Biomedical subjects

T Sugie

Publications and source records attributed to T Sugie.

At least 19 recordsLinked to original sources

PubMed2001

Gene expression and in situ localization of diacylglycerol kinase isozymes in normal and infarcted rat hearts: effects of captopril treatment.

Diacylglycerol (DG) kinase (DGK) terminates signaling from DG, which serves as an activator of protein kinase C (PKC), by converting DG to phosphatidic acid. DGK is thus regarded as an attenuator of the PKC activity. In rats, five DGK isozymes have been cloned, but little is known about their role in the heart. In this study, the spatiotemporal expression of DGK isozymes was investigated in rat hearts under a normal condition and after myocardial infarction (MI) by in situ hybridization histochemistry and immunohistochemistry. In normal left ventricular myocardium, DGKalpha, DGKepsilon, and DGKzeta mRNAs were expressed evenly throughout the myocardium, although the DGKalpha expression was very low. In infarcted hearts, the expression of DGKzeta was enhanced in the peripheral zone of the necrotic area and at the border zone 3 and 7 days after MI, and to a lesser extent in the middle layer of the granulation tissue 21 days after MI. The enhanced DGKzeta expression in the infarcted and border areas could be attributed to granulocytes and macrophages. In contrast, the expression of DGKepsilon in the infarcted and border areas was lower than that in the viable left ventricle (LV) throughout the postoperation period. Furthermore, DGKepsilon expression in the viable myocardium 21 days after MI decreased significantly compared with left ventricular myocardium in the sham-operated rats and was completely restored by treatment with captopril. Our results demonstrate that three DGK isozymes are expressed in the heart and that each isozyme might have different functional characteristics in the healing and LV remodeling after MI.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2001

Immunosuppression by CD4+ regulatory T cells induced by chronic retroviral infection.

Normal levels of CD4(+) regulatory T cells are critical for the maintenance of immunological homeostasis and the prevention of autoimmune diseases. However, we now show that the expansion of CD4(+) regulatory T cells in response to a chronic viral infection can lead to immunosuppression. Mice persistently infected with Friend retrovirus develop approximately twice the normal percentage of splenic CD4(+) regulatory T cells and lose their ability to reject certain tumor transplants. The role of CD4(+) regulatory T cells was demonstrated by the transmission of immunosuppression to uninfected mice by adoptive transfers of CD4(+) T cells. CD4(+) T cells from chronically infected mice were also immunosuppressive in vitro, inhibiting the generation of cytolytic T lymphocytes in mixed lymphocyte cultures. Inhibition occurred at the level of blast-cell formation through a mechanism or mechanisms involving transforming growth factor-beta and the cell surface molecule CTLA-4 (CD152). These results suggest a possible explanation for HIV- and human T cell leukemia virus-I-induced immunosuppression in the absence of T cell depletion.

Adoptive Transfer↗

PubMed2001

Development of a new drug delivery system for protein drugs using silicone (II).

In order to achieve a zero-order release of protein drugs, we have developed a new drug delivery system using silicone, which is named the covered-rod-type formulation. Preparation of the covered-rod-type formulation was conducted under mild conditions without heat treatment or the use of organic solvents. The covered-rod-type formulation released human serum albumin (HSA) or interferon (IFN) at a constant rate for 30-100 days in vitro without significant initial burst. When the IFN covered-rod-type formulation was implanted in nude mice, the serum IFN concentration was maintained at a constant level during the period of observation, i.e., 28 days. The covered-rod-type formulation enabled precise control of the release of the protein drugs and would be expected to increase the duration of the drug effect and to reduce the frequency of administration and side effects.

Animals↗

PubMed2001

[The influence of lifestyle and night-shift work on sleep problems among female hospital nurses in Japan].

STUDY OBJECTIVE: In this study, by conducting a questionnaire survey, we aimed to clarify the situation regarding sleep disorders in female hospital nurses and their relation with night-shift work and lifestyle. METHODS: The subjects were female nurses working at 5 hospitals, each with more than 400 beds. The survey was carried out in July 2000. The questionnaire contained six items concerning sleep quality from the Pittsburgh Sleep Quality Index (PSQI), two new items on sleep drafted by ourselves, and some questions on lifestyle and shift-work status. RESULTS: Among all female nurses, statistically significant differences were observed between those working and those not working night shifts for 7 items regarding sleep (P < 0.05). Significant correlations were observed between sleep disorders and the following factors: (1) working night shift, (2) having anxiety or stress, (3) getting less than 6 hours of sleep, (4) working in cities, (5) having children, and (6) bathing more than 1 hour before going to bed. In addition, significant correlations were observed between getting less than 6 hours of sleep and the following factors: (1) being 40 years of age or older, (2) working in cities, and (3) having anxiety or stress. CONCLUSIONS: The results of this study suggest that sleep problems among nurses are associated not only with night-shift work but also with lifestyle. They also suggest that nurses who work night shifts, especially in Tokyo, should try to get sufficient hours of sleep to ensure good quality of sleep.

Adult↗

PubMed2000

Development of new drug delivery system for protein drugs using silicone (I).

A novel technique, by which protein drugs effective in small doses can be released over a long period, was developed using silicone and a water-soluble substance. In this study, interferon (IFN) was used as a model of the protein drugs. The IFN-silicone formulation released IFN over long periods of time in vitro and suppressed tumor growth in nude mice for about 100 days after a single administration. This indicates that physiologically active IFN is released over a prolonged period of time from the IFN-silicone formulation in vivo. Silicone formulations are expected to be a practically feasible sustained-release formulation.

Animals↗

PubMed1999

Reduction of tumorigenicity by an interferon-gamma-gene-transduced tumor on another syngeneic tumor in a murine model.

To evaluate the effect of interferon-gamma-gene-transduced cells, DS mice were inoculated into their footpads with syngeneic mammary adenocarcinoma SC42 admixed with interferon-gamma producing mammary adenocarcinoma SC115Kgamma, which had been established by an interferon-gamma-gene transduction in another syngeneic mammary adenocarcinoma SC115 using retroviral vectors. These mice rejected both tumor cells and developed resistance to subsequent challenges with either SC115 or SC42 cells inoculated into their opposite posterior footpads. These results thus indicate that systemic immunological memory to each of the independent tumor cell lines developed in these mice. Although the SC42 cells admixed with irradiated SC115Kgamma cells were rejected by these mice, the SC42 cells admixed with irradiated SC115neoR, in which the neo-gene had been transduced, were observed to proliferate. Tumor rejection was reversed by an in vivo administration of anti-interferon-gamma antibody, thus suggesting that locally produced interferon-gamma plays an important role in tumor elimination and immunological memory induction. In conclusion, interferon-gamma-gene-transduced tumor cells are therefore considered to have a therapeutic potential for other types of malignant tumor cell lines.

Adenocarcinoma↗

PubMed1998

Cyclophosphamide given after active specific immunization augments antitumor immunity by modulation of Th1 commitment of CD4+ T cells.

BACKGROUND AND OBJECTIVES: In order to evaluate the regulatory effect of cyclophosphamide (CPA) on active specific immunization (ASI)-induced antitumor immunity, we examined the timing of CPA (100 mg/kg) with ASI, and focused on whether CPA given after ASI augments antitumor immunity by modulation of Th1 commitment of CD4+ T cells. METHODS: We examined the effect of CPA combined with ASI using sonicated tumor supernatant (SS) and recombinant interleukin-1 beta (rIL-1 beta). RESULTS: Survival of i.p. tumor inoculated mice after ASI (days -12, -9, and -6) followed by 100 mg/kg CPA (day -3) (ASI-CPA) was significantly prolonged compared with that of mice treated with ASI alone, whereas CPA (day -15) treatment before ASI (CPA-ASI) completely abrogated the survival prolongation by ASI alone. In early stage (day 0) after ASI-CPA treatment, the CD4+ T cells were determined to play an important role in the protective immunity for the following reasons: 1) the CD4+/CD8+ ratio of spleen cells from immunized mice was higher than that of the control or CPA alone treated group; and 2) the tumor neutralizing activity of fresh spleen cells was abrogated by CD4+ T-cell depletion in vitro. CD4+ T cells of mice treated with ASI-CPA produced more interferon (IFN)-gamma and IL-2 and less IL-4 than those of the ASI alone group. CONCLUSIONS: These results suggest that the protective immunity induced by ASI was augmented through the modification of the Th1 and Th2 balance by CPA injection after ASI.

Animals↗

PubMed1998

Analysis of effector cells in tumor-bearing mice pre-treated with active specific immunization followed by cyclophosphamide.

In order to analyse the effector population in an immunization model, we treated BALB/c mice with intraperitoneal (i.p.) active specific immunization (ASI), which consists of interleukin (IL)-1-beta and sonicated tumor supernatant (SS) of a plasmacytoma MOPC-104E followed by i.p. injection of cyclophosphamide (CY). This ASI-CY treatment provoked a protective immunity against i.p. tumor inoculation more strongly than that of ASI alone. The main effector cells in tumor neutralizing assay were CD4+ T cells at this pont. The number of spleen cells of the ASI-CY treated mice were significantly lower than that of ASI alone treated mice but it increased significantly 6 days thereafter while this increase was not observed on the mice treated with ASI alone. The spleen cells of the ASI-CY treated mice responded to SS in vitro in the presence of IL-2, more profoundly in CD4 enriched population which produced high amount of TNF-alpha. In vivo tumor-neutralizing activity at a later stage was dependent on CD8+ T cells in addition to CD4+ T cells. These results suggest that antitumor activity by ASI and CY is transduced by sequential population shift from CD4 alone to both of CD4 and CD8.

Adjuvants, Immunologic↗

PubMed1997

Involvement of NK1+ CD4- CD8- alphabeta T cells and endogenous IL-4 in non-MHC-restricted rejection of embryonal carcinoma in genetically resistant mice.

Non-MHC-restricted rejection mechanisms against the murine MHC-negative F9 embryonal carcinoma cells were analyzed. Strains of C57BL/6 (B6) background were resistant to the tumors irrespective of H-2 haplotypes, while others, including BALB/c background, were susceptible. This resistance was suggested to be mediated primarily by the host thymus-dependent alphabeta T cells, since both athymic B6 nude and normal B6 mice depleted with alphabeta T cells showed susceptible phenotype. The difference of the nature of alphabeta T cells infiltrating in H-2-identical B6- and BALB.B-derived tumors was then comparatively analyzed. It was revealed that unique T cells with NK1+ CD4- CD8- (double negative (DN)) alphabeta TCR+ phenotype were accumulated significantly in B6, but few in BALB.B mice. The population freshly isolated from the F9 tumor tissues preferentially expressed potent IL-4 mRNA, and was suggested to be mostly responsible for the endogenous IL-4 production. Indeed, the injection of either anti-NK1.1 or anti-IL-4-neutralizing Ab into the normal B6 rendered them significantly susceptible to the tumor cells. These results strongly suggested that NK1+ DN alphabeta T cells were responsible primarily for the rejection mechanisms against F9 tumors. Histologically, F9 tumors in B6 mice were characterized by abundant macrophage infiltration and massive tumor necrosis, neither of which was observed in those in BALB.B nor B6 mice preinjected with anti-IL-4 Ab, indicating that both histologic features in the resistant strain were dependent on the endogenous IL-4. Present results provide one of the first instances in which a recently emerging minor T cell subpopulation, thymus-dependent NK1+ DN alphabeta T cells, plays an essential role in anti-tumor responses in vivo.

Animals↗

PubMed1997

The effectiveness of active specific immunotherapy using interferon-gamma-gene-transduced tumor cells in a murine tumor model.

Active specific immunotherapy was examined in BALB/c mice using sonicated tumor extract(SE) from plasmacytoma MOPC104E or interferon-gamma-(IFN-gamma)-gene-transduced MOPC104E (Mu gamma), employing interleukin-1 (IL-1) as an adjuvant. Subcutaneous (s.c.) MOPC104E tumor growth was significantly suppressed in mice given a single preimmunization of IL-1 plus Mu gamma-SE, 9 days prior to inoculation, whereas the tumor growth in mice similarly pretreated with IL-1 alone or IL-1 plus MOPC104E-SE(MOPC-SE) was not affected; the mean tumor diameters on day 21 being 6.8 mm, 15.3 mm, and 13.2 mm, respectively. Two-dose preimmunization with Mu gamma-SE alone or IL-1 alone given 10 and 7 days prior to s.c. inoculation also resulted in profound suppression of tumor growth compared to the control. As postsurgical immunization, MOPC104E cells were injected into the foot pads of mice, followed by amputation of the tumor-bearing foot 20 days later, then treatment with IL-1 plus MOPC-SE or IL-1 plus Mu gamma-SE on days 4, 7, and 10 after the amputation. The mean survival of the mice treated with IL-1 plus Mu gamma-SE was significantly prolonged compared to that of the mice treated with IL-1 plus MOPC-SE, at 90.3 days vs 40.9 days, respectively (P < 0.05 by the Cox-Mantel test). These results suggest that SE prepared from IFN-gamma-gene-transduced MOPC104E is more effective for active specific immunotherapy than SE prepared from MOPC104E.

Animals↗

PubMed1996

NK 1+ CD4- CD8- alphabeta T cells in the peritoneal cavity: specific T cell receptor-mediated cytotoxicity and selective IFN-gamma production against B cell leukemia and myeloma cells.

NK1+ double negative (DN) alphabeta T cells were present in the peritoneal exudate cells (PEC) of both normal and athymic B6 mice, accounting for as much as 25% of the total T cells, while their numbers were far less in the PEC of BALB/c and (BALB/c x B6)F1 mice. IL-2-dependent clones established from the DN alphabeta T cell population in the PEC of IL-2 receptor alpha-chain transgenic B6 mice exhibited potent cytotoxicity against a series of B cell lineage leukemias and myelomas, such as CD5+BCL1 and MOPC, without affecting NK-susceptible targets. The cytotoxicity of the clones against BCL1 and MOPC was specifically inhibited by anti-CD3, anti-alphabetaTCR, or anti-relevant Vbeta (Vbeta8) Ab, but not by control Abs, indicating that it was mediated by the specific alphabetaTCR/CD3. Other BALB/c-derived target cells expressing both MHC class I and class II were not affected, and neither Ab against them affected the cytotoxicity, strongly suggesting that the cytotoxicity of NK1+ DN alphabeta T cell clones was independent of the particular MHC Ags. The clones produced IFN-gamma, but little IL-2 or IL-4, in response to anti-CD3 stimulation, to the susceptible, but not resistant, targets, and to IL-12. The clones exhibited TCRalpha (Valpha8) distinct from an invariant TCRalpha (Valpha14) reported to dominate in thymic NK1+ alphabeta T cells. The presence of DN alphabeta T cells with similar functional features in the normal PEC was confirmed by the short term stimulation in vitro. The present results along with other recent reports strongly suggested that, like the mainstream alphabeta T cells, the NK1+ DN alphabeta T cell population consisted of functionally heterogeneous subsets.

Amino Acid Sequence↗

PubMed1996

A new model of active specific immunotherapy using interleukin-1 and sonicated tumor supernatant in murine tumor system.

The possibility of active specific immunotherapy using interleukin-1 (IL-1) plus sonicated tumor supernatant (SS) was examined in a murine tumor model. The growth of intraperitoneally or subcutaneously inoculated plasmacytoma MOPC104E, which is syngeneic to BALB/c mice, was significantly suppressed by intraperitoneal pretreatment with IL-1 and SS from MOPC104E cells (MOPC-SS), on days 10, 7, and 4 before tumor inoculation. Pretreatment with IL-1 plus MOPC-SS or MethA-SS (SS from MethA cells) suppressed the growth of subcutaneous tumor of only the corresponding tumor cells, indicating the development of tumor-specific immunity in vivo. The splenic cells of immunized mice with IL-1 and MOPC-SS showed tumor neutralizing activity. However, their tumor neutralizing activity was abrogated when they were treated in vitro with anti-Thy1.2 or anti-L3T4 plus complement. Moreover, when combined with indomethacin per oral, IL-1 plus MOPC-SS significantly suppressed the growth of established subcutaneous tumor and prolonged survival of post-operative mice. These results suggest that this new type of active specific immunotherapy could be a useful method for cancer immunotherapy, especially when combined with oral indomethacin.

Animals↗

PubMed1995

Expansion of circulating gamma delta T cells in active sarcoidosis closely correlates with defects in cellular immunity.

The relationship between the level of gamma delta T cells and cellular immunity of T lymphocytes was assessed in the peripheral blood of active sarcoidosis patients and healthy controls. We divided the active sarcoidosis patients into two groups: a group of patients with a normal distribution of circulating gamma delta T cells (group A; n = 11, less than 8.2% lymphocytes) and another group with increased gamma delta T cell levels (group B; n = 11, greater than 8.2% lymphocytes). The proportion and absolute count of CD4+ lymphocytes in group B (28.6 +/- 11.2%, 374.1 +/- 193.8/microliters) were remarkably smaller than control subjects (45.7 +/- 6.8%, 818.3 +/- 290.2/microliters, P < 0.001, P < 0.002, respectively). Group A, however, showed a moderate reduction in CD4+ lymphocytes when compared with controls. Serial measurements of T cell subtypes were performed on five patients in group B. gamma delta T cells and CD4+ lymphocytes were inversely correlated over the observation period which ranged from 2 to 18 months. When peripheral blood T cells were stimulated with PHA or PPD in vitro, the responses were weaker in group B compared with both group A and control subjects. These results suggest that the increase in circulating gamma delta T cells in sarcoidosis closely relates to a defect in cellular immunity which progresses during the disease process.

Adult↗

PubMed1995

[Periodic breathing at high altitude relation to acclimatization and acute mountain sickness].

Periodic breathing (PB) during sleep at an altitude of 5100 m was studied with a pulse oximeter. The subjects were six Japanese who stayed at about 5100 m (group A), nine Japanese who climbed above 7000 m (group B) and eight Sherpase (high landers). Among Japanese subjects, PB was observed most often in group A. The sherpas almost never breathed periodically. PB and symptoms of acute mountain sickness correlated positively among Japanese subjects. The cycle time of PB did not differ among the three groups. PB may be related to acclimatization.

Acclimatization↗

PubMed1994

The synergistic antitumor effect of recombinant interleukin-1 and low-dose of cyclophosphamide in tumor-bearing mice.

Intraperitoneal (i.p.) treatment of MOPC104E ascitic tumor-bearing BALB/c mice with interleukin-1 (IL-1) followed by a low dose of cyclophosphamide (CPA) resulted in synergistic prolongation of their survival time. This antitumor effect was abolished when administration of CPA preceded that of IL-1. The combined i.p. therapy also eradicated subcutaneous (s.c.) tumors, indicating a systemically operating antitumor mechanism. In Winn assay, splenocytes from MOPC104E-bearing mice treated with the combined therapy completely suppressed the growth of MOPC104E cells, but not that of another syngeneic tumor cell line, RL female-8 cells. This tumor-neutralizing activity was completely abrogated by treatment with anti-asialo-GM1 or anti-Thy1.2 and complement, and reduced by treatment with anti-Lyt2.2 and complement. Treatment of splenocytes with 1-leucine methyl ester (Leu0Me), which depletes natural killer (NK) cells and macrophages in vitro, did not affect the neutralizing activity.

Animals↗

PubMed1994

The induction of specific antitumor immunity by in vivo treatment with interleukin-1 and sonicated tumor extract in a murine model.

BALB/c mice were pretreated intraperitoneally with interleukin-1 (IL-1) and sonicated tumor extract (SE) from plasmacytoma MOPC104E, 10, 7, and 4 days prior to the intraperitoneal or subcutaneous inoculation of MOPC104E cells, following which significant suppression was observed. The mean survival time and tumor diameter on day 21 were 46.7 days and 0 mm, respectively, in contrast to the 20.9 days and 20.4 mm of control mice. Mice pretreated with IL-1 and SE from MOPC104E (MOPC-SE) were not suppressed following fibrosarcoma MethA inoculation, which indicates the tumor specificity of immunity in this model. This systemically operating antitumor immunity was also achieved by the intramuscular administration of IL-1, or when tumor challenge was performed on day 7 or 14. Moreover, MOPC104E-specific delayed-type hypersensitivity was detected in these mice. The results of this study suggest the possibilities of a new type of active specific immunotherapy, which could prove useful as postsurgical adjuvant therapy for cancer patients.

Animals↗

PubMed1994

Gamma-delta T cells in sarcoidosis. Correlation with clinical features.

This study investigated the relationship between the clinical features of sarcoidosis and the level of peripheral blood gamma-delta (gamma delta) T cells. Both the mean percentage of T cells and the mean cell number of gamma delta T cells in the peripheral blood were significantly higher in patients with clinically active sarcoidosis than in patients with inactive sarcoidosis or active tuberculosis and in normal subjects (active sarcoidosis: 18.9 +/- 17.2%, 142 +/- 130.4 cells/microliters, n = 29; inactive sarcoidosis: 7.0 +/- 3.7%, 48.7 +/- 35.0 cells/microliters, n = 16; active tuberculosis: 4.3 +/- 3.2%, 47.9 +/- 36.6 cells/microliters, n = 19; control subjects: 5.0 +/- 1.9%, 77.6 +/- 37.7 cells/microliters, n = 12). gamma delta T cells were significantly elevated in patients with sarcoidosis for 2 yr or more or those with Stage III radiographs. The level of gamma delta T cells, however, showed no correlation to the serum angiotensin-converting enzyme, a marker of active granuloma formation. gamma delta T cells were scarcely seen in bronchoalveolar lavages and in biopsy specimens, suggesting that these cells did not increase at the sites of inflammation. These findings suggest that increased levels of gamma delta T cells in the peripheral blood occur in active, long-term sarcoidosis, but that they are not directly related to granuloma formation.

Adult↗

PubMed1994

[Investigation on the treatment of infection due to Mycobacterium Kansasii].

Mycobacterium kansasii infection responds well to antituberculous drugs, and in the initial phase of treatment, many patients with M. kansasii infection are regarded as tuberculosis. This study was carried out to know whether the regimen of chemotherapy be continued or changed after the confirmation of diagnosis as M. kansasii infection. The treatment result of 107 cases with M. kansasii infection of the lung encountered at Fukujuji Hospital was compared with that of pulmonary tuberculosis. Sputum culture of all patients treated with drug regimens containing RFP converted to negative within 3 months after starting chemotherapy, while sputum culture of many patients treated with regimens not containing RFP converted to negative 4 months or later after the start of chemotherapy. Hence, the effectiveness of RFP in treating M. kansasii infection was confirmed. Among 65 patients with no relapse during a follow-up period of at least one year after the completion of chemotherapy, 58 patients (89.2%) were treated with drug regimens containing INH and RFP, and the treatment of 40 patients (61.5%) was finished within 12 months. Among three patients deteriorated during chemotherapy or relapsed within one year after the completion of chemotherapy, two patients were treated with drug regimens containing RFP and one of them had serious complications. The chemotherapy regimen for tuberculosis is considered to be sufficient for the initial treatment of pulmonary disease caused by M. kansasii.

Adult↗