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Biomedical subjects

S Hirohata

Publications and source records attributed to S Hirohata.

At least 91 records · Page 5Linked to original sources
PubMed1994

Comparative inhibitory effects of bucillamine and D-penicillamine on the function of human B cells and T cells.

OBJECTIVE: Clinical trials have suggested that the efficacy of bucillamine (BUC) in rheumatoid arthritis (RA) may be superior to that of D-penicillamine (DP), although the basis of the differences remains unclear. Previous studies have revealed that BUC has unique immunomodulatory effects that depend upon its capacity to form an intramolecular disulfide (BUC-ID). We therefore examined the effects of BUC-ID on the in vitro function of human B cells and T cells compared with those of DP, at their pharmacologically attainable concentrations. METHODS: IgM production was induced in highly purified B cells from healthy donors by stimulation with Staphylococcus aureus Cowan 1 (SAC) plus interleukin-2 (IL-2) or with immobilized anti-CD3-activated CD4+ T cells. Interferon-gamma (IFN gamma) production was induced in CD4+ T cells by stimulation with immobilized anti-CD3. RESULTS: BUC-ID suppressed IgM production induced by SAC+IL-2 as well as that induced by immobilized anti-CD3-activated CD4+ T cells, whereas DP suppressed the latter more markedly than the former. DP (3 micrograms/ml) significantly suppressed IFN gamma production by immobilized anti-CD3-stimulated CD4+ T cells, but not IgM production induced by SAC + IL-2 stimulation. By contrast, BUC-ID (0.3 microgram/ml) significantly suppressed IgM production induced by SAC + IL-2, but not T cell IFN gamma production. Of note, BUC-ID did not suppress IL-6 production by SAC-activated B cells. CONCLUSION: These results indicate that the target cells of BUC and DP in vivo might be different, with the former inhibiting the function of B cells and the latter that of T cells. The data suggest the possibility that BUC may have a different effect in RA patients compared with the effect of DP, and may be effective in patients who do not respond to DP.

Adult↗
PubMed1994

The interplay of interleukin-10 (IL-10) and interleukin-2 (IL-2) in humoral immune responses: IL-10 synergizes with IL-2 to enhance responses of human B lymphocytes in a mechanism which is different from upregulation of CD25 expression.

The role of the interplay of interleukin-2 (IL-2) and interleukin-10 (IL-10) in responses of human peripheral blood B cells stimulated by ligation of antigen receptors was examined in detail. Highly purified peripheral blood B cells from normal human individuals were cultured with Staphylococcus aureus Cowan I (SA) in the presence or absence of IL-10 and IL-2. Although IL-10 alone could modestly induce Ig production by SA-activated B cells, IL-10 markedly enhanced the Ig production in synergism with IL-2. This synergistic effect between IL-2 and IL-10 was completely abrogated by addition of either anti-CD25 mAb or anti-IL-10 mAb, indicating signals through high-affinity IL-2 receptors are involved in the synergism. In fact, IL-10 upregulated the expression of alpha-chain of IL-2 receptors (CD25) on B cells stimulated by SA alone or SA + IL-2 for 72 hr. However, such upregulation of CD25 expression did not result in significant enhancement of subsequent responses of the activated B cells to IL-2. Of note, during the initial activation phase of B cells, IL-2 was much more effective than IL-10 in enhancing the subsequent responses to either IL-2 or IL-10. By contrast, IL-10 was much more effective than IL-2 in supporting the maturation of B cells following the initial activation. Finally, the synergy between IL-2 and IL-10 was not observed in the initial activation phase, but in the subsequent maturation phase of activated B cells. These results indicate that IL-10 and IL-2 synergistically enhance Ig production of SA-activated B cells in a mechanism which is different from the upregulation of IL-2 receptors. Moreover, the data emphasize the importance of the interplay of IL-2 and IL-10 in determining the outcome of humoral immune responses.

Adult↗
PubMed1994

Systemic lupus erythematosus presenting with diffuse low density lesions in the cerebral white matter on computed axial tomography scans: its implication in the pathogenesis of diffuse central nervous system lupus.

We describe a patient with systemic lupus erythematosus (SLE) with severe organic brain syndrome, who showed diffuse low density areas in the cerebral white matter on computed axial tomography (CAT) scans. A 43-year-old woman with SLE showed disturbances in various intellectual functions, followed by the development of consciousness disturbances and urinary incontinence. CAT scans, single photon emission computed tomography (SPECT) and cerebrospinal fluid (CSF) interleukin 6 (IL-6) were serially examined during the clinical course before and after treatment with high doses of prednisolone. CSF IL-6 activity paralleled the central nervous system (CNS) disease activity most consistently. By contrast, the diffuse low density areas in cerebral white matter on CAT scans as well as the decreased blood flow in the cerebral cortices on SPECT persisted long after the improvement of the CNS manifestations. Magnetic resonance imaging (MRI) scans also revealed the diffuse areas of increased signal intensity in the subcortical white matter on T2 weighted images. The diffuse lesions in the cerebral white matter are considered to reflect the edema as well as other irreversible changes that have resulted from the disturbed cerebral circulation presumably due to the diffuse microangiopathies in the cerebral cortices and not to be necessarily correlated with the CNS disease activities. Moreover, it is suggested that the inflammatory process evidenced by the elevation of CSF cytokines in addition to the disturbed circulation in the cerebral cortices might play an important role in the pathogenesis of CNS lupus in our patient.

Adult↗
PubMed1994

[Gluteal abscess caused by Staphylococcus aureus in a patient with systemic lupus erythematosus].

We describe here a 44-year-old female patient with systemic lupus erythematosus (SLE), who developed gluteal abscess resulting in symptoms suggestive of aseptic necrosis of the right femoral head. The patient was diagnosed as active SLE with organic brain syndrome in December 1992, and has been treated with high doses of methylprednisolone (initial dose: 100 mg daily). As she recovered from the manifestations, the dose of methylprednisolone has been gradually decreased. In June 1993, she began to complain of right leg pain on walk with positive Patrick sign in the right hip. A massive gluteal abscess was identified by X-ray and CT scan, and drained. Cultures of the purulent fluid yielded Staphylococcus aureus. Of note, Staphylococcus aureus had been detected from repeated cultures of pharyngeal swabs, suggesting that the organism invading from the pharynx was carried in the blood to a small hematoma in the right gluteal muscle to form an abscess. The importance of an awareness of the possibility of the infection of Staphylococcus aureus in SLE patients is discussed.

Abscess↗
PubMed1993

Modulation of T cell production of interferon-gamma by human monocytes: effect of engagement of CD14 on monocytes.

It has been suggested that CD14 might have influences on a variety of immunoregulatory functions of monocytes. The current studies therefore examined in detail the immunoregulatory roles of CD14 by studying the effects of anti-CD14 mAb. Anti-CD14 mAb suppressed the monocyte-dependent interferon-gamma (IFN-gamma) production by CD4+ T cells induced by soluble anti-CD3. Although anti-CD14 mAb also suppressed the IL-6 production by monocytes, the inhibition of the IFN-gamma production induced by soluble anti-CD3 was not restored by addition of exogenous IL-6 or factors generated from cultured monocytes. Of note, anti-CD14 mAb decreased the expression of CD54, but not that of CD11a or CD18, on monocytes, suggesting that inhibition of the soluble anti-CD3-induced IFN-gamma production by anti-CD14 mAb might be a result from decrease in CD11a/CD18-CD54-mediated interactions between CD4+ T cells and monocytes. By contrast, anti-CD14 mAb enhanced the IFN-gamma production by immobilized anti-CD3-activated CD4+ T cells in the presence of monocytes. This enhancement of the IFN-gamma production required physical contact between monocytes and T cells, which does not involve MHC class II antigen-CD4 interactions. These results indicate that CD14 on monocytes plays a variety of immunomodulatory functions depending upon the nature of stimulation. The data thus demonstrated the presence of several different interactions between monocytes and T cells that regulate the T cell cytokine production.

Antibodies, Monoclonal↗
PubMed1993

Growth inhibition of human lung cancer cell lines by interleukin 6 in vitro: a possible role in tumor growth via an autocrine mechanism.

It has been considered that growth of human lung cancer cells, like other malignant cells, is positively and negatively regulated by a variety of growth factors via autocrine as well as paracrine mechanisms. The autocrine mechanism is considered to be important in the autonomy of proliferation of cancer cells. Recently, the role of autocrine growth-inhibiting factors such as transforming growth factor beta attracts special attention for better understanding of growth regulation of malignant cells. Here, we have demonstrated that a multifunctional cytokine interleukin 6 (IL-6) had an inhibitory effect on the proliferation of human non-small cell lung cancer cell lines, as shown by the growth accelerating effect of the specific anti-IL-6 antibody as well as the effect of exogenously added IL-6. Moreover, IL-6 can be expressed and released by human lung cancer cells, and these cells had specific IL-6 receptors on their cell surfaces, suggesting an autocrine mechanism. The growth-inhibitory effect of IL-6 was additive to that of transforming growth factor beta, and could not be neutralized by the addition of anti-transforming growth factor beta antibody. These results suggested that IL-6 may function as another class of autocrine growth-inhibiting factor in the growth regulation of human lung cancer. Relatively lower IL-6 sensitivity of these cells than noncarcinogenic human bronchial epithelial cells also suggested that escape from growth regulation by inhibitory factors such as IL-6 could be involved in lung cancer oncogenesis.

Adenocarcinoma↗
PubMed1993

Regulation of human B cell responsiveness by interferon-alpha: interferon-alpha-mediated suppression of B cell function is reversed through direct interactions between monocytes and B cells.

Previous studies have revealed that interferon-alpha (IFN-alpha) suppresses the B cell responses stimulated with Staphylococcus aureus (SA) + IL-2 in the complete absence of monocytes but enhances the responses of B cells contaminated with monocytes. The current studies therefore examined in detail the combined effects of IFN-alpha and monocytes on the B cell responses induced by SA + IL-2. Monocytes overcome the suppressive effects of IFN-alpha on the IgM production induced by SA + IL-2. Thus, in the presence of monocytes, IFN-alpha enhanced the IgM production by B cells stimulated with SA + IL-2. IFN-alpha still enhanced the IgM production induced by SA + IL-2 in the presence of monocytes and indomethacin. The IFN-alpha-mediated suppression of B cell responsiveness was not overcome by addition of factors generated from SA-activated monocytes, or any of IL-1 beta, IL-6, and TNF-alpha. Of note, the IFN-alpha-mediated suppression of B cell responsiveness was overcome only when B cells and monocytes were allowed to contact with each other. This reversal of the IFN-alpha-mediated suppression of B cell function was not blocked by any of the mAb to CD11a, CD18, CD54, or monomorphic determinants of HLA-DR. These results indicate that IFN-alpha enhances the B cell responses induced by SA + IL-2 through direct interactions between monocytes and B cells that do not involve lymphocyte-function-associated-1 molecules, intercellular adhesion molecule-1, or HLA-DR antigens. Thus, the data demonstrate the presence of unique direct interactions between B cells and monocytes that regulate human B cell responsiveness.

Adult↗
PubMed1993

Inhibition of B cell expression of DNA polymerase alpha by CD4+ suppressor T cells.

Human CD4+ T cells stimulated with immobilized monoclonal antibodies to the CD3 molecular complex (64.1) have been shown to exert suppressive effects on B cell differentiation by inhibiting the G1-S transition of the cell cycle of B cells. The present study investigates the influences of the anti-CD3-induced CD4+ suppressor T cells on the expression of DNA polymerase alpha in B cells. The expression of DNA polymerase alpha in B cells cocultured with immobilized anti-CD3-stimulated CD4+ T cells without mitomycin C treatment (control T4 cells) was significantly decreased after 72 hr of the cultures compared with that in B cells cocultured with immobilized anti-CD3-stimulated CD4+ T cells that had been treated with mitomycin C to abrogate the suppressive effects. The inhibition of the expression of DNA polymerase alpha in B cells was reversible upon removal of anti-CD3-activated control T4 cells from the culture. The B cell expression of proliferating cell nuclear antigen, which is closely related to the auxiliary protein for DNA polymerase delta, was not inhibited by anti-CD3-activated control T4 cells at any time of the cultures. Thus, the results demonstrate that the suppression of human B cell maturation by the anti-CD3-induced CD4+ suppressor T cells is closely related with the inhibition of the expression of DNA polymerase alpha in B cells. Moreover, the data suggest that the activity of DNA polymerase alpha and that of DNA polymerase delta in B cells might be independently regulated.

Adult↗
PubMed1993

Bidirectional modulation of human B cell stimulation by activated T cells.

Although human T cells have been shown to exert effects of both help and suppression on B cells, the precise sequelae for these different effects have not yet been delineated. The present study therefore examined in detail the functions of human peripheral blood T cells activated for various periods by immobilized anti-CD3 to modulate B cell responses. CD4+ (CD45RA+ or CD45RA-) or CD8+ (CD45RA+ or CD45RA-) T cell subsets were cultured in wells with immobilized anti-CD3 for as long as 20 days. At various periods of time, these activated T cells were harvested and cocultured with either fresh resting B cells or preactivated B cells. CD4+ and CD8+ T cells, irrespective of their expression of the CD45RA molecule, were able to stimulate resting B cells to express transferrin receptor (CD71) and IL-2 receptor (CD25) up to 17 days after activation with immobilized anti-CD3, although CD8+ but not CD4+ T cell subsets appeared to become less potent in stimulating resting B cells after 17 days of activation. By contrast, these CD4+ and CD8+ T cell subsets activated by immobilized anti-CD3 suppressed the maturation of the B cells preactivated with anti-CD3-stimulated CD4+ T cells, at the same time as when they provided help for resting B cells. The suppression, but not the help, was abrogated by treatment of the T cells with mitomycin C up to 13 days after activation. The suppression was not abrogated by addition of exogenous IL-2, irrespective of the length of stimulation of suppressor-effector T cells. These results indicate that human activated T cells can provide help and suppression simultaneously, irrespective of their phenotypes. Moreover, the data suggest that the state of activation of B cells might be important in determining the functions of the activated T cells.

Adult↗
PubMed1993

Regulation of B cell function by bucillamine, a novel disease-modifying antirheumatic drug.

Bucillamine [N-(2-mercapto-2-methylpropionyl)-L-cysteine] (BUC) is a thiol compound that differs from D-penicillamine (DPC) in that it contains two free sulfhydryl groups. Clinical trials have demonstrated that its efficacy in rheumatoid arthritis is superior to that of DPC, but its mechanism of action remains unclear. We therefore examined the effects of BUC on the in vitro function of human B cells in comparison to those of DPC. IgM production was induced from highly purified B cells from healthy donors by stimulation with Staphylococcus aureus Cowan I (SA) plus factors generated from mitogen-activated T cells (TF) or interleukin-2 (IL-2) or with immobilized anti-CD3-activated CD4+ T cells. BUC suppressed the production of IgM at concentrations of 0.3-100 micrograms/ml irrespective of the presence of CuSO4. Whereas BUC suppressed the production of IL-2 and interferon-gamma by immobilized anti-CD3-activated CD4+ T cells, its suppressive effects on the production of IgM in anti-CD3-stimulated cultures were not overcome by addition of TF or IL-2, indicating that the action of BUC involves direct inhibition of B cell function. BUC suppressed the initial stages of B cell activation, but not the maturation of previously activated B cells. In contrast to DPC, the suppressive activities of BUC did not require the presence of copper and were not overcome by the addition of monocytes or catalase. The effects of SA981, a metabolite of BUC with an intramolecular disulfide, on B cell function were more marked than those of BUC, whereas the effects of SA679, another metabolite of BUC with one of the two sulfhydryl bonds methylated, were similar to those of DPC. SA672, a metabolite of BUC with both of the two sulfhydryl bonds methylated, did not suppress B cell function. These results indicate that BUC as well as some of its metabolites inhibit cytokine production by T cells and also suppress the production of IgM at least in part by directly inhibiting B cells. These compounds exert immunosuppressive effects that are similar to those of DPC, but also unique inhibitory effects that depend upon the capacity of BUC to form an intramolecular disulfide between its two sulfhydryl groups.

Adult↗
PubMed1993

Elevation of cerebrospinal fluid interleukin-6 activity in patients with vasculitides and central nervous system involvement.

The pathogenesis of central nervous system (CNS) involvement in vasculitides remains unclear. We evaluated cerebrospinal fluid (CSF) interleukin-6 (IL-6) activity in relation to the CNS disease activity in vasculitides. Three patients with vasculitides of different categories who showed CNS manifestations were studied, including polyarteritis nodosa, temporal arteritis, and Behcet's disease. All three patients showed marked elevation of CSF IL-6 activity in parallel with the CNS disease activity. In one of the three patients, cerebral vasculitis was demonstrated histologically. All these patients also showed elevation of serum IL-6 activity in parallel with systemic symptoms, such as fever and/or elevation of C-reactive protein and erythrocyte sedimentation rate. These results strongly suggest that elevation of CSF IL-6 activity may underly the common pathogenetic mechanism of CNS involvement of vasculitides irrespective of their category. Taken together with the histopathological findings in one patient, the data also suggest that inflammation might not be restricted within the CNS blood vessels, but rather be extended to brain parenchyma to promote IL-6 production presumably by glial cells.

Adult↗
PubMed1993

Pharmacological studies on a new dihydrothienopyridine calcium antagonist. 3rd communication: antihypertensive effects of S-(+)-methyl-4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)thieno[2, 3-b] pyridine-5-carboxylate in hypertensive rats and dogs.

Hypotensive and antihypertensive effects of S-312-d (S-(+)-methyl-4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)thieno[2, 3- b]pyridine-5-carboxylate, CAS 120056-57-7) in Wistar Kyoto rat (WKY), spontaneously hypertensive rat (SHR), stroke-prone SHR (SHRSP), and DOCA-salt hypertensive rat (DOCA-HR) were compared with those of other representative calcium antagonists. The minimal effective hypotensive dose of S-312-d in WKY was 3 mg/kg p.o. and those in SHR, SHRSP, and DOCA-HR were 1 mg/kg p.o. in gum arabic suspension. The minimal antihypertensive dose of S-312-d in polyethylene glycol solution was 0.3 mg/kg p.o. in SHRSP. The antihypertensive effects of S-312-d was the most potent and long-lasting compared with the calcium antagonists, nifedipine, nicardipine, nimodipine, nilvadipine, and flunarizine. In conscious two-kidney Goldblatt-type hypertensive dogs, a significant antihypertensive effect and concomitant increases of heart rate with S-312-d at 1 mg/kg lasted for 4 to 6 h after oral administration. Determination of the plasma concentration of S-312-d by HPLC showed that more than 4.3 ng/ml of S-312-d is required for a significant antihypertensive effect. Subcutaneous administration of atenolol at 20 mg/kg 30 min before S-312-d significantly inhibited the tachycardia with S-312-d at 1 mg/kg p.o. but not its antihypertensive effect. S-312-d is considered useful for the treatment of essential hypertension and related organ disorders.

Animals↗
PubMed1993

[Analysis of the state of patients with rheumatoid arthritis using a personal computer].

The present study was designed to analyze the state of 203 patients with rheumatoid arthritis (RA) in our clinic using a personal computer. The duration of the disease was significantly correlated with the progression of radiographical stages of RA, indicating that no drugs were able to prevent the progression of joint destruction. Nevertheless, bucillamine, a newly developed anti-rheumatic drug, was found to be effective in some patients who did not respond to D-penicillamine, but not vice versa. Although seropositive RA patients had more severe disease than seronegative RA patients, serum rheumatoid factor levels were not significantly correlated with Lansbury indices in seropositive RA patients. Overall, either the liver function or the renal function was not significantly affected in any category of the patients. Taken together, it is suggested that analysis of the data of the RA patients with personal computer systems provide useful information on the management of the RA patients.

Age Factors↗
PubMed1992

Interleukin 6/B cell stimulatory factor-II is expressed and released by normal and transformed human bronchial epithelial cells.

Airway epithelial cells have a potential to participate in local immune and inflammatory responses via releasing biologically active compounds. We studied the expression and release of interleukin 6 (IL-6), a multifunctional cytokine possibly involved in tissue immune responses. Primary culture of normal human bronchial epithelial cells and its transformed cell line BEAS-2B released significant amount of biologically and immunologically intact IL-6 into media. A protein synthesis inhibitor cycloheximide abolished the IL-6 release, suggesting a de novo synthesis. Northern blot analysis demonstrated the expression of the specific IL-6 mRNA. Human bronchial epithelial cells can produce IL-6 and contribute to the local activity of IL-6, suggesting that these cells may play a role in the regulation of airway immune responses.

Antibodies, Monoclonal↗
PubMed1992

Regulation of B cell function by lobenzarit, a novel disease-modifying antirheumatic drug.

OBJECTIVE: Lobenzarit (disodium 4-chloro-2,2'-iminodibenzoate [CCA]) is a novel disease-modifying drug for the treatment of rheumatoid arthritis (RA). Although its clinical efficacy has been demonstrated, its mechanism of action remains unclear. We therefore examined the effects of CCA on in vitro IgM and IgM rheumatoid factor (IgM-RF) production by human B cells. METHODS: IgM and IgM-RF production was induced from highly purified B cells from 8 healthy donors by stimulation with Staphylococcus aureus Cowan 1 (SAC) plus factors generated from mitogen-activated T cells (TCF) or with immobilized anti-CD3-activated CD4+ T cells. RESULTS: CCA suppressed the production of IgM-RF as well as IgM at concentrations of 25-50 micrograms/ml (therapeutic serum concentrations of the drug), although the IgM-RF production induced by SAC plus TCF was suppressed at lower concentrations of CCA (1-3 micrograms/ml). Whereas CCA suppressed interleukin-2 (IL-2) production by anti-CD3-activated CD4+ T cells, its suppressive effects on B cells were not overcome by addition of IL-2 or TCF. CCA did not inhibit the initial stages of B cell activation in either culture system, but rather, suppressed the maturation of previously activated B cells. Cell cycle analysis by acridine orange staining indicated that CCA-mediated inhibition of B cell responsiveness induced by anti-CD3-activated CD4+ T cells was the result of a block at the G1-S interphase. CONCLUSION: These results indicate that CCA suppresses the production of IgM and IgM-RF by directly inhibiting activated B cells. Thus, one of the actions of CCA in RA may be the suppression of the function of activated B cells.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1992

Interferon-alpha in lupus psychosis.

OBJECTIVE: Since the level of interferon-alpha (IFN alpha) is increased in the sera of patients with active systemic lupus erythematosus (SLE) and is detectable in the cerebrospinal fluid (CSF) of some SLE patients with neuropsychiatric manifestations, we investigated the contribution of IFN alpha to the pathogenesis of the neuropsychiatric manifestations of SLE. METHODS: IFN alpha levels were quantitated by radio-immunoassay in CSF and serum samples from 17 SLE patients with neuropsychiatric manifestations and 28 patients with SLE alone or SLE and other neurologic disorders. RESULTS: Levels of IFN alpha were increased in the CSF of 5 of 6 patients with lupus psychosis, and in 4 of these 5 patients, the levels in CSF were higher than those in serum. IFN alpha levels decreased when the manifestation of lupus psychosis subsided. In contrast, IFN alpha levels in CSF samples from patients with seizures alone were not increased. One patient with lupus psychosis died of complications of generalized seizures resulting from the SLE. At autopsy, we investigated whether IFN alpha protein or messenger RNA was detectable in the subject's brain. IFN alpha protein was immunohistochemically demonstrated in the neurons and in the microglia (focal accumulation), features not present in the brain tissues of subjects who died of other diseases. CONCLUSION: These findings support the hypothesis that IFN alpha, possibly synthesized in the brain, is the cause of the manifestation of psychosis in patients with SLE.

Brain↗