[International guidelines for the clinical evaluation of anti-infective drugs].
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Anti-Bacterial Agents↗
Biomedical subjects
K Sagawa
Publications and source records attributed to K Sagawa.
MAGE-1 gene is expressed in T-cell leukemia.
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Antigens, Neoplasm↗
Diagnosis of silent myocardial ischemia using ambulatory electrocardiographic monitoring with pedometer, analysis of heart rate, and ST loop in ambulatory electrocardiogram.
BACKGROUND: It has been suggested that episodes of silent myocardial ischemia (SMI) might influence the prognosis of patients with ischemic heart disease, as its consequences are similar to those of myocardial ischemia accompanied by pain. Ambulatory electrocardiogram (ECG) is generally employed in diagnosis as well as in evaluation of clinical efficacy in patients with SMI, but problems related to its application remain because of the difficulty in differentiating between nonischemic and ischemic ST-segment depressions and because of the absence of data concerning body movement. METHODS AND RESULTS: We developed a method for simultaneously recording onto magnetic tape both the ECG chart and pedometer count, as well as a program which enables semi-automatic analysis of the heart rate (HR)-ST relationship. This new method was employed to record ambulatory ECG along with pedometer count for a total of 70 patients, consisting of 53 with coronary heart disease who were shown to have ischemic heart disease, and 17 with various heart diseases in whom coronary angiography revealed no coronary stenosis. The HR-ST relationship was assessed for periods during which steps were recorded by the pedometer, that is, when patients were confirmed to have been under exertion effort. Patients demonstrating the following findings were diagnosed as true positive for SMI: the ST segment level did not decline until HR increased to a certain threshold, and the rate of change in the ST-segment level noted thereafter was -0.025 mm/beats/min or lower; or the ST-segment depression induced by effort continued even after discontinuation of exercise, after which time HR began to decrease, and the HR-ST loop consequently described a counterclockwise rotation. Evaluation of the HR-ST relationship based on these criteria revealed excellent results, as demonstrated by values of 79.2% for sensitivity and 94% for specificity. CONCLUSION: Our newly developed method of assessment of the HR-ST relationship via analysis of simultaneous data from an ambulatory ECG and a pedometer appears to be time saving, highly objective, and useful with regard to the diagnosis of SMI and evaluation of the therapeutic effect of drugs in patients with ischemic heart disease.
Aged↗
Suppression by IL-10 and IL-4 of cytokine production induced by two-way autologous mixed lymphocyte reaction.
The immune response of T cells to self-HLA antigens on autologous non-T cells is known as the autologous mixed lymphocyte reaction (AMLR), and is defective in various diseases. We have investigated the effects of exogenous IL-10, a potential agent to treat various inflammatory diseases, on cytokine production induced by two-way AMLR in human peripheral blood mononuclear cells (PBMC). Effects of exogenous IL-4 were also investigated. IL-10 suppressed IL-6, IL-8, TNF-alpha and GM-CSF production when added at the beginning of culture and added 24 h after incubation. It abolished IL-1 alpha production only when added at the beginning of culture. IL-10 did not inhibit IL-3 production. The pattern of suppression by IL-10 of cytokine production induced by anti-CD3 mAb or PHA was similar to that induced by AMLR. Although IL-4 showed a largely similar pattern of inhibition when added at the beginning of culture, the level of inhibition was much lower than that of IL-10. IL-4 did not inhibit cytokine production when added 24 h after culture. These results indicate that IL-10, but not IL-4, is a potent inhibitor to cytokine production induced by two-way AMLR.
Cell Line↗
Melanocyte lysis by cytotoxic T lymphocytes recognizing the MART-1 melanoma antigen in HLA-A2 patients with Vogt-Koyanagi-Harada disease.
The MART-1/Melan-A melanoma antigen recognized by the majority of HLA-A2-restricted tumor-infiltrating lymphocytes is a self antigen expressed on melanocytes and the retina. We have investigated whether Vogt-Koyanagi-Harada (VKH) disease and sympathetic ophthalmia (SO), systemic inflammatory disorders affecting various organs containing melanocytes, are autoimmune diseases directed toward the MART-1 antigen. In two of three patients with VKH disease and one patient with SO, CD8(+) T cell clones (TCC) form intraocular fluid of HLA-A2(+) patients lysed T2 cells when pulsed with a HLA-A2-binding MART-1 peptide, but not a HLA-A2-binding pMel-17 or tyrosinase peptide, in a HLA-A2-restricted manner. In addition, Th, TCC recognizing a HLA-A2-binding MART-1 peptide were also established from peripheral blood mononuclear cells of a patient with VKH disease. In contrast, either CD4(+) TCC from these patients or CD8(+) TCC from the intraocular fluid of HLA-A2(+) patients with uveitis associated with Behcet's disease or HTLV-1 uveitis did not show this cytotoxicity. The results demonstrate that the MART-1 peptide-specific cytotoxic T lymphocytes lyse melanocytes in the eye of patients with VKH disease or SO, suggesting that these diseases are autoimmune diseases directed toward the MART-1 antigen in HLA-A2(+) patients.
Antigens, Neoplasm↗
HTLV-I uveitis.
Human T-cell lymphotropic virus type I (HTLV-I) is known to cause adult T-cell leukemia/T-cell lymphoma and tropical spastic paraparesis/HTLV-I-associated myelopathy. Recent seroepidemiologic, clinical, and virologic studies indicate that the virus is also related to a certain type of uveitis, which has been classified as uveitis without defined etiologies or idiopathic uveitis. According to the seroepidemiologic survey, the seroprevalence of HTLV-I in patients with idiopathic uveitis was significantly higher than that of two control groups, that is, patients with uveitis with defined etiologies and patients with nonuveitic ocular diseases. Clinically, the uveitis seen in HTLV-I carriers is characterized by moderate to severe cellular infiltration in the eye and by moderate retinal vasculitis, and the intraocular inflammation responds well to corticosteroid therapy. Interestingly, 25% of female patients with the disease had a previous history of Graves disease with hyperthyroidisms. The following virologic, molecular biologic findings suggest that cytokines produced by HTLV-I-infected T cells in the eye play the central role in the pathogenic mechanisms of the uveitis: (a) the virus load in the peripheral blood monocytes analyzed by the quantitative polymerase chain reaction methods was significantly greater in patients with the uveitis than in asymptomatic carriers, (b) the proviral DNA of HTLV-I and the gene expression of the virus at the mRNA level was detected in the infiltrating cells from the eyes of the patients, (c) the virus particles were detected by electron-microscopic examination in the T-cell clones established from the intraocular fluid of the patients, and (d) the HTLV-I-infected T cells produced a variety of cytokines without any stimuli, such as interleukin (IL)-1 alpha, IL-2, IL-3, IL-6, IL-8, IL-10, tumor necrosis factor alpha, interferon-gamma, and granulocyte-macrophage colony-stimulating factor. Based on the seroepidemiologic, clinical, and virologic data, the uveitis seen in HTLV-I carriers is considered to be a distinct clinical entity related to HTLV-I infection, and the disease is designated as HTLV-I uveitis.
Adolescent↗
In vitro effects of immunosuppressive agents on cytokine production by HTLV-I-infected T cell clones derived from the ocular fluid of patients with HTLV-I uveitis.
The present study was designed to investigate the in vitro effects of potential therapeutic agents on cytokine production by five HTVL-I-infected T cell clones (TCC) established from the ocular fluid of patients with HTLV-I uveitis. Each of the five HTLV-I-infected TCC was cultured at 1 x 10(6) cells/ml with or without an immunosuppressive agent (hydrocortisone, FK506, rapamycin, indomethacin, or prostaglandin E2) for 22 hr in humidified 5% CO2 in air at 37 C. The production of various cytokines in the culture supernatant from each TCC was measured by ELISA. The HTLV-I-infected TCC produced high amounts of IL-1 alpha, IL-3, IL-6, IL-8, TNF-alpha, IFN-gamma, and GM-CSF, and low but significant levels of IL-2 and IL-10 without any stimuli. Hydrocortisone severely depressed the production by these TCC of all the cytokines except for IL-2, which was slightly increased. Prostaglandin E2 depressed the production of IL-1 alpha, while it up-regulated the production of IL-6, TNF-alpha, and IFN-gamma. Rapamycin depressed the production of IL-6 and TNF-alpha, and FK506 depressed the production of TNF-alpha. Hydrocortisone also severely depressed the cytokine production by PHA-stimulated peripheral blood mononuclear cells obtained from healthy volunteers. Of the immunosuppressive agents tested, hydrocortisone exhibited the strongest suppression of cytokine production by HTLV-I-infected TCC. This result was in agreement with the in vivo effects of hydrocortisone in patients with HTLV-I uveitis. These TCC will be useful in investigating the effects of potential therapeutic agents for HTLV-I uveitis in vitro.
Body Fluids↗
Induction of MAGE genes in lymphoid cells by the demethylating agent 5-aza-2'-deoxycytidine.
MAGE genes encoding tumor antigens recognized by cytotoxic T lymphocytes are appropriate target molecules for specific immunotherapy of cancer. We have investigated whether the demethylating agent 5-aza-2'-deoxycytidine (DAC) induces MAGE-1, -2, -3, and -6 in normal and malignant lymphoid cells. DAC induced these MAGE genes in both PHA/interleukin-2 (IL-2)-activated T cells from healthy donors and MAGE-negative T and B cell leukemias in most cases. It also induced MAGE-1 in IL-2-dependent T cell clones and all MAGE genes tested in Epstein-Barr virus-transformed B cell lines. Expression of MAGE-1 protein in the cells was confirmed by western blot analysis with anti-MAGE-1 polyclonal antibody. Therefore, demethylation is a potent stimulus to induce MAGE genes in both normal and malignant lymphoid cells.
Amino Acid Sequence↗
Production of IL-6 by T cells from the femoral head of patients with rapidly destructive coxopathy (RDC).
RDC is a syndrome with unknown etiology that causes rapid destruction of a hip joint. We have investigated the production of osteoclast-activating cytokines (IL-6, IL-1alpha and tumour necrosis factor-alpha (TNF-alpha)), interferon-gamma (IFN-gamma) and IL-8 by T cells in the affected joint. The level of IL-6 produced by the T cell lines (TCL) established from the femoral head was significantly higher than that from patients' or healthy donors' peripheral blood mononuclear cells (PBMC). IL-6 production by the TCL from synovial membrane or from patients' PBMC was also significantly higher than that from healthy donors' PBMC. IL-1alpha production by the TCL from the femoral head was significantly higher than any of the other groups when all the TCL were used for the analysis. TNF-alpha production was highest in the TCL from patients' PBMC. The levels of IFN-gamma or IL-8 were not significantly different among these four groups. The plasma levels of all these cytokines except for IFN-gamma, that was rather lower, in RDC patients were not significantly different from those in osteoarthrosis or trauma patients, or healthy donors. These results suggest that T cells at the affected femoral head, and also synovial membrane to some extent, are involved in bone resorption through the production of IL-6 and probably IL-1alpha in patients with RDC.
Aged↗
Monoclonal antibodies (NU-T1 and NU-T2) recognizing antigens expressed on human T cells.
Two murine monoclonal antibodies (mAb) designated as NU-T1 and NU-T2 were generated to identify the novel antigens expressed on human T cells. NU-T1 reacted with peripheral blood T cells, but not with granulocytes or monocytes, whereas NU-T2 were not reactive with peripheral blood lymphocytes, granulocytes or monocytes. Both NU-T1 and NU-T2 reacted with thymocytes. The incidence of NU-T1 or NU-T2 reactivity with the leukemic cells from patients with various types of leukemia was as follows: 12/12 or 4/12 in acute lymphocytic leukemia (ALL) of T cell type, 6/6 or 0/7 in adult T cell leukemia, 0/6 or 0/19 in ALL of non-T non-B cell type, and 0/8 or 0/8 in acute myelocytic leukemia, respectively. The incidence of NU-T1 and NU-T2 reactivity with human leukemic T cell lines were 4/10 and 5/10, respectively. In contrast, neither NU-T1 nor NU-T2 reacted with B cell lines, non-T non-B cell lines, or myeloid cell lines tested. These results indicate that NU-T1 and NU-T2 recognize two distinct differentiation antigens expressed on the cells in the T cell lineage. These mAb would be useful reagents to study the function of human T cells and the immunophenotyping of human T cell malignancies.
Antibodies, Monoclonal↗
Expression of the MAGE gene family in human lymphocytic leukemia.
The MAGE gene family, encoding tumor-rejection antigens recognized by cytotoxic T lymphocytes, is frequently expressed in human solid cancers. However, its expression in leukemia has not been well studied. We have investigated MAGE gene expression at the mRNA level in human leukemia. The MAGE gene family was expressed in 17 of 34 (50%) examples of T cell leukemia (12/21 patients' peripheral blood mononuclear cells and 5/13 cell lines), in 7 of 16 (44%) cases of B cell leukemia (1/8 and 6/8 respectively), but in none of 23 myelomonocytic leukemia cases (0/16 and 0/7), as evaluated by the primers common to the MAGE-1, -3, -4 (-4a and/or -4b), and -6 genes and the semi-quantificative reverse transcription/polymerase chain reaction method. None of a panel of normal lymphoid cells expressed the MAGE gene family. As revealed by the primers specific for each of the MAGE genes, the MAGE-1, -2, -3, -4 or -6 gene was expressed in 8, 8, 6, 2, or 6 respectively out of 23 types of leukemia cell lines. Expression of the MAGE-1 protein in both the cell lines and patients' cells was confirmed by immunoblot analysis with the polyclonal antibody to recombinant MAGE-1 protein. Cellular MAGE-4 protein in the cell lines was measured by an enzyme-linked immunosorbent assay with the polyclonal and monoclonal antibodies to recombinant MAGE-4b protein. In summary, the MAGE gene family was found to be expressed in the substantial proportion of T cell leukemias, but in no case of myelomonocytic leukemia. Antigens coded by the MAGE gene family could be important molecules for understanding specific immunity against lymphocytic leukemia.
Acute Disease↗
Effects of acute caffeine ingestion and menopause on sulfate homeostasis in women.
Inorganic sulfate is a physiological anion which is utilized in the metabolism of both endogenous compounds and xenobiotics. Its homeostasis is maintained predominantly by facilitated reabsorptive processes in the kidneys. The objectives of the present investigation were to evaluate the effects of menopausal status and caffeine ingestion on the serum concentrations and clearance of inorganic sulfate. Thirty-nine women who were classified as premenopausal, postmenopausal with or without estrogen treatment, and postmenopausal with osteoporosis participated in the study. The women were studied on two separate occasions following the ingestion of a decaffeinated beverage to which 6 mg caffeine/kg lean body mass or no caffeine was added. All women were habitual caffeine users (mean ingestion of 588 mg caffeine per day) but abstained from all caffeine sources for 2 weeks prior to the control study day. Postmenopausal women with estrogen supplementation exhibited significantly lower sulfate serum concentrations (0.24 +/- 0.02 mM vs. 0.32 +/- 0.04 mM in premenopausal women, mean +/- SD, p < 0.05) and a decreased renal reabsorption of sulfate for the control (no caffeine) period. There was no difference in serum sulfate or sulfate reabsorption in estrogen supplemented postmenopausal women, compared with women not taking estrogen. Postmenopausal women with osteoporosis had significantly lower creatinine and sulfate clearances than postmenopausal women with estrogen supplementation which may be related to their older age, or factors related to the disease process. The 6 mg/kg dose of caffeine caused a diuresis, but no change in GFR, as indicated by urine volume and creatinine clearance values, respectively. Caffeine administration resulted in an increase in the sulfate excretion rate; there was no change in sulfate serum concentrations. The results of this investigation indicate that menopause results in decreased sulfate serum concentrations that may be the consequence of a decreased renal reabsorption of sulfate. Secondly, this investigation demonstrated that caffeine ingestion increases the urinary excretion of sulfate, an effect that may be related to the diuretic effect of caffeine or due to a caffeine-induced alteration in the renal reabsorption of sulfate.
Adult↗
Elevated levels of plasma endothelin-1 in young patients with pulmonary hypertension caused by congenital heart disease are decreased after successful surgical repair.
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Child↗
Characterization of an established human hepatoma cell line constitutively expressing non-structural proteins of hepatitis C virus by transfection of viral cDNA.
A human hepatoma cell line constitutively expressing proteins of hepatitis C virus (HCV) was established by transfection with cDNA encoding part of the virus nonstructural (NS) genome region. Proteins consistent with authentic processing at NS3/NS4A, NS4A/NS4B and NS4B/NS5A were identified. Pulse-chase experiments indicated that the cleavage between NS3 and NS4A occurred first and cleavage at other sites followed. Expression of specific surface antigens in response to the presence of HCV proteins was analysed by flow cytometry. A significant increase in CD26 expression was observed in cells expressing the HCV proteins. CD26 plays an important role in cellular signal transduction. Its upregulation in response to the presence of HCV proteins may play a role in viral pathology.
Base Sequence↗
Characteristics of the inhibitory effect of mitoxantrone and pirarubicin on lung metastases of colon carcinoma 26.
This study was performed to evaluate the antimetastatic activity of antitumor agents against metastatic colon carcinoma 26 (Co 26Lu), and to investigate their mechanisms of action. Pirarubicin demonstrated the most striking antitumor activity in mice bearing intravenously injected Co 26Lu cells. Etoposide and mitoxantrone also showed marked antitumor activity. Pirarubicin and mitoxantrone also exerted remarkable inhibitory effect on spontaneous lung metastases from subcutaneously implanted Co 26Lu. Pirarubicin showed marked inhibition of both primary tumor growth and lung metastases. Mitoxantrone was effective in preventing lung metastases even at doses that did not exhibit an antitumor effect on the primary tumor. Moreover, mitoxantrone administered two days after intravenous injection of tumor cells obviously reduced the number of lung colonies, while simultaneous injection of the drug did not inhibit colony formation. Mitoxantrone effectively inhibited angiogenesis on the chorioallantoic membrane at doses that did not affect the growth rate of embryos. These results suggest that mitoxantrone, besides its direct antitumor effect on tumor cells, may inhibit lung metastases by inhibiting angiogenesis.
Animals↗
Characterization of CD4+ T helper cells in patients with Kawasaki disease (KD): preferential production of tumour necrosis factor-alpha (TNF-alpha) by V beta 2- or V beta 8- CD4+ T helper cells.
KD is an acute febrile illness in children characterized by coronary arteritis accompanied by aneurysm and thrombotic occlusion. The etiology of KD is unknown. It has been recently reported that KD is associated with the selective expansion of V beta 2+ and V beta 8.1+ T cells in peripheral blood lymphocytes (PBL), by studying the T cell receptor (TCR) repertoire of in vitro activated T cells. KD may therefore be caused by a superantigen [1-3]. To understand better the immunopathology of KD, we investigated TCR V beta 2 and V beta 8.1 expression on both the T cells of freshly isolated PBL and T cell clones (TCC) from patients with KD. Cytokine production by TCC was also studied. Blood samples were obtained from patients with acute (n = 20) and convalescent (n = 20) KD, age-matched children with non-infectious diseases (n = 18), and healthy adults (n = 20). Among these four groups, there were no significant differences in the percentages of either V beta 2+ or V beta 8.1+ T cells of freshly isolated PBL. The same was true for the CD4+ or CD8+ T cell subsets. One hundred and five TCC (98 CD3+ CD4+ CD8- and seven CD3+ CD4- CD8+) established from the affected skin, lymph node or PBL of six patients with KD were also negative for either V beta 2 or V beta 8.1 TCR. Sixty-eight of 105 TCC (65%) produced detectable levels (> 5 pg/ml) of TNF-alpha (6-1016 pg/ml), in the absence of any stimuli. In contrast, only 11 (10%) of 105 TCC or 7 (7%) of 97 TCC produced detectable levels of IL-2 or IL-6, respectively, in the absence of any stimuli. Stimulation with phytohaemagglutinin (PHA) and phorbol myristate acetate (PMA) induced most TCC to produce higher amounts of TNF-alpha, IL-2 and IL-6. These results suggest that CD4+ T helper cells expressing TCR-beta other than V beta 2 or V beta 8 receptor, primarily through TNF-alpha production, are involved in the immunopathology of KD.
Adult↗
Adenosine deaminase isoenzyme levels in patients with human T-cell lymphotropic virus type 1 and human immunodeficiency virus type 1 infections.
In serum, the enzyme adenosine deaminase (ADA) is known to be divided into two isoenzymes, ADA1 and ADA2, which have different molecular weights and kinetic properties. The present study investigated ADA isoenzyme levels in the sera of patients infected with retroviruses associated with adult T-cell leukemia (ATL), human T-cell lymphotropic virus type 1 (HTLV-1)-associated myelopathy (HAM), and AIDS, ADA isoenzyme activities were found to be significantly (P < 0.001) higher in the sera of patients with ATL, HAM, and AIDS than in the sera of healthy controls. In the case of the ADA subtypes in the sera of patients with ATL, ADA1 activity was significantly (P < 0.001) elevated in patients with the acute and lymphoma types of ATL compared with that in patients with the chronic and smoldering types of ATL. ADA2 activity was significantly elevated in the sera of patients with the acute, lymphoma, and chronic types of ATL (P < 0.001) compared with that in patients with smoldering ATL and HTLV-1 carriers. In the case of patients with human immunodeficiency virus type 1 (HIV-1) infection, ADA1 and ADA2 activities in the sera of patients with AIDS and HIV-1 antibody-positive individuals were significantly (P < 0.001) higher than those in the sera of HIV-1 antibody-negative individuals. A significant elevation in ADA2 activity was also seen in the sera of AIDS patients (P < 0.01) compared with that in the sera of HIV-1 antibody-positive individuals. These results suggest that the magnitude of elevation of ADA isoenzyme levels in serum correlates well with the clinical conditions of the patients with these diseases. Measurement of the activities of ADA isoenzymes may therefore provide an additional parameter for distinguishing the subtypes of ATL and may prove to be useful as prognostic and therapeutic monitors in diseases associated with HTLV-1 and HIV-1 infections.
Acquired Immunodeficiency Syndrome↗
Immunopathological mechanisms of human T cell lymphotropic virus type 1 (HTLV-I) uveitis. Detection of HTLV-I-infected T cells in the eye and their constitutive cytokine production.
The immunopathology of human T cell lymphotropic virus type 1 (HTLV-I) uveitis was addressed by using T cell clones (TCC) established from the intraocular fluid of patients with HTLV-I uveitis. Proviral DNA of HTLV-I was identified in 55 out of 94 (59%) or 13 out of 36 (36%) TCC from the ocular fluid or the peripheral blood of these patients, respectively. Most of HTLV-I-infected TCC had a CD3+ CD4+ CD8- phenotype. HTLV-I infection on TCC was confirmed by analysis of the viral mRNA, nucleotide sequence, virus-associated proteins, and virus particles. HTLV-I-infected TCC, but not HTLV-I negative TCC, constitutively produced high amounts of IL-6 (1,336 +/- 1,050 pg/ml) and TNF-alpha (289 +/- 237 pg/ml) in the absence of any stimuli. HTLV-I-infected TCC from the ocular lesion also constitutively produced high amounts of IL-1 alpha (12,699 pg/ml), IL-2 (61 pg/ml), IL-3 (428 pg/ml), IL-8 (1,268 pg/ml), IL-10 (28 pg/ml), IFN-gamma (5,095 pg/ml), and GM-CSF (2,886 pg/ml). Hydrocortisone, a drug effective in vivo for the treatment of HTLV-I uveitis, severely depressed cytokine production in vitro in most cases. In summary, the results demonstrated direct evidence of HTLV-I infection of the eye and suggest that cytokines produced by HTLV-I-infected T cells are responsible for the intraocular inflammation in patients with HTLV-I uveitis.
Adult↗