, we found that the anti-CD3 monoclonal antibody (MoAb) OKT3 could induce the proliferation of GLs from patients with T-cell lineage GLPDs (T-cell receptor-alpha beta+/CD3+16+), but not that of natural killer (NK) cell lineage GLs (T-cell receptor-alpha beta-/CD3-16+). In contrast, the anti-CD16 MoAb 3G8 that reacts with NK-lineage GLs could induce the proliferation of these GLs but not that of GLs with a T-cell phenotype. Furthermore, the anti-CD16 MoAbs CLB FcR gran1 (VD2) and OK-NK, which react with both T- and NK-lineage GLs, induced the proliferation of GLs with both T- and and NK-cell phenotypes. The proliferative response induced via the CD3 or IgG Fc receptor III (Fc gamma RIII: CD16) pathway was shown to be associated with the IL-2-dependent autocrine pathway by various findings, including the induction of endogenous IL-2 production, the coexpression of the IL-2R alpha chain (p55) and the IL-2R beta chain, and the inhibition of GL proliferation by anti-IL-2 or anti-IL-2R MoAb. These results suggest that GL proliferation is mediated at least partly through the IL-2-dependent autocrine pathway, and that the TCR/CD3 complex in T-cell phenotype GLs and the Fc gamma RIII in both T- and NK-cell phenotype GLs play a role in their activation in GLPDs.

Antibodies, Monoclonal↗
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↗