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Biomedical subjects

T Hasunuma

Publications and source records attributed to T Hasunuma.

At least 55 records · Page 3Linked to original sources
PubMed1996

Therapeutic effect of the anti-Fas antibody on arthritis in HTLV-1 tax transgenic mice.

We have recently demonstrated Fas-mediated apoptosis in the synovium, of patients with rheumatoid arthritis (RA) and suggested that it may be one factor responsible for the regression of RA. To examine whether the induction of apoptosis caused by anti-Fas mAb may play a potential role as a new therapeutic strategy for RA, we investigated the effect of anti-Fas mAb (RK-8) on synovitis in an animal model of RA, the human T cell leukemia virus type I (HTLV-1) tax transgenic mice. We report here that administration of anti-Fas mAb into mice intra-articularly improved the paw swelling and arthritis within 48 h. Immunohistochemical study and in vitro culture studies showed that 35% of synovial fibroblasts, 75% of mononuclear cells, and some of polymorphonuclear leukocytes infiltrating in synovium underwent apoptosis by anti-Fas mAb. In situ nick end labeling analysis and electron microscope analysis clearly showed that many cells in synovium were induced apoptosis by anti-Fas mAb administration. However, local administration of anti-Fas mAb did not produce systemic side effects. Results demonstrated that administration of anti-Fas mAb in arthritic joints of the HTLV-1 tax transgenic mice produced improvement of arthritis. These findings suggest that local administration of anti-Fas mAb may represent a useful therapeutic strategy for proliferative synovitis such as RA.

Alanine Transaminase↗
PubMed1996

Activation of transcription factor NF-kappa B in human synovial cells in response to tumor necrosis factor alpha.

OBJECTIVE: To examine whether nuclear factor kappaB (NF-kappaB) is activated in cultured synovial cells in response to tumor necrosis factor alpha (TNFalpha) and to investigate the correlation between NF-kappaB activation and synovial cell proliferation. METHODS: Activation of NF-kappaB was detected by electrophoretic mobility shift assay. The transcription of several NF-kappaB-dependent genes was evaluated by reverse transcriptase polymerase chain reaction and transient expression assay using human immunodeficiency virus-long terminal repeat chloramphenicol acetyltransferase. Proliferative activity was determined by measurement of 3H-thymidine incorporation. RESULTS: Stimulation of synovial cells with TNFalpha activated NF-kappaB and subsequent transcription of several genes. Treatment of synovial cells with N-acetyl-L-cysteine (NAC), an antioxidant agent, inhibited TNFalpha-induced NF-kappaB activation and transcription. Moreover, NAC also inhibited synovial cell proliferation induced by TNFalpha. CONCLUSION: Our results suggest that NF-kappaB plays a pivotal role in synovial cell activation by TNFalpha. Thus, suppression of NF-kappaB could be a potential therapeutic modality for synovitis such as that of rheumatoid arthritis.

Acetylcysteine↗
PubMed1996

Human T lymphotropic virus type I in arthropathy and autoimmune disorders.

The progressive nature of the disease and the persistent inflammation affecting various organs are common features of idiopathic autoimmune disorders of unknown etiology. Therefore, the HTLV-I-associated disorders described in the present review are outstandingly important models for our understanding of the pathologic mechanisms of organ-specific immune disorders. HTLV-I arthropathy is characterized by chronic inflammatory and proliferative synovitis with lymphoid follicles and pannus formation in the affected joints, indistinguishable from the findings in idiopathic RA. The presence of the tax gene in HTLV-I-negative SS patients suggests that it is responsible for the exocrine gland abnormality, characterized by extensive lymphoproliferative epithelial lesions. Furthermore, the pulmonary lesions of HTLV-I bronchopneumonopathy are similar to those of idiopathic interstitial pneumonitis. Based on these observations, the clinical findings associated with the immunologic abnormalities in HTLV-I-infected patients provide us with valuable information for understanding the pathogenetic mechanisms of chronic inflammatory conditions associated with immune regulatory disorders. Although the clinical and pathologic features of the 2 common HTLV-I-associated disorders, ATL and HAM/TSP, have been well characterized and are clearly distinguishable from those of the idiopathic forms of these disorders, other HTLV-I-related autoimmune diseases, e.g., arthropathy, SS, or bronchopneumonopathy, are clinically indistinguishable from the idiopathic forms of the diseases. Such similarity may serve as a clue to the pathogenetic mechanisms of idiopathic autoimmune disorders.

Autoimmune Diseases↗
PubMed1996

Induction of Fas-dependent apoptosis in synovial infiltrating cells in rheumatoid arthritis.

Apoptosis is a feature of the synovium of rheumatoid arthritis (RA). We have recently shown that RA synoviocytes were susceptible to anti-Fas mAb and undergo apoptosis in vitro. To investigate whether infiltrating mononuclear cells also undergo Fas-dependent apoptosis, double-labeling techniques combined with immunohistochemical examination with anti-CD3 mAb and the TdT-mediated dUTP-blotin nick end labeling (TUNEL) method to detect apoptotic cells, or in situ RT assay to detect Fas mRNA, were performed using frozen tissue sections. We also examined the in vitro induction of Fas-dependent apoptosis in freshly isolated synovium infiltrating mononuclear cells (SIM), synovial stromal cells (SSC) and peripheral blood lymphocytes (PBL) using tissues from nine patients with RA and three with osteoarthritis (OA). The results showed expression of Fas antigen and apoptotic cells in a number of CD3-bearing cells in RA synovial tissues. In vitro treatment with anti-Fas mAb produced a significant apoptosis of RA SIM and SSC, while none of PBL, and neither SIM nor SSC from OA exhibited apoptosis. Moreover, approximately 50% of CD4+, CD3+ and CD45RO+ cells, and > 90% of Fas-expressing cells of RA SIM underwent apoptosis in response to anti-Fas mAb, as detected by flow cytometry. Our results suggest that RA synovial infiltrating lymphocytes acquire high susceptibility to anti-Fas mAb and undergo apoptosis. Such a phenomenon of infiltrating T cells in RA synovium may play an important pathophysiological role and suggest a possible therapeutic effect for anti-Fas mAb in RA.

Aged↗
PubMed1996

High prevalence of arthropathy in HTLV-I carriers on a Japanese island.

OBJECTIVE: To determine the aetiological relationship between human T cell leukaemia virus type-I (HTLV-I) and arthritis, by performing an epidemiological study of the inhabitants of Tsushima, an island northwest of the main island of Kyushu, Japan, which is an endemic area of HTLV-I. METHODS: A total of 7087 people underwent an annual health check, and those with arthropathy had further physical and radiological examinations by rheumatologists. The presence of HTLV-I antibody was determined by the particle agglutinin method, and integration of the proviral DNA in peripheral lymphocytes was confirmed by polymerase chain reaction. RESULTS: HTLV-I was positive in 26.1% of inhabitants; the incidence increased to 37.0% in patients with symptoms of polyarthritis. The prevalence of rheumatoid arthritis (RA) was significantly different between HTLV-I carriers (0.56%) and non-carriers (0.31%). The stage of bone destruction in HTLV-I carriers with articular symptoms was milder than that in RA patients without HTLV-I. The relative risk of HTLV-I infection for polyarthritis was 1.66 (p < 0.05). CONCLUSION: This is the first epidemiological report clarifying the association between HTLV-I and polyarthritis. Our results suggest that this viral infection has a relationship to RA.

Antibodies, Viral↗
PubMed1996

[Expression of Fas/Fas ligand and proto-oncogenes in rheumatoid synovial tissues].

Expression of Fas antigen and Fas ligand (-L) were observed in synovial tissue from rheumatoid arthritis (RA) patients, whereas in only a few cells expressed these molecule osteoarthritis synovial tissue. Fas-L was expressed on CD45RO, CD4, CD8 or CD56 positive cells in RA synovial tissue. Moreover, 10 to 30% of synovial cells expressing Fas antigen were observed to be identical with apoptotic synovial cells and Fas expression was closely related to c-fos and c-myc. These findings suggest that activated T cells and natural killer cells infiltrating into the RA synovium may play an important role in the induction of apoptosis of RA synovial cells through Fas/Fas-L interactions.

Apoptosis↗
PubMed1996

Direct suppression of human synovial cell proliferation in vitro by salazosulfapyridine and bucillamine.

OBJECTIVE: The mechanism of disease modifying antirheumatic drugs (DMARD) is incompletely understood. We investigated in vitro the effect of DMARD such as bucillamine (Buc), salazosulfapyridine (SASP), and D-penicillamine (D-Pen) on the proliferation of human synovial cells in patients with rheumatoid arthritis (RA). METHODS: We evaluated the inhibitory effect of DMARD on [3H]-thymidine incorporation and cytokine production in synovial cells from patients with RA. Moreover, the expression of cytokine and protooncogene mRNA in synovial cells was determined by reverse transcription polymerase chain reaction methods. RESULTS: The proliferation of synovial cells and interleukin 1 beta (IL-1 beta) and interleukin 6 (IL-6) production of synovial cells were significantly inhibited by Buc and SASP in the concentration range of 1 to 100 microM in a dose dependent manner. In contrast D-Pen had no apparent effect at the same concentrations. Subsequently, the inhibitory effects of these compounds on transcriptional regulation of IL-1 beta, IL-6, and c-fos, which are well known to play an important role in synovial cell proliferation, were clarified. Overexpression of c-fos mRNA was inhibited by Buc and SASP. Moreover, the combination of low dose Buc and SASP inhibited synovial cell growth and transcriptional regulation of these mRNA. CONCLUSION: DMARD may have a direct inhibitory effect on rheumatoid synovial cell proliferation without the involvement of other cellular factors, which may be a mechanism of clinical remission induced by DMARD in patients with RA.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1996

Novel mechanisms of selective apoptosis in synovial T cells of patients with rheumatoid arthritis.

OBJECTIVE: To analyze whether T cells infiltrating the synovium of patients with rheumatoid arthritis (RA) express functional Fas antigen. METHODS: Mononuclear T cells, mainly from synovial tissues, synovial fluids (SF), and peripheral blood mononuclear cells (PBMC) from 14 patients with RA and 5 with osteoarthritis (OA), were treated with anti-Fas monoclonal antibody (Mab) (CH11) for 24 h in vitro. Cell viability and DNA fragmentation were examined. The expression of Fas antigen, Fas ligand, and T cell subpopulations was examined using flow cytometry and reverse transcription polymerase chain reaction. RESULTS: More than 50% of T cells from synovial tissue and SF of patients with RA underwent apoptosis, whereas no effect was observed in PBMC from RA or PBMC and synovial T cells from OA, suggesting that functional Fas antigens are specifically expressed on synovial T cells. Flow cytometric analysis demonstrated higher expression of Fas antigen in T cells from RA synovium than from PBMC. The T cell subpopulations susceptible to anti-Fas Mab were mainly CD45RO+ and CD4 or CD8 single positive T cells, indicating that activated mature T cells express functional Fas antigen. Fas ligand was overexpressed only in synovial nonadherent cells in RA at the level of mRNA, whereas T cells account for more than 60% of the total, but not in OA. CONCLUSION: These findings suggest the majority of activated T cells infiltrating the synovium express functional Fas antigen and Fas ligand specifically in patients with RA but not OA. This phenomenon may provide a clue to understanding the pathogenesis of RA.

Adult↗
PubMed1995

Spectral analyses of R-R interval and systolic blood pressure in diabetic autonomic neuropathy.

We studied autonomic nervous system function using the principle of maximum entropy (ME) to perform spectral analyses of the R-R interval and systolic blood pressure in 32 diabetic patients and 40 healthy controls. The R-R interval and systolic blood pressure were measured using a continuous, noninvasive monitoring system. The power spectra of both the R-R interval (RR) and systolic blood pressure (SYS) were obtained using ME and the areas of two frequency components were measured: a low- (LFC) and a high-frequency component (HFC). The RR-LFC, RR-HFC and SYS-LFC of diabetic patients were significantly smaller than those of healthy controls. The results of the spectral analyses in diabetic patients correlated with neither disease duration nor nephropathy, while the SYS-LFC showed significant correlations with both retinopathy and the delay in median motor nerve conduction velocity. In the mild autonomic neuropathy group, the RR-LFC and SYS-LFC were not differ from those of healthy controls or patients without autonomic neuropathy. However, the RR-HFC was significantly smaller than that of healthy controls or patients without atonomic neuropathy. In the setting of mild diabetic autonomic neuropathy, it was suggested that cardiac parasympathetic dysfunction preceded both alpha and beta sympathetic dysfunction.

Adult↗
PubMed1995

Oligoclonal proliferation of human T-cell leukemia virus type I infected lymphocytes in lesions of virus-induced arthropathy.

To investigate the pathogenesis of human T-cell leukemia virus type I associated arthropathy, the mode of proviral integration in the pathological lesions was analyzed using ligation-mediated polymerase chain reaction. Peripheral blood mononuclear cells (PBMC) of these patients possessed multiple dominant clones of the virus-infected cells. On the other hand, synovial fluid cells of the affected joints exhibited fewer dominant clones even though the copy numbers of the provirus were comparable to those of PBMC. Thus, restricted HTLV-I infected T cell clones may proliferate and expand in the lesions.

Aged↗
PubMed1995

Apoptosis and functional Fas antigen in rheumatoid arthritis synoviocytes.

OBJECTIVE: To determine whether apoptosis occurs in rheumatoid arthritis (RA) synoviocytes, and if this phenomenon is dependent on the Fas/Apo-1 pathway. METHODS: Apoptotic change in vivo was examined in RA synovial cells by several standard methods. The ability of cells to undergo Fas-induced apoptosis was determined in vitro. RESULTS: Typical apoptotic change was demonstrated in RA synovial cells by each method. Anti-Fas antibody induced apoptotic synovial cell death in vitro. CONCLUSION: This is the first reported study to demonstrate apoptosis in RA synovial cells. The findings indicate that rheumatoid synoviocytes undergo Fas-mediated apoptosis.

Antibodies↗
PubMed1994

Establishment and characterization of synovial cell clones with integrated human T-cell leukemia virus type-I.

Human T cell leukemia virus type-I (HTLV-I)-integrated synovial cell clones (SCCs) were established from four HTLV-I-infected patients with chronic proliferative arthropathy. Extracted DNAs of these SCCs were examined for the existence of HTLV-I proviral DNA. Electron microscopic analysis and immunohistochemical staining were also performed to examine the nature of the HTLV-I integrated SCCs. SCCs derived from all four patients consisted of either HTLV-I integrated or nonintegrated cells. HTLV-I integrated SCCs also produced viral messenger RNA which was detected by reverse transcriptase-polymerase chain reaction as well as viral protein which was detected by immunohistochemical staining. Phenotypically, these SCCs containing HTLV-I proviral DNA were shown to be all cell types as observed by electron microscopic analysis and immunohistochemical analysis. Moreover, expression of HTLV-I glycoprotein was greater in SCCs with a monocyte marker. These findings suggest that SCCs harboring HTLV-I have an important role in synovial hyperplasia.

Aged↗
PubMed1994

A young case with multi-infarct dementia associated with lupus anticoagulant.

A 39-year-old man was admitted because of an abrupt onset of right-side weakness and dysarthria. During the 2 years before admission, he had suffered from insomnia, depressed mood and progressive memory disturbance. Neurological and psychiatric examination revealed severe intellectual impairment in addition to the neurological deficits. Neuroradiological examinations revealed multiple brain infarcts. He had no risk factor for stroke except for lupus anticoagulant. He was diagnosed as having multi-infarct dementia associated with antiphospholipid antibodies. This case suggests that it is necessary to investigate antiphospholipid antibodies in addition to neuroradiological examination when relatively young patients present with unexplained cognitive or behavioral symptoms.

Adult↗
PubMed1993

Overgrowth of human synovial cells driven by the human T cell leukemia virus type I tax gene.

One of the salient pathological features of rheumatoid arthritis is synovial cell proliferation with bone erosion. Despite extensive investigation, the factors essential for synovial cell proliferation remain to be identified. Recent studies suggest that human T cell leukemia virus type I (HTLV-I) may play an important role in synovial overgrowth observed in patients with one type of chronic inflammatory synovitis. In order to confirm and extend these observations, we have established synovial cell clones (SCCs) from three HTLV-I carriers who demonstrated synovial overgrowth but were otherwise asymptomatic. HTLV-I proviral DNA randomly integrated into the cellular genome was present in 20-30% of SCCs. The SCCs carrying HTLV-I proviral DNA and expressing the tax gene exhibited high levels of proliferative potential. HTLV-I was found to function as a transcriptional trans-activator in these SCCs. Moreover, transfection of the tax expression plasmid into SCCs resulted in the same phenotype of increased proliferation and cytokine expression as exhibited by HTLV-I provirus-carrying and tax-expressing SCCs. These data suggest that tax plays a critical role not only in leukemogenesis but also in synovial overgrowth in humans.

Arthritis↗
PubMed1993

Rheumatic manifestation of human leukemia virus infection.

Rheumatic disorders associated with retroviruses are described in this article. A recent study of human T-cell leukemia virus type-I (HTLV-I) revealed that it appeared to be associated with the pathogenesis of several immune disorders such as myelopathy, broncho-pneumopathy, Sjogren's syndrome, and arthropathy. HTLV-I-associated arthropathy (HAAP) shows remarkable synovial proliferation with nuclear convoluted T-cell infiltration in both synovium and synovial fluid. Synovial cells obtained from HAAP patient-integrated HTLV-I proviral DNA and also expressed mRNA for HTLV-1 tax gene; moreover, HTLV-1 integrated synovial cell clones expressed a high level of mRNA for several oncogene and growth factors compared with HTLV-I non-integrated clones. These findings suggest that HTLV-I is the first exogenous retrovirus that contributes to synovial proliferation with immune disorders in humans.

Aged↗
PubMed1992

Simian immunodeficiency virus-specific cytotoxic T lymphocytes are present in the AIDS-associated skin rash in rhesus monkeys.

An infiltration of CD8+ lymphocytes in the dermis and epidermis underlies the skin rash that commonly occurs as a primary manifestation of an AIDS virus infection. These cutaneous lymphocytes were characterized in simian immunodeficiency virus of macaques (SIVmac)-infected rhesus monkeys. Skin rash-associated lymphocytes exhibited greater lysis of SIVmac-expressing target cells and a higher cloning efficiency for SIVmac-specific effector T cells than PBL. Moreover, both SIVmac envelope- and gag-specific CTL could be readily cloned from these skin rash-associated lymphocytes. In fact, the skin rash-associated CTL exhibited the same MHC restriction and epitope specificity as those CTL derived from PBL. These studies, therefore, demonstrate that the cutaneous infiltrating CD8+ lymphocytes in SIVmac-infected rhesus monkeys include SIVmac-specific CTL. Thus, whereas virus-specific CTL are likely to represent an important mechanism for controlling AIDS virus infections, they also may play a role in the pathogenesis of the skin lesions that occur after this infection.

Animals↗
PubMed1992

Regions of the CD4 molecule not involved in virus binding or syncytia formation are required for HIV-1 infection of lymphocytes.

Cell surface-expressed CD4 binds to the envelope glycoprotein of HIV-1 and mediates syncytia formation through interacting with membrane expressed HIV-1 gp120. Further possible roles of the CD4 molecule in the process of cell infection by HIV-1 remain poorly understood. In our study we describe two mAb that recognize the V3/V4 domain of the CD4 molecule. Although these mAb do not inhibit gp120-CD4 binding or HIV-1-induced syncytia formation, they inhibit HIV-1 infection of human PBL. These findings suggest that discrete, definable domains of the CD4 molecule may be involved in interactions after HIV-1 envelope binding that lead to virus entry into the cell.

Antibodies, Monoclonal↗