[Show abstract][Hide abstract] ABSTRACT: To perform a case-control study of a functional M196R polymorphism of tumour necrosis factor receptor type 2 (TNF-RII) in a Japanese population and a meta-analysis of all published reports on the polymorphism to investigate the association of the M196R polymorphism of TNF-RII with systemic lupus erythematosus (SLE).
The functional M196R polymorphism of TNF-RII was genotyped by using polymerase chain reaction combined with the subsequent single-strand conformation polymorphism (PCR-SSCP) analysis for screening, followed by nucleotide sequencing for confirmation. A total of 331 patients and 359 controls were subjected to a case-control study. A meta-analysis of the available case-control studies including all published data as well as our own data was performed to investigate the association of the functional M196R polymorphism of TNF-RII with SLE.
Our case-control study did not show any significant association of a functional M196R polymorphism of TNF-RII with SLE, although there was a trend towards association. A meta-analysis of seven case-control studies in eight different ethnic populations including our own showed that 196M/R and 196R/R genotypes combined was significantly associated with an increased risk of SLE (odds ratio (OR) 1.29, 95% confidence interval (CI) 1.04 to 1.60; p = 0.02). Stratification by ethnicity showed a more significant association in Asians, including Japanese, Korean and Vietnamese (OR 1.40, 95% CI 1.10 to 1.78; p = 0.006). The effect of the 196R allele on SLE was not clear in Caucasians.
The 196R allele of the functional M196R polymorphism of TNF-RII is a risk factor for SLE, especially in the Asian population.
Annals of the Rheumatic Diseases 04/2007; 66(3):320-4. DOI:10.1136/ard.2006.058917 · 10.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A growing body of evidence indicates that genetic factors are involved in an increased risk of infection. We investigated whether mannose-binding lectin (MBL) gene polymorphisms that cause low levels of MBL are associated with the occurrence of major infections in patients, mainly bearing hematological malignancies, after high-dose chemotherapy (HDT) rescued by autologous peripheral blood stem cell transplantation (auto-PBSCT). A retrospective evaluation of 113 patients treated with HDT and auto-PBSCT revealed that the low-producing genotypes, B/B and B/LXA, were associated with major bacterial infection (P=0.0016, OR 7.9). We next performed a nation-wide large-scale study to assess the allele frequency of the MBL coding mutation in a total of 2623 healthy individuals in Japan. The frequency of allele B was estimated to be approximately 0.2, almost the same in seven different areas of Japan. This common occurrence suggests that MBL deficiency may play an important role in the clinical settings of immunosuppression.
Genes and Immunity 04/2005; 6(2):162-6. DOI:10.1038/sj.gene.6364165 · 2.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 1998, a consensus meeting was held in Miyazaki, Japan, to develop an approach to management of febrile neutropenia (FN). The K-HOT study group decided to examine whether this proposal was applicable to clinical practice in a multicenter study. Patients who developed fever with neutrophil counts <1,000/microL were randomized to receive either a single antibiotic, cefepime or one of the carbapenems, or a combination of cefepime and an aminoglycoside. Patients who became afebrile within the first 3 days were continued on the same treatment. Patients who remained febrile were switched to a combination regimen if they were randomized to receive a single agent, and patients on combination medication were changed from cefepime to another cephalosporin. A total of 165 patients were entered into the trial. One hundred fifty-three patients were evaluable for response. The average age was 52 years, and 70% of the patients had acute leukemia. Severe neutropenia, defined as <100/microL at the time of FN, was seen in 62% of the patients on entry and during the course of treatment 71% of patients experienced neutrophil counts of <100/microL. Microbiologically documented infection was seen in 6.5% for monotherapy, and 10.5% for a combination treatment, and fever of unknown origin occurred in 75.3% and 59.2% of the patients in each regimen, respectively. Excellent to good response was seen in two-thirds of the patients in all treatment groups. Adverse events were minimal, and three early deaths were observed at days 9, 16, and 16 among patients treated with a single antibiotic and three in the combination regimen group at days 14, 15, and 20. These results indicate that cefepime or a carbapenem alone is as effective as a combination of cefepime and an aminoglycoside for treating FN.
American Journal of Hematology 12/2002; 71(4):248-55. DOI:10.1002/ajh.10236 · 3.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Trials of immunosuppressive therapy have been reported in some case reports of hypoplastic myelodysplastic syndrome (MDS). In this study, we gave immunosuppressive therapies to eight patients with normo- or hyperplastic MDS of refractory anemia subtype without karyotypic abnormalities and analyzed the HLA-DRB1 type or the presence of paroxysmal nocturnal hemoglobinuria (PNH) neutrophils in these patients. Cyclosporin A (CyA) therapy was effective for improving cytopenia in four of the eight MDS patients. While the side effects of CyA were mostly mild and transient, one patient demonstrated karyotypic abnormality following CyA therapy and accelerated to refractory anemia with an excess of blasts. Additional antithymocyte globulin (ATG) therapy was effective in one of three nonresponders to CyA therapy. One patient died due to leukemic transformation after ATG therapy. When we analyzed the correlation between the response to CyA therapy and the HLA-DRB1 type, there were more responders with DRB1*1501 (three of four patients) than without (one of four patients), but a statistically significant difference was not evident between the two groups. In addition, the presence of PNH neutrophils was not correlated with the response to CyA and/or ATG therapy. These results indicate the usefulness of immunosuppressive therapies even for normo- or hyperplastic MDS patients. Further trials using more patients with a long follow-up period would be worthwhile in order to clarify the possibility of disease progression and in order to predict the response of patients.
Annals of Hematology 12/2001; 80(11):634-8. DOI:10.1007/s002770100360 · 2.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chronic lymphocytic leukemia (CLL) is a rare disease in Japan. Recent advances in molecular biology, diagnostic criteria and classification of CLL have reinforced the concept of each category of CLL as a distinct entity. Since there have been no recent studies on the incidence and prevalence of CLL in Japan, the Kyushu Hematology Organization for Treatment (K-HOT) Study Group conducted two studies of CLL. One study is a prospective registration of newly diagnosed hematological disorders, which gave us some idea of the incidence of CLL in our region (Kyushu island) where adult T-cell leukemia is endemic. A total of 677 patients with hematological disorders were registered over a 6-month period and 11 patients were diagnosed as having CLL among 182 leukemia patients. This amounts to 6% of all leukemias, which is twice as frequent as previously reported in Japan. The other study is a retrospective analysis of CLL. Eleven institutions of the K-HOT Group analysed their diagnostic records of chronic lymphoid leukemia, and 145 patients with CLL were found over a period of 3-12 yr. After the data were reviewed 11 patients were excluded through having a different type of leukemia. The proportion of chronic B-cell lymphoid leukemia was 73% (98/134), while that of T-cell leukemia was 18% (24/134). The proportion of T-cell chronic leukemia was 5-6 times higher than that in Western countries. Two institutions had a complete database on hematological disorders. From this database, the annual incidence of CLL was estimated to be 0.48 per 100 000. Thus, the incidence of CLL in Japan is at least 4-5 times lower than that in Western countries, suggesting that chronic B-cell leukemia is really rare, but chronic leukemia of T-cell lineage develops in Japan as frequently as in Western societies. Further investigation is required to delineate why the incidence of B-CLL is so low in Japan.
European Journal Of Haematology 10/2001; 67(3):152-7. DOI:10.1034/j.1600-0609.2001.5790514.x · 2.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It has been speculated that a soluble form of G-CSFR might be physiologically present in humans, since G-CSFR mRNA that lacks a transmembrane domain has been identified from a human myelomonocytic cell line. Here, we demonstrate human soluble G-CSFR (sG-CSFR) of two different molecular sizes (80 and 85 kDa) on an immunoblot analysis using Abs generated against the amino-terminal, extracellular domain of the full-length G-CSFR. Both isoforms of sG-CSFR were able to bind recombinant human G-CSF (rhG-CSF). RT-PCR analysis with primers targeted outside of the transmenbrane region revealed that membrane-anchored G-CSFR is expressed at all maturation stages of purified myeloid cells, including CD34+CD13+ cells (blasts), CD11b-CD15+ cells (promyelocytes or myelocytes), CD11b+CD15+ cells (metamyelocytes and mature neutrophils), and CD14+ cells (monocytes). On the other hand, sG-CSFR mRNA was detectable in CD11b-CD15+, CD11b+CD15+, and CD14+ cells, but not in the CD34+CD13+ blast population. The serum concentration of both isoforms of sG-CSFR appeared to be correlated with the numbers of neutrophils/monocytes before and after rhG-CSF treatment in normal individuals. Thus, two isoforms of sG-CSFR are physiologically secreted from relatively mature myeloid cells and might play an important role in myelopoiesis through their binding to serum G-CSF.
The Journal of Immunology 01/2000; 163(12):6907-11. · 4.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In the present study, we examined the effects of interleukin-3 (IL-3) on the proliferation of leukaemic progenitor cells from 11 Japanese patients with acute myeloblastic leukaemia (AML), including the effect of its combination with granulocyte/macrophage colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF). The results showed that IL-3 sufficiently stimulated the proliferation of AML progenitor cells in almost all the cases examined, and that the stimulation pattern of IL-3 was similar to that of GM-CSF, although different from that of G-CSF. Furthermore, IL-3 worked synergistically with G-CSF, whereas IL-3 and GM-CSF together were less actively synergistic (P < 0.05). These findings suggest the possibility of IL-3/G-CSF/cytosine arabinoside (Ara-C) combination therapy, which may be able to enhance the cytotoxic effect of Ara-C on AML progenitor cells powerfully in a wider range of patients including cases refractory for IL-3/Ara-C combination therapy.
[Show abstract][Hide abstract] ABSTRACT: The effect of interleukin-10 (IL-10) on the growth of leukemic blast cells from patients with acute myeloblastic leukemia (AML) is in need of clarification. We therefore examined the effect of IL-10 on AML cells obtained from 10 patients. Although granulocyte colony-stimulating factor (G-CSF) and/or granulocyte/macrophage colony-stimulating factor (GM-CSF) was able to stimulate the growth of AML progenitor cells to form leukemic blast colonies, IL-10 itself demonstrated no leukemic blast colony-forming activity and no synergistic stimulating activity with other cytokines. However, leukemic blast colonies were formed without the addition of exogenous cytokines in four cases and IL-10 suppressed these spontaneous colony formations in two of the four cases. Since the production of G-CSF and GM-CSF was observed in these two cases, the presence of an autocrine growth mechanism mediated by these cytokines was suggested. When serial concentrations of IL-10 were added, the production of G-CSF and GM-CSF was dramatically inhibited in a dose-dependent manner. These findings suggested that IL-10 could suppress the autocrine growth of AML cells by inhibiting their production of G-CSF and/or GM-CSF. In addition, the administration of IL-10 may be harmless to normal hematopoiesis because IL-10 did not suppress the growth of normal hematopoietic progenitor cells. Our study provides experimental support for the clinical application of IL-10 in patients with AML.
International Journal of Hematology 01/1998; 66(4):445-50. DOI:10.1016/S0925-5710(97)00070-4 · 1.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The biological roles of the soluble granulocyte colony-stimulating factor (G-CSF) receptor, which arises as a result of alternative RNA splicing, are as yet unknown. In this study, we examined the in vitro effect of a chimeric protein composed of the extracellular region of a murine G-CSF receptor and the human IgG1 Fc region because a human natural soluble G-CSF receptor was not available. First, we found that this chimeric soluble G-CSF receptor could inhibit the biological activity of G-CSF on normal bone marrow colony formation. Because G-CSF also plays an important role in the proliferation of leukemic blast cells, we next examined the effect of the soluble G-CSF receptor on leukemic blast colony formation in 10 acute myeloblastic leukemia cases. Although G-CSF stimulated the proliferation of leukemic progenitor cells to form leukemic blast colonies, the chimeric soluble G-CSF receptor completely inhibited this stimulatory effect. Furthermore, the chimeric soluble G-CSF receptor also inhibited spontaneous leukemic blast colony formation in two cases. Because a high concentration of G-CSF was observed in the supernatants of leukemic blast cells from these two cases, it seems likely that the soluble G-CSF receptor cut off the autocrine growth mechanism of leukemic blast cells mediated by G-CSF. These findings suggest the possibility that the soluble G-CSF receptor could be used in a clinical application for acute myeloblastic leukemia patients in the future.
Cancer Research 09/1997; 57(16):3395-7. · 9.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We investigated surface immunophenotypes of peripheral blood mononuclear cells (PBMC) collected by cytotoxic and cytotoxic/G-CSF mobilization of peripheral blood stem cells (PBSC) from 38 patients with haematological malignancies in complete remission who underwent consolidation chemotherapy. PBMC were collected by leucapheresis during the haematopoietic recovery phase after intensive chemotherapy. G-CSF was used for mobilization of PBSC in 19 cases. Surface immunophenotyping of frozen-thawed PBMC was performed by flow cytometry. Our findings showed that monocytes and T cells were the two major cell components of PBMC. There were very few B cells in PBMC. Expression of CD45RO and HLA-DR was elevated in lymphocytes, suggesting that T cells in PBMC were activated. The percentage of CD34 positive cells were significantly increased in PBMC collected by cytotoxic/G-CSF mobilization (group 1) compared with PBMC collected by cytotoxic mobilization (group 2). There were significantly higher percentages of CD14 and CD33 positive cells in group 1 than in group 2. The percentage of CD4 positive lymphocytes positive for HLA-DR was significantly higher in group 1 compared with group 2. These observations indicated that PBMC contained a large number of monocytes and activated T cells, especially in cytotoxic/G-CSF mobilization.
[Show abstract][Hide abstract] ABSTRACT: Treatment with recombinant interferon-alpha (rIFN-alpha) may induce autoimmunity. We have evaluated the effect of rIFN-alpha on pre-existing thyroid disease with special reference to changes in TSH receptor antibody.
Five patients, who had a history of autoimmune thyroid disease diagnosed between 2 and 16 years earlier (three patients had Graves' disease while two had Hashimoto's thyroiditis), were treated with rIFN-alpha for chronic hepatitis C. Before, during and after rIFN-alpha therapy, we determined thyroid function, antithyroid antibody, thyroid echogenicity and the surface phenotype of the peripheral and intrathyroidal lymphocytes.
Four of the patients developed overt hypothyroidism after 4-7 months of rIFN-alpha therapy, and two of them had a preceding history of low-uptake thyrotoxicosis. Recovery of thyroid function was observed in all four patients. Strongly positive blocking type TSH receptor antibody was detected and an increase in the percentage of CD19 positive cells in the intrathyroidal lymphocytes was also observed in three of the patients even though the goitre size increased in two of them. One of the patients became thyrotoxic later when stimulating type TSH receptor antibody became positive. Another patient suffered from reversible hypothyroidism although stimulating type TSH receptor antibody remained strongly positive throughout the clinical course.
Our data thus indicated a high incidence of an unusual type of reversible hypothyroidism with TSH receptor antibodies in patients with chronic hepatitis C and pre-existing autoimmune thyroid disease after recombinant interferon-alpha therapy through a mechanism involving both the humoral and cellular immune systems.
[Show abstract][Hide abstract] ABSTRACT: We previously identified a receptor for granulocyte colony-stimulating factor (G-CSFR) on platelet membranes, and reported that G-CSF enhanced ADP-induced platelet aggregation. Here, we investigated the priming effect of G-CSF on the hemostatic system in healthy volunteers given G-CSF. Following the administration of rhG-CSF (10 micrograms/kg for 30 min div) to 10 healthy volunteers, we found a significant elevation in the maximum platelet aggregation rate induced by ADP or collagen, thromboxane B2 level and amount of thrombin-antithrombin III complex. The D-D dimer and plasminogen activator inhibitor-1 showed no significant changes. These observations indicate that G-CSF administration may induce hypercoagulability in susceptible subjects. Therefore, patients or donors at risk of thrombosis or hypercoagulable state should be followed carefully after G-CSF administration.
International Journal of Hematology 07/1996; 63(4):311-6. DOI:10.1016/0925-5710(96)00459-8 · 1.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We studied the generation of human natural killer (NK) cells from CD34+ cells that were isolated from peripheral blood stem cells (PBSC) mobilized by granulocyte colony-stimulating factor (g-CSF). The isolated CD34+ cells were cultured in the presence of a combination of interleukin-1 (IL-1alpha), IL-2, and stem cell factor for 5 weeks without marrow stroma. We found that the CD34+ cells isolated from G-CSF-mobilized PBSC (G-CSF/PBSC) could differentiate into a population of NK cells which were CD56+(bright)/CD3- and showed morphologic characteristics of large granular lymphocytes. Immunophenotypic analysis of the NK cells thus generated showed that a small proportion of them expressed CD2, CD8 and CD16 surface markers and approximately half of them coexpressed CD7. This NK population exhibited cytotoxic activity against a NK-sensitive cell line, K562. These observations suggest that CD34+ cells from G-CSF/PBSC contain precursors of NK cells that can differentiate into functional NK cells.
British Journal of Haematology 04/1996; 92(4):788-94. · 4.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 15-Deoxy-11-O-methylspergualin (MeDSG) is an analogue of 15-deoxyspergualin, which has potent immunosuppressive activity. The present study was designed to evaluate the in vitro effects of MeDSG on the functions of peripheral blood mononuclear cells (PBMC) and bone marrow cells derived from healthy volunteers. MeDSG failed to suppress the proliferation of PBMC stimulated with mitogens. In the allogeneic mixed lymphocyte reaction, MeDSG strongly suppressed both the proliferation of lymphocytes and the generation of alloreactive cytotoxic T lymphocytes, but did not affect the cytolytic activity of the established cytotoxic T lymphocytes. MeDSG had no effect on the cytolytic activity of natural killer cells. Concerning positive hematopoietic regulators, MeDSG had a slight enhancing effect on the release of granulocyte-macrophage colony-stimulating factor and a slight inhibitory effect on the release of interleukin-6 and granulocyte-colony-stimulating factor from PBMC stimulated with mitogens. Significantly, MeDSG completely suppressed the colony formation of bone marrow cells in the presence of granulocyte colony-stimulating factor.
The Journal of Antibiotics 04/1995; 48(3):243-7. DOI:10.7164/antibiotics.48.243 · 1.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Leucopenia is often observed in patients with liver cirrhosis. We measured levels of serum granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with liver cirrhosis by a sensitive enzyme linked immunosorbent assay. Eight out of 22 patients with liver cirrhosis had detectable serum GM-CSF (range, 55 to 245 pg/ml:mean, 135 pg/ml). Serum GM-CSF was detected in all patients with a granulocyte count below 2.0 x 10(9)/l, but in only one patient with a granulocyte count above 2.0 x 10(9)/l. Haemoglobin concentration, platelet count, serum albumin, total bilirubin and aminotransferase levels did not correlate with serum GM-CSF levels. These findings may reflect a feedback mechanism between the number of circulating granulocytes and serum GM-CSF levels in patients with cirrhosis.
[Show abstract][Hide abstract] ABSTRACT: The presence of granulocyte colony-stimulating factor receptor (G-CSFR) in CD34+ hematopoietic progenitors is demonstrated by flow cytometry. Cord blood mononuclear cells (MNCs) contain about 1.09 +/- 0.2% CD34+ cells, 0.32 +/- 0.1% CD34+/G-CSFR+ (G-CSFR+) cells, and 0.77 +/- 0.1% CD34+/G-CSFR- (G-CSFR-) cells. The colony-forming ability of G-CSFR+ cells in the presence of G-CSF, granulocyte-macrophage CSF (GM-CSF), interleukin-3 (IL-3), and erythropoietin (Epo) was higher than that of G-CSFR- cells (29.5 vs. 9.8%; p < 0.01). In the fraction of G-CSFR+ cells, the most frequently formed colony type was CFU-G/GM, while burst-forming unit-erythroid (BFU-E) or colony-forming unit-macrophage (CFU-M) were rare. On the other hand, the incidence of BFU-E and CFU-G/GM was similar in the fraction of G-CSFR- cells. This indicates that most granuloid colonies of CD34+ cells were derived from G-CSFR+ cells. These results suggest a lineage commitment for the vast majority of G-CSFR+ hematopoietic progenitors.
[Show abstract][Hide abstract] ABSTRACT: Granulocyte colony-stimulating factor (G-CSF) stimulates a rapid phosphorylation on tyrosines of several proteins of Mr. 130, 100, 90, 70, 44 kd in human myeloid leukemia cell line cells, Kasumi-1, which respond to G-CSF to proliferate in vitro. In HL60 cells, only a 100 kd protein was phosphorylated, and no detectable phosphorylated proteins were observed in neutrophils by the stimulation of G-CSF. Among these proteins, the 130 kd protein was immunoprecipitated by anti- JAK2 serum. While JAK2 is a non receptor tyrosine kinase and is reported to be involved in the signal transduction by various cytokines including growth hormone, erythropoietin, and granulocyte-macrophage colony-stimulating factor/interleukin-3, it is strongly suggested that a signaling pathway that relates to the cell proliferation triggered by G-CSF in immature hematopoietic cells also involves JAK2.
Biochemical and Biophysical Research Communications 10/1994; 203(2):922-8. DOI:10.1006/bbrc.1994.2270 · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A 37-year-old Japanese man with chronic myeloid leukemia (CML) developed myasthenia gravis 29 months after bone marrow transplantation (BMT) from an HLA one locus-mismatched brother. Proximal muscle weakness and bilateral ptosis occurred along with the exacerbation of chronic GVHD shortly after sudden cessation of cyclosporine (CYA) and prednisolone. The diagnosis of myasthenia gravis was made based on clinical symptoms and elevation of an anti-acetylcholine receptor antibody titer and all symptoms related to myasthenia gravis promptly diminished with the start of treatment for chronic GVHD. In most previously reported cases, the underlying disease was aplastic anemia (6 of 7 cases) and donors were of the opposite sex (6 of 7 cases). The haplotypes HLA B7 (3 of 5 cases), B35 (3 of 5 cases), and DR2 (3 of 3 cases) were common. All cases suffered from chronic GVHD. The present case had only chronic GVHD and HLA B7 as a background for myasthenia gravis after BMT. The abrupt cessation of immunosuppressive therapy may also be related to the development of myasthenia gravis after BMT.
Bone Marrow Transplantation 08/1994; 14(1):155-6. · 3.57 Impact Factor