Biomedical subjects

T Sumida

Publications and source records attributed to T Sumida.

At least 127 records · Page 7Linked 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

Common T cell receptor clonotype in lacrimal glands and labial salivary glands from patients with Sjögren's syndrome.

Sjogren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration into lacrimal and salivary glands leading to symptomatic dry eyes and mouth. Immunohistological studies have clarified that the majority of infiltrating lymphocytes around the lacrimal glands and labial salivary glands are CD4 positive alphabeta T cells. To analyze the pathogenesis of T cells infiltrating into lacrimal and labial salivary glands, we examined T cell clonotype of these cells in both glands from four SS patients using PCR-single-strand conformation polymorphism (SSCP) and a sequencing method. SSCP analysis showed that some infiltrating T cells in both glands expand clonally, suggesting that the cells proliferate by antigen-driven stimulation. Intriguingly, six to sixteen identical T cell receptor (TCR) Vbeta genes were commonly found in lacrimal glands and labial salivary glands from individual patients. This indicates that some T cells infiltrating into both glands recognize the shared epitopes on autoantigens. Moreover, highly conserved amino acid sequence motifs were found in the TCR CDR3 region bearing the same TCR Vbeta family gene from four SS patients, supporting the notion that the shared epitopes on antigens are limited. In conclusion, these findings suggest that some autoreactive T cells infiltrating into the lips and eyes recognized restricted epitopes of a common autoantigen in patients with SS.

Amino Acid Sequence↗

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

Autoimmune disease of exocrine organs in immunodeficient alymphoplasia mice: a spontaneous model for Sjögren's syndrome.

Mice homozygous for an autosomal recessive mutation aly (alymphoplasia) lack both lymph nodes and Peyer's patches, and show defects in both humoral and cellular immunity. Histopathological analysis revealed chronic inflammatory changes in exocrine organs such as the salivary gland, lacrimal gland, and pancreas of the homozygotes (aly/aly), but not the heterozygotes (aly/+). In these exocrine organs, mononuclear cells consisting mainly of CD4+ T cells infiltrate periductal areas, and, in some cases, the cell infiltration extended to lobules. The inflammatory changes in exocrine organs were transferred by a T cell-enriched fraction of spleen cells from homozygous animals. These results suggest that autoimmune mechanisms mediated by self-reactive T cells may be involved in the inflammatory lesions of various exocrine organs in the homozygous mice, although these mice show immunodeficiency. Inflammatory changes were also observed in the lung of the homozygotes. Since Sjögren's syndrome is characterized by diffuse lymphocyte infiltration in the periductal areas of the lacrimal and salivary glands and is occasionally associated with pulmonary disease, aly/aly mice may serve as a unique spontaneous model of Sjögren's syndrome.

Adoptive Transfer↗

PubMed1996

Expression of Fas antigen and Fas ligand in the rheumatoid synovial tissue.

To understand the role of apoptosis through Fas/Fas ligand (Fas-L) interaction in the pathogenesis of rheumatoid arthritis (RA), we examined the expression of Fas antigen, Fas-L, and apoptosis in synovial tissue obtained from eight patients with RA and five patients with osteoarthritis (OA). Immunohistochemical staining demonstrated the significant expression of Fas antigen and Fas-L in RA synovial tissue compared with that in OA synovial tissue. Immunohistochemical staining and the DNA nick end labeling (TUNEL) method were combined and revealed that approximately 10 to 30% of Fas antigen-expressing cells in the RA synovium showed DNA fragmentation characteristic for apoptosis. In double-staining analysis, Fas-L was expressed on up to 10% of CD45RO-, CD4-, CD8-, or CD56-positive mononuclear cells in RA synovial tissue. Our results suggest that activated T cells and natural killer cells infiltrating into the RA synovium may contribute to the induction of apoptosis of RA synovial and mononuclear cells through Fas/Fas-L interaction.

Aged↗

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

T-cell receptor repertoire of infiltrating T cells in lachrymal glands, salivary glands and kidneys from alymphoplasia (aly) mutant mice: a new model for Sjögren's syndrome.

Alymphoplasia (aly) mice are thought to provide a new model for systemic Sjögren's syndrome (SS), since they reveal remarkable infiltration of mononuclear cells into salivary glands, lachrymal glands and kidneys, and show histological findings similar to those in patients with SS. Cell transfer experiments demonstrate that T cells induce the infiltration of mononuclear cells into several tissues in aly mice. To analyse the pathogenesis of cell infiltration in various tissues, we examined T-cell receptor (TCR) V beta usage of T cells in salivary glands, lachrymal glands and kidneys from aly mice, using family-polymerase chain reaction (PCR) and PCR-single-strand conformation polymorphism (SSCP) methods. The results of SSCP demonstrated that the infiltrating T cells in the three organs expanded clonally, suggesting that they proliferate by antigen-driven stimulation. Some TCR V beta genes (V beta 1, 3, 6, 11, 12, 16) were commonly used in salivary glands, lachrymal glands and kidneys, while the V beta 7 gene was specifically expressed in kidneys. SSCP also showed that there were a few shared T-cell clones (V beta 3- and V beta 6-positive cells) among the three tissues. Indeed, sequence analysis of accumulated T cells showed that a conserved amino acid (leucine) at position 98 in the TCR V beta complementary determining region (CDR) 3 was detected in all organs at high frequency (41-57%) and the amino acid sequence motif (LG) was specifically conserved at a frequency of 32% in the three organs. In conclusion, T cells that infiltrate into lachrymal glands, salivary glands and kidneys of aly mutant mice might recognize shared common epitopes in all three organs and a kidney-specific antigen.

Animals↗

PubMed1996

Synthesis and biological activities of optically active 6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]-2(1H)-quinolinone (OPC-18790).

The enantiomers of 6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]-2(1H)-quinolinon e (OPC-18790), a novel cardiotonic agent, were synthesized and evaluated for positive inotropic activity. The key intermediates, 2,3-epoxypropoxy derivatives, were obtained by the alkylation of 6-hydroxy-2(1H)-quinolinone with optically active epichlorohydrin and subsequent ring closure. In an in vitro study, the (R)-(+)-isomer was about 10-fold more potent than the (S)-(-)-isomer.

Animals↗

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

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↗

PubMed1996

[Tropical eosinophilia in a man from Sri Lanka].

A 21-year-old man from Sri Lanka came to Japan in August 1992 and worked as a painter. He had often complained of dyspnea on exertion before coming to Japan. He was admitted to Ogaki Municipal Hospital in June 1993 for further examination of persistent coughing, dyspnea, and fever. A chest X-ray film showed bilateral diffuse reticulonodular shadows. Blood examinations revealed marked eosinophilia (9440/mm3) with elevation of the serum IgE level (4982 IU/ml). IgG enzyme-linked immunosorbent assay showed a high titer against Dirofilaria immitis. Microfilaria were not detected in blood sampled at night. He was given a diagnosis of tropical eosinophilia. We could not give diethyl-carbamazine. Filariasis is seldom encountered in Japan, but we emphasize that parasitic disease such as tropical eosinophilia must be considered in the differential diagnosis if the patient is from a tropical area where filariasis is common.

Adult↗

PubMed1995

Limited TCR repertoire of infiltrating T cells in the kidneys of Sjögren's syndrome patients with interstitial nephritis.

To analyze the mechanism of interstitial nephritis in patients with Sjörgren's syndrome (SS), we examined the TCR repertoire of infiltration T cells in kidney, labial salivary glands, and PBLs using a PCR. The repertoire of the TCR V beta gene on infiltrating T cells from the kidneys of SS patients was more restricted than those on infiltrating T cells in labial salivary glands and PBL. The TCR V beta 2 gene was expressed predominantly in six of seven (86%) SS patients. Junctional sequences of cDNAs encoding the V beta 2 gene on infiltrating T cells in the kidneys of five SS patients showed that some of the cells expanded clonally, indicating Ag-driven stimulation rather than superantigen-induced proliferation. The same V beta 2 clones in the kidney were not detected in labial salivary glands of the same SS patients; the conserved amino acid (arginine at position 96) in the CDR3 region of the V beta 2 gene was found at a frequency of 48.0% in the kidney, whereas it was detected in only 15.4% of the clones in lips. In conclusion, these findings suggest the possibility that T cells that infiltrate the kidneys of SS patients with interstitial nephritis might recognize different autoantigens than those that infiltrate labial salivary glands.

Amino Acid Sequence↗

PubMed1995

Selective reduction of T cells bearing invariant V alpha 24J alpha Q antigen receptor in patients with systemic sclerosis.

A novel subset of T cells characterized by the expression of an invariant T cell antigen receptor (TCR) encoded by V alpha 24J alpha Q gene segments was investigated in patients with systemic sclerosis (SSc). Polymerase chain reaction analysis demonstrated that the V alpha 24 TCR repertoire was selectively used in CD4-CD8- double-negative T cells both in patients and in healthy individuals, while almost all families of TCR V alpha were expressed in single-positive T cell fractions. The V alpha 24+ double-negative T cells were increased by approximately fivefold in patients. However, sequence analysis clearly showed significant differences in the V alpha 24 TCR repertoire dominating in patients and healthy donors. In healthy individuals, the invariant V alpha 24J alpha Q was expanded and comprised 20-50% of the total TCR-alpha, while their selective reduction was observed in SSc patients who also showed expansion of invariant V alpha 24 TCR other than V alpha 24J alpha Q. Analogous to murine invariant V alpha 14J alpha 281 TCR, these results suggest that T cells with invariant V alpha 24J alpha Q TCR would function as regulatory T cells, whereas T cells bearing other invariant V alpha 24 TCR in SSc patients could be autoaggressive T cells in nature.

Asian People↗

PubMed1995

Restricted V beta gene usage of tumour-infiltrating T lymphocytes in primary gastric malignant B-cell lymphoma.

Ten cases of primary gastric malignant lymphoma (PGL) were investigated by immunohistochemical and molecular genetic analysis. These cases were diagnosed histopathologically as follicular small cleaved cell type (1 case), diffuse small cleaved cell type (3 cases) and diffuse large cell type (6 cases) based on the WF (Working Formulation) classification. Seven cases classified as small cleaved or diffuse large cell type belong to low (4 cases) or high (3 cases) grade MALT lymphoma according to Isaacson's classification. All PGL belonged to B lineage cells according to immunohistochemical study and immunoglobulin rearrangements. Rearrangements of TCR beta chain genes were observed in four of the ten cases. The possibility that the TCR beta rearrangements were caused by tumour-infiltrating T-cells (TILs) was supported by the following observations: the tumours did not show T- and B-cell biphenotype, TCR beta exhibited functional VDJ rearrangement and V beta usage pattern was not a neoplastic type. Analysis of the repertoire of the TCR beta chain in TILs revealed a common usage of V beta 2 in the above four cases, and furthermore, predominant usage of a particular beta chain composed of V beta 2-D beta 2.1-J beta 2.3 was observed in one of the four cases. These results indicate that the TILs of PGL have a restricted TCR repertoire.

Adult↗

PubMed1995

Intravenous midazolam suppresses noxiously evoked activity of spinal wide dynamic range neurons in cats.

The effects of intravenously (i.v.) administered midazolam on noxiously evoked activity of spinal wide dynamic range (WDR) neurons were investigated in decerebrate, spinal-cord-transected cats. Extracellular, single-unit recordings were measured during stimulation by pinching the receptive field on the hind paw and the effect of midazolam at doses of 0.25, 0.5, 1, 2, and 4 mg/kg were measured. Two series of experiments were performed to characterize the analgesic effects of midazolam. In the first, dose-response experiments (n = 59) demonstrated a dose-dependent suppression of the noxiously evoked activity of spinal WDR neurons after midazolam administration. This effect of midazolam was maximal at a dose of 1 mg/kg i.v.. The second series of experiments (n = 14) demonstrated that a benzodiazepine antagonist, flumazenil (n = 8), promptly reversed the effect of midazolam, while an opioid antagonist, naloxone (n = 6), had no effect on the effect of midazolam. The present study demonstrates that i.v. administered midazolam suppresses noxiously evoked activity of spinal WDR neurons that is reversible by a benzodiazepine antagonist. This is consistent with an analgesic action of midazolam.

Animals↗

PubMed1995

[Effects of fluconazole on onychomycosis in the patients with collagen diseases].

Thirty-four patients with collagen diseases suffering from onychomycosis were treated with fluconazole and showed remarkable improvement. Thirty-one patients showed improvement while only four patients showed adverse reactions. More than half of the cases with onychomycosis in their fingers showed improvement within four weeks and complete recovery within 20 weeks after the administration of fluconazole. Patients with collagen diseases are liable to have onychomycosis as an opportunistic infection which is recalcitrant and resistant disease from the previous therapy. In this trial it became obvious that fluconazole was not only effective on onychomycosis but also a safe drug for the patients with collagen diseases.

Adult↗

PubMed1995

[Molecular mechanism on Sjögren's syndrome].

Sjögren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration into lachrymal and salivary glands leading to symptomatic dye eyes and mouth. Immunohistological studies have clarified that the majority of infiltrating lymphocytes around the lachrymal glands and labial salivary glands are CD4 positive alpha beta T cells. To analyze the nature of T cells in lachrymal glands and labial salivary glands, we examined TCR V beta genes of infiltrating T cells into both glands from SS patients, using PCR-SSCP and sequencing methods. The results showed the following two findings. 1) Some of T cells infiltrating in both glands expand clonally, suggesting that these cells proliferate by antigen-driven stimulation. 2) The common T cells accumulated in lachrymal and labial salivary glands. In conclusion, autoreactive T cells in lips and eyes should recognize the same epitopes of autoantigen in individual patients with SS. Further analysis on autoantigen using T cell lines from labial salivary glands supports the notion that Ro/SS-A 52 kD is a possible autoantigen recognized by autoreactive T cells.

Autoantigens↗

PubMed1995

[Expression of sequences homologous to HTLV-I pXIV gene in the labial salivary glands of Japanese patients with Sjögren's syndrome and pathogenesis].

To address the question of whether the human T cell leukemia virus type I (HTLV-I) gene is associated with the etiology of Sjögren's syndrome (SS), RNA expression of HTLV-I gag, pol, env, and tax genes in labial salivary glands (LSGs) from SS patients who were seronegative for antibodies to HTLV-I was examined using RT-PCR method. The HTLV-I tax gene, but not the HTLV-I gag, pol, or env genes, was detected in LSG samples from 4 of 14 patients (29%). The nucleotide sequences of the HTLV-I pXIV region in these 4 patients' LSGs showed 100% homology to the HTLV-I pXIV gene from the MT-2 cell line. In conclusion, these findings suggest that products encoding sequences homologous to the HTLV-I pXIV gene in SS patients' LSGs might be candidates for self-antigen and/or lead to activation of autoreactive T lymphocytes through trans-acting transcriptional activation.

Asian People↗