Immunologic intervention in the pathogenesis of osteoarthritis.
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Cartilage, Articular↗
Biomedical subjects
Tomohiro Kato
Publications and source records attributed to Tomohiro Kato.
Virus-associated arthritis.
The occurrence of arthritis in patients who were infected by a virus has been widely observed. In some cases, the clinical appearance seems to resemble that of rheumatoid arthritis. The mechanism by which the viral infection proceeds to the arthritic manifestation is, however, still to be investigated. Several biological and immunological pathways are suggested to be involved in the pathogenesis. The representatives of such potentially 'arthritogenic' viruses include human T-cell lymphotropic virus type I (HTLV-I), which causes destructive inflammatory arthritis in model animals. Other examples are hepatitis C virus and rubella virus. Clinical and pathological features of these virus-induced forms of arthritis are discussed.
Animals↗
Inhibition of nuclear factor kappaB and phosphatidylinositol 3-kinase/Akt is essential for massive hepatocyte apoptosis induced by tumor necrosis factor alpha in mice.
BACKGROUND/AIMS: Tumor necrosis factor (TNF)-alpha itself does not induce liver injury in normal mice or hepatocytes. Rather, this event, especially in vitro, is explained by the fact that the TNF-alpha/TNF receptor system not only triggers downstream signals leading to apoptosis but also induces an antiapoptotic pathway through the activation of nuclear factor (NF)-kappaB. The aim of this study was to determine whether inhibition of antiapoptotic pathways influences the susceptibility of mice to TNF-alpha. Here, we focused on the roles of NF-kappaB and phosphatidylinositol 3-kinase (PI3K)-regulated serine/threonine kinase Akt. METHODS: TNF-alpha was administered to BALB/c mice after treatment with an adenovirus expressing a mutant form IkappaBalpha (Ad5IkappaB), the PI3K inhibitor wortmannin, or both. Liver injury was assessed biochemically and histologically. The expression of Bcl-2 family members and caspase activity were examined. RESULTS: In the mice livers, treatment with Ad5IkappaB or the wortmannin suppressed the activation of NF-kappaB or Akt, respectively. Suppression of either NF-kappaB or Akt showed a slight increase in transaminase levels and focal liver cell death after TNF-alpha administration. However, in mice treated with both Ad5IkappaB and wortmannin, TNF-alpha administration resulted in massive hepatocyte apoptosis and hemorrhagic liver destruction in mice. The combination of Ad5IkappaB, wortmannin, and TNF-alpha markedly increased the activation of caspase-3 and -9, and activated caspase-8 to a lesser degree, suggesting that TNF-alpha-induced hepatocyte apoptosis is dependent on type II cell death signaling pathway, probably through the mitochondria. Inhibition of the NF-kappaB and PI3K/Akt pathways had no effect on expression of Bcl-2 families. CONCLUSION: The inducible activation of NF-kappaB and constitutive activation of Akt regulate hepatocyte survival against TNF-alpha, which occurs independent of Bcl-2 families.
Androstadienes↗
Autoantibodies to CD69 in patients with chronic hepatitis type C: a candidate marker for predicting the response to interferon therapy.
OBJECTIVE: To understand the autoimmunity associated with chronic hepatitis C (CHC), we investigated autoantibodies (autoAbs) to CD69. METHODS: With this aim, we tested the reactivity of serum samples from patients with CHC and asymptomatic carriers of hepatitis C virus (HCV), as well as from patients with chronic hepatitis B (CHB) and autoimmune hepatitis (AIH), to recombinant CD69 molecules. RESULTS: Frequencies of anti-CD69 autoAbs were 38.7% in CHC, 15.8% in AIH and 12.3% in CHB. None of the tested asymptomatic HCV carriers had autoAbs to CD69. It is important clinically that the presence of anti-CD69 autoAbs was found to be associated with a poor response to interferon-alpha (IFN-alpha) therapy. In the epitope analysis, multiple epitopes were mapped on CD69, indicating antigen-driven production of the autoAbs. CONCLUSION: We evidenced existence of anti-CD69 autoAbs in patients with CHC, and found that the anti-CD69 autoAb may have potential for predicting responses to IFN-alpha therapy.
Adult↗
Changes in heart rate variability in horses during immersion in warm springwater.
OBJECTIVE: To determine the effects of immersion in warm springwater (38 degrees to 40 degrees C) on autonomic nervous activity in horses. ANIMALS: 10 male Thoroughbreds. PROCEDURE: Electrocardiograms were recorded from horses for 15 minutes during a warm springwater bath after being recorded for 15 minutes during stall rest. Variations in heart rate (HR) were evaluated from the power spectrum in terms of low frequency (LF, 0.01 to 0.07 Hz) power and high frequency (HF, 0.07 to 0.6 Hz) power as indices of autonomic nervous activity. RESULTS: Mean (+/- SE) HR during stall rest and immersion in warm springwater was 31.1 +/- 1.7 and 30.3 +/- 1.0 beat/min, respectively. No significant difference was found between the HR recorded during stall rest and that recorded during immersion in warm springwater. The HF power significantly increased from 1,361 +/- 466 milliseconds2 during stall rest to 2,344 +/- 720 milliseconds2 during immersion in warm springwater. The LF power during stall rest and immersion in warm springwater was 3,847 +/- 663 and 5,120 +/- 1,094 milliseconds2, respectively, and were not significantly different from each other. Similarly, the LF:HF ratio did not change during immersion in warm springwater. The frequency of second-degree atrioventricular block, which was observed in 2 horses, increased during immersion in warm springwater, compared with during stall rest. CONCLUSIONS AND CLINICAL RELEVANCE: Increases in HF power indicates that the parasympathetic nervous activity in horses increases during immersion in warm springwater. Thus, immersion in warm springwater may provide a means of relaxation for horses.
Animals↗
[A case of gastrointestinal stromal tumor of the duodenum].
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Duodenal Neoplasms↗
[A case report of an advanced esophageal carcinoma (stage II) without signs of recurrence in 5 years after chemoradiotherapy. With reference to p53 immunohistochemistry as an indicator for prognostic evaluation of chemoradiotherapy].
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Aged↗
Metachronous colon tumors: risk factors and rationale for the surveillance colonoscopy after initial polypectomy.
PURPOSE: We analyzed the possible risk factors for metachronous colon tumors after endoscopic resection of initial tumors. METHODS: Three hundred and twenty-one patients entered the surveillance study after colonoscopic resection of initial tumors between 1985 and 1999. Histology of initial tumors was adenoma in 214 patients and carcinoma in 107 patients. Solitary tumor was observed in 196 patients and multiple tumors in 125 at initial endoscopy. The median surveillance period was 39 (range, 12-112) months, and the median frequency of surveillance colonoscopy was three (range, 2-10) times. RESULTS: Metachronous neoplasms were identified in 114 of 321 surveillance cases (36%). In the 114 cases, the number of patients with metachronous adenoma was 103 (90%) and that of carcinoma was 11 (10%). Clinical characteristics at entry - including age, gender, multiplicity of polyp, histology of polyp, and site of polyp - were not different between patients with metachronous tumors and those without metachronous tumors. Kaplan-Meier analysis revealed that patients with a histology of carcinoma and those with multiple polyps at entry developed metachronous tumors significantly earlier than did patients with initial adenomas and initial solitary polyp, respectively ( P<0.001, P<0.001). However, other characteristics at entry did not produce significant differences in the rate of the development of metachronous tumors using Kaplan-Meier analysis. Proportional hazards model analysis revealed that histology of the initial tumor as carcinoma (relative risk, 1.690, 95% confidence interval, 1.118-2.555) and multiplicity (1.472, 1011-2.143) were significant risk factors for metachronous colon tumors. The 75%, 50%, and 25% metachronous tumor-free periods after initial polypectomy were 14, 21, and 39 months, respectively. CONCLUSIONS: These results may help optimizing surveillance strategies for metachronous colon tumors and raising the economic benefit of colonoscopy.
Adenocarcinoma↗
Expression of the anaphylatoxin receptor C5aR (CD88) by human articular chondrocytes.
Although the complement system is implicated in the inflammatory process in arthritic diseases, a direct interaction between chondrocytes and complement has not been demonstrated. In this study, we investigated expression of the C5a receptor (C5aR) on chondrocytes of cartilage from patients with rheumatoid arthritis (RA), osteoarthritis (OA), and bone fracture as normal controls by reverse transcriptase polymerase chain reaction (RT-PCR), flow cytometry, and immunohistochemistry. The RT-PCR detected mRNA for C5aR in most or all of the tested samples (73% in OA, 100% in RA, 89% in normal). The FACS analysis revealed different expression ratios between individuals varying from 0.7% to 77.1%; however, expression ratios of C5aR were significantly higher in RA than in controls (26.0% in RA, 9.0% in OA, 6.9% in normal). The expression of C5aR was upregulated significantly by addition of IL-1beta in RA and normal samples but not in OA. In addition, the C5aR-positive chondrocytes were confirmed by immunohistochemistry. In conclusion, expression of C5aR and the effect of IL-1beta on the expression were different between RA and OA. The C5aR may contribute to chondrocyte metabolism and the pathogenesis of arthritis differently between in RA and OA.
Adult↗
Detection of a novel specificity (CTLA-4) in ATG/TMG globulins and sera from ATG-treated leukemic patients.
BACKGROUND: T-cell costimulation has been shown to provide positive signals for T-cell activation and generation of effector activity. In this study, we analyzed the presence of antibodies (Abs) against the T-lymphocyte costimulatory molecules CD28, CTLA-4, CD80, and CD86 in anti-T-lymphocyte (ATG) and antithymocyte (TMG) globulin preparations to address their mechanism of action. We focused our attention on the role of CTLA-4-specific Abs in the immunosuppressive effect of ATG/TMG, because anti-CTLA-4 agonistic Abs may suppress T-cell proliferation and nonagonistic Abs may lead to T-cell depletion through an Ab-dependent cell cytotoxicity mechanism. METHODS: ATG/TMG and patients' sera were tested for binding to recombinant human costimulatory molecules by ELISA techniques. CTLA-4 specificity was also analyzed by cytoplasmic immunofluorescence staining of a CTLA-4 transfectant by competitive inhibition immunofluorescence and by cell proliferation assay in allogeneic mixed lymphocyte reaction (MLR). RESULTS: Either ATG or TMG predominantly contained anti-CTLA-4 Abs, with higher reactivity in ATG followed by anti-CD86 and -CD28 Abs, whereas anti-CD80 Abs were found only in ATG. Anti-CTLA-4 Abs present in ATG/TMG recognized the native form of CTLA-4 molecule, and their removal reduced the effect of ATG in an allogeneic MLR. Kinetic studies indicated that such Abs were present in the sera of 12 ATG-treated leukemic patients up to 21 days after ATG administration. CONCLUSIONS: These data suggest that the novel anti-CTLA-4 Abs found in ATG may greatly contribute to its immunosuppressive effect, thus accounting for the absence of rejection and exceptionally low incidence of graft-versus-host disease in the group of patients analyzed.
Abatacept↗
Expression of MHC class I molecules together with antigenic peptides on filamentous phages.
The availability of combinatorial T cell epitope libraries made using a phage display system would be useful for identifying the antigens recognized by T cells of unknown specificity. To this end, we have investigated here whether single chain-MHC class I molecules (scMHC-I) could be expressed together with antigenic peptides on filamentous phages. The results show that filamentous phages can express scMHC-I. Moreover, the expressed scMHC-I was able to bind antigenic peptide. These data support the use of combinatorial scMHC/T cell epitope libraries for screening potential T cell antigens.
Antigens↗
Analysis of gene expression profile induced by hepatocyte nuclear factor 4alpha in hepatoma cells using an oligonucleotide microarray.
Hepatocyte nuclear factor 4alpha (HNF-4alpha), a liver-specific transcription factor, plays a significant role in many liver-specific functions, including lipid, glucose, drug, and ammonia metabolism, and also in embryonal liver development. However, its functions and regulation are not yet clearly understood. In this study, we constructed an adenovirus vector carrying rat HNF-4alpha cDNA and transfected the adenovirus to human hepatoma cells, HuH-7, to enforce expression of the exogenous HNF-4alpha gene. We analyzed HNF-4alpha-induced genes using cDNA microarray technology, which included over 9000 genes. As a result, 62 genes showed a greater than 2.0-fold change in expression level after the viral transfection. Fifty-six genes were consistently induced by HNF-4alpha overexpression, and six genes were repressed. To assess HNF-4alpha function, we attempted to classify the genes, which had been classified by their encoding protein functions in a previous report. We could classify 45 genes. The rest of the HNF-4alpha-sensitive genes were unclassified (4 genes) or not identified (13 genes). Among the classified genes, almost half of the induced genes (26 of 40) were related to metabolism genes and particularly to lipid metabolism-related genes. This cDNA microarray analysis showed that HNF-4alpha is one of the central liver metabolism regulators.
Adenoviridae↗
Therapeutic effect of intraarterial prednisolone injection in severe intestinal Behçet's disease.
A 64-year-old woman with severe intestinal Behçet's disease who was unresponsive to conventional therapies, including intensive intravenous steroid injections, underwent intraarterial steroid injection therapy. After the infusion of prednisolone into the mesenteric arteries, her colon ulcers improved markedly, and the frequency of bloody stools decreased immediately. The present case suggests that intraarterial steroid injection therapy may be potentially useful in severe intestinal Behçet's disease.
Anti-Inflammatory Agents↗
T-cell clonotypes specific for Dermatophagoides pteronyssinus in the skin lesions of patients with atopic dermatitis.
T-cell mediated immune response, toward the house dust mite (HDM) antigens in particular, has been reported to be involved in the pathogenesis of atopic dermatitis (AD). On the other hand, studies on the infiltrating lymphocytes in the skin lesion of AD revealed oligoclonal T-cell accumulation. However, it is not clear exactly what antigen(s) the accumulating T cells are exactly recognize in situ. Therefore, this study attempted to determine whether or not the clonally expanded T-cell clones in the diseased skin recognize HDM. Specifically, peripheral blood mononuclear cells (PBMC) obtained from six patients with AD, who revealed high titers of anti-HDM IgE, were stimulated with HDM antigens purified from Dermatophagoides pteronyssinus (Dp). T-cell clonotypes expanded by the stimulation were then identified by the analysis of their T-cell receptor (TCR) B-gene sequences using a combination of the reverse transcription-polymerase chain reaction and subsequent single strand conformation polymorphism separation. The Dp-responding T-cell clonotypes were compared with those that accumulated in the AD skin lesion in vivo. Nucleotide sequences of the TCR were also determined. As a result, the Dp stimulation induced oligoclonal T-cell expansion from the originally heterogeneous peripheral T-cell population of AD patients. However, only a small part of the Dp-reacting T-cell clonotypes detected in PBMC was identical to those accumulated in the AD skin lesion in vivo, and vice versa. This indicates that the frequency of the clonal expansion of Dp-specific T-cell clonotypes in the skin lesion of AD would be rather limited.
Allergens↗
Prognostic value of energy metabolism in patients with viral liver cirrhosis.
The effect of energy malnutrition on survival in patients with non-alcoholic viral liver cirrhosis has not been well defined. We characterized energy metabolism at study entrance and prospectively analyzed its effect on subsequent survival in cirrhotics. One hundred nine consecutive patients with viral liver cirrhosis and 22 healthy control subjects participated in the study. By indirect calorimetry after overnight bedrest and fasting, resting energy expenditure (REE) was measured and non-protein respiratory quotient (npRQ) was calculated. Survival of cirrhotics were followed for up to 8 y. Survival rate was estimated with the Kaplan-Meier method. REE at entrance was significantly higher than the predicted basal metabolic rate (BMR) in cirrhotics (P < 0.001). NpRQ was significantly lower in cirrhotics than in controls (P < 0.001). Survival rate was significantly lower in patients with low npRQ ( < 0.85) than in patients with scores above 0.85 (P < 0.01) and was significantly higher in normal metabolic patients (0.9 < REE/BMR < 1.1) than in hypometabolic (REE/BMR < 0.9) or hypermetabolic (1.1 < REE/BMR) patients (P < 0.05). The proportional hazards model showed that npRQ (relative risk = 0.0003, 95% confidence interval = 0.0000-0.0970), REE/BMR (0.0199, 0.0007-0.5652), prothrombin time, and ammonia were independent significant factors determining survival. Thus evaluation of energy metabolism can be used to predict survival in patients with viral liver cirrhosis.
Basal Metabolism↗
Detection of clonally expanded T-cells by RT-PCR-SSCP and nucleotide sequencing of T-cell receptor beta-CDR3 regions.
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Genes, T-Cell Receptor beta↗
Autoimmunity against YKL-39, a human cartilage derived protein, in patients with osteoarthritis.
OBJECTIVE: Our previous study revealed that some patients with rheumatoid arthritis (RA) possessed autoantibodies to YKL-39, a cartilage related protein. We investigated whether patients with osteoarthritis (OA) also displayed autoimmunity to YKL-39. METHODS: Autoantibodies to recombinant YKL-39 as well as human cartilage glycoprotein-39 were detected by ELISA and Western blotting. The tested serum samples were derived from 117 patients with OA, 94 patients with RA, and 2 groups of 50 arthropathy-free healthy donors who matched the OA and RA groups for age and sex. We determined autoepitopes on YKL-39 using 3 overlapping fragments of YKL-39 (designated F1, F2, F3). T cell proliferation response to YKL-39 was analyzed using the 3H-thymidine incorporation assay. RESULTS: Autoantibodies to YKL-39 were detected in 13 (11.1%) patients with OA and 11 (11.8%) with RA. In the epitope mapping, all the 3 fragments of YKL-39 were found to carry autoepitopes, but F1 was recognized most frequently. Proliferative responses of peripheral blood mononuclear cells against YKL-39 were detected in 6 (46%) of the 13 OA patients who were positive for the anti-YKL-39 autoantibodies and in 2 (17%) of the 11 antibody positive RA patients. CONCLUSION: These results show that autoimmunity to YKL-39 in patients with OA was present at equal or somewhat higher frequency than in patients with RA. The cellular and humoral immune responses to YKL-39 may be involved in the pathological process of OA as well as RA.
Adipokines↗
[A new combination therapy with low-dose FP and daily oral administration of low-dose etoposide--a report of 2 cases].
We report 2 patients with advanced gastric cancer treated with a new combination chemotherapy of low-dose FP and daily oral administration of low-dose etoposide. Patient 1 was an 84-year-old man. He was diagnosed with cancer of the remnant stomach with multiple liver metastases. For eight months, he was treated as an outpatient and his performance status (PS) stayed at stage 1. Patient 2 was a 67-year-old man with lymph node metastasis of the lung. For the first 6 weeks, he was treated under hospitalization and for the following 10 months he was treated as an outpatient. His PS remained in stage 1 and blood CEA value fell from 2,420 ng/ml to 46.9 ng/ml. Upper gastrointestinal series showed a recovery of the extension of his lower gastric body. Both cases were so-called prolonged NC. From the viewpoint of patient QOL, this new combination is a possible candidate for a more effective chemotherapy.
Adenocarcinoma↗