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Masataka Kuwana

Publications and source records attributed to Masataka Kuwana.

At least 37 records · Page 2Linked to original sources
PubMed2005

Donor fibroblast chimerism in the pathogenic fibrotic lesion of human chronic graft-versus-host disease.

PURPOSE: Tissue atrophy and excessive fibrosis are prominent histologic features of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation, but the underlying mechanism remains unknown. The current study was undertaken to investigate whether the increase in fibroblasts at the site of pathogenic fibrosis originated from transplanted donor cells in patients with chronic GVHD. METHODS: Lacrimal gland biopsy specimens were obtained from nine patients with chronic GVHD. The male-specific sequences detected by fluorescein in situ hybridization (FISH) and in situ hybridization (ISH) were used as markers for the donor cells in seven female patients who had received a transplant from male donors. Primary fibroblast cultures were generated from lacrimal gland biopsy specimens and examined for mismatched genetic markers between recipients and donors. RESULTS: In lacrimal gland specimens obtained from seven female patients who received a sex-mismatched transplant, 13.4% to 26.7% of CD34+ fibroblasts that accumulated in the fibrotic lesion were donor derived, as determined by FISH for the Y-chromosome. The male-specific mRNA was also detected in the lacrimal gland fibroblasts by ISH. Primary lacrimal gland fibroblast cultures were generated from four patients with chronic GVHD and further examined for mismatched genetic markers between recipients and donors. As a result, the presence of donor origin of the fibroblasts was demonstrated by detecting the Y-chromosome sequence and donor-specific microsatellite genetic markers. CONCLUSIONS: These findings together indicate the chimeric status of accumulated CD34+ fibroblasts in the lacrimal gland of patients with chronic GVHD. Fibroblasts originating from circulating donor-derived precursors may participate in the excessive fibrosis in these patients.

Adult↗
PubMed2005

Is eradication therapy useful as the first line of treatment in Helicobacter pylori-positive idiopathic thrombocytopenic purpura? Analysis of 207 eradicated chronic ITP cases in Japan.

A retrospective study was performed to determine the prevalence of Helicobacter pylori (H pylori) infection, the effect of H pylori eradication on platelet counts, and the characteristic clinical features of chronic immune or idiopathic thrombocytopenic purpura (ITP) with H pylori infection. H pylori infection was found in 300 patients, a group that was significantly older (P < .005) and had more cases of hyperplastic megakaryocytes in the bone marrow (P = .01) than patients without H pylori infection. H pylori eradication therapy was performed in 207 H pylori-positive ITP cases, and the platelet count response was observed in 63% of the successful eradication group and in 33% of the unsuccessful eradication group (P < .005). In the successful group, the complete remission and partial remission rates were 23% and 42%, respectively, 12 months after eradication. In the majority of responders, the platelet count response occurred 1 month after eradication therapy, and the increased platelet count continued without ITP treatment for more than 12 months. H pylori eradication therapy was effective even in refractory cases, which were unresponsive to splenectomy. In conclusion, H pylori infection was involved in most ITP patients older than 40 years in Japan, and eradication therapy should be the first line of treatment in H pylori-positive ITP patients.

Adult↗
PubMed2005

The role of autoreactive T-cells in the pathogenesis of idiopathic thrombocytopenic purpura.

Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease mediated by antiplatelet autoantibodies. The major target of these autoantibodies is a platelet membrane glycoprotein, GPIIb-IIIa, which is a receptor for fibrinogen and other ligands. We recently identified CD4+ T-cells autoreactive to GPIIb-IIIa in ITP patients. These T-cells are considered pathogenic because they help B-cells produce antibodies that bind to normal platelet surfaces. GPIIb-IIIa-reactive T-cells respond to chemically reduced and tryptic peptides of GPIIb-IIIa but not to native GPIIb-IIIa, indicating that the epitopes they recognize are "cryptic" determinants generated at a subthreshold level by the processing of native GPIIb-IIIa under normal circumstances. Although GPIIb-IIIa-reactive T-cells are also detected in healthy individuals, they are activated in vivo only in ITP patients. Activation of GPIIb-IIIa-specific T-cells and the subsequent production of pathogenic anti-GPIIb-IIIa antibodies can be induced by functional antigen-presenting cells in the spleen that present cryptic GPIIb-IIIa peptides to these T-cells. The pathogenic process of ITP can be explained as a continuous loop in which B-cells produce antiplatelet autoantibodies, splenic macrophages phagocytose antibody-coated platelets and present GPIIb-IIIa-derived cryptic peptides, and GPIIb-IIIa-reactive CD4+ T-cells exert their helper activity. Further studies examining the mechanisms that induce the processing and presentation of cryptic peptides derived from the platelet antigen at disease onset will clarify how the pathogenic autoantibody response in ITP is initiated.

Autoimmunity↗
PubMed2005

Novel autoantibodies against 7SL RNA in patients with polymyositis/dermatomyositis.

OBJECTIVE: Autoantibodies against signal recognition particle (SRP) are detected in patients with polymyositis/dermatomyositis (PM/DM). The SRP consists of 7SL RNA and 6 protein components. We examined autoantibodies against deproteinized 7SL RNA in PM/DM patients with anti-SRP antibodies and evaluated the association of anti-7SL RNA antibodies with PM/DM clinically and serologically. METHODS: Sera from 10 Japanese and 22 North American PM/DM patients with anti-SRP antibodies were tested for the presence of anti-7SL RNA antibodies, using the sera to immunoprecipitate deproteinized RNA extracts derived from HeLa cells. RESULTS: The immunoprecipitation analysis indicated that 5 Japanese (50%) and one North American (5%) patient with anti-SRP antibodies had novel autoantibodies against deproteinized 7SL RNA. The frequency of anti-7SL RNA antibodies was significantly higher in Japanese than North American patients (p = 0.006). The presence of anti-7SL RNA antibodies appeared to be associated with DM (2 patients) and finger swelling (2 PM patients). The seasonal onset of the disease was different (p = 0.008) for Japanese PM/DM patients with anti-7SL RNA antibodies, who developed the disease between October and January (mean month November; p = 0.01) from that of patients without these antibodies, who developed it between June and August (mean month July; p = 0.01). CONCLUSION: Novel autoantibodies against 7SL RNA were identified in patients with PM/DM, and the presence of these antibodies was correlated to ethnic background, clinical features, and season of disease onset. These findings indicated that autoantibodies against 7SL RNA are a novel serological marker for a subset of PM/DM cases.

Adult↗
PubMed2005

[Clinical significance of anti-phosphatidylserine-prothrombin complex antibodies in antiphospholipid syndrome].

We clarified the clinical significance of IgG anti-phosphatidylserine-prothrombin complex (PS-PT) antibodies in the antiphospholipid syndrome (APS). The study population consisted of 122 patients with SLE and lupus-like disease. IgG anti-PS-PT antibodies were detected in 44% of 59 patients according to the diagnostic criteria by Harris and Hughes. This frequency was significantly (p < 0.005) higher than the 14% seen in patients without APS. IgG anti-PS-PT antibodies were strongly (p < 0.005) associated with thrombosis. In addition, IgG anti-PS-PT antibodies were positive in 64% of IgG beta2-GPI dependent anti-cardiolipin antibody negative APS patients under the Sapporo criteria. The above findings indicate that IgG anti-PS-PT antibodies as well as beta2,-GPI dependent anti-cardiolipin antibodies should be examined in the diagnosis of APS.

Adult↗
PubMed2004

Binding of beta 2-glycoprotein I to anionic phospholipids facilitates processing and presentation of a cryptic epitope that activates pathogenic autoreactive T cells.

Antiphospholipid syndrome (APS) is an autoimmune prothrombotic disorder in association with autoantibodies to phospholipid (PL)-binding plasma proteins, such as beta(2)-glycoprotein I (beta(2)GPI). We have recently found that CD4(+) T cells autoreactive to beta(2)GPI in patients with APS preferentially recognize a cryptic peptide encompassing amino acid residues 276-290 (p276-290), which contains the major PL-binding site, in the context of DR53. However, it is not clear how previously cryptic p276-290 becomes visible to the immune system and elicits a pathogenics autoimmune response to beta(2)GPI. Here we show that presentation of a disease-relevant cryptic T-cell determinant in beta(2)GPI is induced as a direct consequence of antigen processing from beta(2)GPI bound to anionic PL. Dendritic cells or macrophages pulsed with PL-bound beta(2)GPI induced a response of p276-290-specific CD4(+) T-cell lines generated from the patients in an HLA-DR-restricted and antigen-processing-dependent manner but those with beta(2)GPI or PL alone did not. In addition, the p276-290-reactive T-cell response was primed by stimulating peripheral blood T cells from DR53-carrying healthy individuals with dendritic cells bearing PL-bound beta(2)GPI in vitro. Our finding is the first demonstration of an in vitro mechanism eliciting pathogenic autoreactive T-cell responses to beta(2)GPI and should be useful in clarifying the pathogenesis of APS.

Animals↗
PubMed2004

Autoreactive CD8+ cytotoxic T lymphocytes to major histocompatibility complex class I chain-related gene A in patients with Behçet's disease.

OBJECTIVE: To detect and characterize the autoreactive CD8+ T cells to major histocompatibility complex class I chain-related gene A (MICA), a stress-inducible antigen preferentially expressed on the epithelium and endothelium, in patients with Behcet's disease (BD). METHODS: A candidate for the antigenic MICA peptide was selected based on its predicted binding affinity for HLA-B51 and proteasomal cleavage sites. Peripheral blood T cells from 14 patients with BD and 15 healthy controls were repeatedly stimulated with the MICA peptide, and the specific T cell response was measured by peptide-induced interferon-gamma. Cytotoxic T lymphocyte activity was examined by chromium-51 release from an HLA-B51-transfected B cell line in the presence of the MICA peptide. RESULTS: A 9-mer peptide AAAAAIFVI (termed MICA transmembrane [MICA-TM]) was selected as a candidate for the antigenic peptide presented by HLA-B51. A specific T cell response to MICA-TM was detected in 4 patients with BD (29%) but in none of the 15 healthy donors. All 4 responders had HLA-B51 and active disease, and the specific T cell response was lost after the BD-related symptoms disappeared. The MICA-induced T cell response was specifically inhibited by anti-HLA class I antibody or by CD8+ cell depletion. MICA-reactive T cells recognized an HLA-B51-transfected B cell line pulsed with MICA-TM or a B cell line transfected with both HLA-B51 and MICA in the absence of exogenous peptides. Finally, MICA-stimulated T cell lines lysed the HLA-B51-expressing B cell line in the presence of MICA-TM. CONCLUSION: HLA-B51-restricted cytotoxic T lymphocytes autoreactive to MICA may be involved in the pathogenesis of BD.

Autoimmunity↗
PubMed2004

Beta2-glycoprotein I: antiphospholipid syndrome and T-cell reactivity.

There is increasing evidence showing that recurrent thrombosis and intrauterine fetal loss in antiphospholipid syndrome (APS) are attributable to antiphospholipid (aPL) antibodies. We have recently identified autoreactive CD4+ T cells to beta2-glycoprotein I (beta2GPI) that promote production of pathogenic antiphospholipid antibodies. beta2GPI-specific CD4+ T cells preferentially recognize the antigenic peptide containing the major phospholipid (PL)-binding site in the context of DR53. T-cell helper activity that stimulates B cells to produce IgG anti-beta2GPI antibodies is mediated through IL-6 and CD40-CD154 interaction. beta2GPI-specific T cells respond to reduced beta2GPI and recombinant beta2GPI fragments produced in a bacterial expression system but not to native beta2GPI, indicating that the epitopes recognized by beta2GPI-specific T cells are 'cryptic' determinants, which are generated at a subthreshold level by the processing of native beta2GPI under normal circumstances. Although beta2GPI-specific T cells are detected in both APS patients and healthy individuals, these autoreactive T cells are activated in vivo in APS patients but not in healthy individuals. These findings indicate activation of beta2GPI-specific T cells and subsequent production of pathogenic anti-beta2GPI antibodies can be induced by the exposure of such T cells to cryptic peptides of beta2GPI efficiently presented by functional antigen-presenting cells (APC). Delineating the mechanisms that induce the efficient processing and presentation of cryptic determinants of beta2GPI as a consequence of antigen processing would clarify the etiology that initiates the autoantibody response in APS.

Amino Acid Motifs↗
PubMed2004

Single nucleotide polymorphisms of the inflammatory cytokine genes in adults with chronic immune thrombocytopenic purpura.

Single nucleotide polymorphisms (SNPs) of inflammatory cytokine genes were examined in 84 adult Japanese patients with chronic immune thrombocytopenic purpura (ITP) and 56 race-matched healthy controls. The SNPs examined were within the genes encoding tumour necrosis factor (TNF)-alpha (-238 G/A and -308 G/A), TNF-beta (+252 G/A), and interleukin (IL)-1beta (-511 C/T and +3953 T/C). Of these SNPs, the frequency of the TNF-beta (+252) G/G phenotype was significantly higher in ITP patients than in healthy controls (21% vs. 7%, P = 0.04, odds ratio = 3.6, 95% confidence interval 1.1-11.1), while no significant association was detected for the other SNPs. The distribution of the TNF-beta (+252) phenotype was not associated with human leucocyte antigen class II alleles or the therapeutic response in ITP patients. The frequency of circulating anti-glycoprotein IIb/IIIa antibody-producing B cells was significantly higher in ITP patients with the TNF-beta (+252) G/G phenotype than in those with the G/A or A/A phenotype (11.9 +/- 4.9 vs. 6.8 +/- 4.9 and 3.7 +/- 2.8 per 10(5) peripheral blood mononuclear cells; P = 0.02 and P < 0.001, respectively). These findings suggest that the SNP located at TNF-beta (+252) contributes to susceptibility to chronic ITP by controlling the autoreactive B-cell responses to platelet membrane glycoproteins.

Adult↗
PubMed2004

[Collagen diseases with pulmonary involvement].

Pulmonary involvement is a common feature in patients with various collagen diseases. Some types of the pulmonary involvement are resistant to currently available treatment regimens and thus considered as intractable conditions. These include acute/subacute interstitial pneumonia in dermatomyositis, pulmonary interstitial fibrosis in scleroderma, and diffuse alveolar hemorrhage. Acute/subacute interstitial pneumonia with the histology of diffuse alveolar damage (DAD) is mainly occurred in patients with amyopathic or hypomyopathic dermatomyositis who lack autoantibodies to aminoacyl tRNA synthetases. Intensive immunosuppressive treatment in the early phase of the disease may be effective for this intractable complication. Nearly one-third of patients with scleroderma have slowly progressive pulmonary interstitial fibrosis, leading to end-stage respiratory failure. Non-specific interstitial pneumonia (NSIP) with an excessive fibrotic change is a major histology of these patients. There are accumulating evidences showing the effectiveness of cyclophosphamide in patients with this intractable condition, especially those with active alveolitis. Diffuse alveolar hemorrhage is a fatal complication mainly occurred in patients with systemic lupus erythematosus and those with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, including microscopic polyangitis (MPA) and Wegener's granulomatosus. Immediate diagnosis and introduction of intensive treatment are necessary to save the patients with this complication.

Collagen Diseases↗
PubMed2004

[Effective treatment with rituximab in a patient with refractory idiopathic thrombocytopenic purpura].

A 75-year-old woman had an episode of sudden nasal and oral bleeding. After that, petechiae appeared on her entire body. She received a platelet transfusion, and was referred to our hospital. On admission, the platelet count was as low as 1.2 X 10(4)/microl, and the PAIgG level was slightly elevated. Bone marrow cellularity was low, with a normal count of megakaryocytes. Anti-glycoprotein IIb/IIIa antibody-secreting B cells in the peripheral blood and platelet-associated anti-glycoprotein IIb/ IIIa antibodies were significantly high, and the patient was diagnosed as having idiopathic thrombocytopenic purpura (ITP). She failed to respond to corticosteroids, splenectomy and other therapies, so we administered rituximab, anti-CD20 monoclonal antibody, 375 mg/m2 weekly for four weeks. After the second infusion of rituximab, the platelet count began to increase. The platelet count continued to rise until a peak count (15.0 x 10(4)/microl) observed after 2 weeks from the fourth infusion, and the response was maintained for 8 more weeks. The levels of anti-glycoprotein IIb/IIIa antibody-secreting B cells and platelet-associated anti-glycoprotein IIb/IIIa antibodies decreased after the administration of rituximab. Rituximab was effective in this case of refractory ITP.

Aged↗
PubMed2003

A novel protein highly expressed in testis is overexpressed in systemic sclerosis fibroblasts and targeted by autoantibodies.

Nearly all autoantibody specificities in sera from patients with systemic sclerosis (SSc) target proteins distributed ubiquitously, and Abs against proteins whose expression is restricted to the affected sites have not been identified. In this study we describe SSc-specific autoantibody to a novel testicular Ag, termed protein highly expressed in testis (PHET), which is ectopically overexpressed in SSc dermal fibroblasts. A partial cDNA encoding PHET was isolated by immunoscreening of a HepG2 cDNA library with an SSc serum. PHET appeared to be a member of the UniGene cluster Hs.129872, but had a unique exon composition and a characteristic mRNA expression profile restricted to the testis. Serum Abs to a recombinant PHET fragment were detected in nine (8.4%) of 107 SSc patients, but in none of 50 systemic lupus erythematosus patients or 77 healthy controls. In SSc patients, the presence of anti-PHET Abs was associated with diffuse cutaneous SSc and lung involvement (p = 0.02 and 0.01, respectively). PCR-based quantitative analysis of PHET mRNA expression in cultured dermal fibroblasts showed increased expression of PHET mRNA in SSc fibroblasts compared with control fibroblasts. PHET-reactive Abs purified from SSc sera stained the cytoplasm of SSc dermal fibroblasts, and the staining intensity tended to be more prominent on SSc compared with control fibroblasts. These findings suggest that the autoantibody response to PHET can be induced by ectopic overexpression of PHET in dermal fibroblasts in SSc patients.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Effect of a single injection of humanized anti-CD154 monoclonal antibody on the platelet-specific autoimmune response in patients with immune thrombocytopenic purpura.

Blockade of the CD40/CD154 signal is a potential immunomodulatory strategy for T-cell-mediated diseases. As a part of a phase 1, multicenter, dose-escalating trial of humanized monoclonal antibody to CD154 (IDEC-131/E6040) in patients with refractory immune thrombocytopenic purpura (ITP), the autoimmune response to glycoprotein IIb/IIIa (GPIIb/IIIa) was evaluated at successive time points. Five patients each were given a single infusion of 1, 2, 5, or 10 mg/kg IDEC-131/E6040 and followed for 3 months. All adverse events were mild, and there were no severe infections or thromboembolic events. No increase in platelet count was observed in patients treated at 1, 2, or 5 mg/kg, but an increase was observed in 3 patients treated at 10 mg/kg. In only the patients treated at 5 or 10 mg/kg, the frequency of B cells producing anti-GPIIb/IIIa antibodies, GPIIb/IIIa-induced T-cell proliferation, and anti-GPIIb/IIIa antibody production by antigen-dependent T-B-cell collaboration were all suppressed in parallel after the treatment, with a slow return to baseline. In contrast, T-cell response to an irrelevant antigen was not affected. These findings suggest that CD40/CD154 blockade therapy is potentially effective for refractory ITP, through selective suppression of autoreactive T and B cells to platelet antigens.

Adult↗
PubMed2003

Human circulating CD14+ monocytes as a source of progenitors that exhibit mesenchymal cell differentiation.

Circulating CD14+ monocytes are precursors of phagocytes, such as macrophages and dendritic cells. Here we report primitive cells with a fibroblast-like morphology derived from human peripheral blood CD14+ monocytes that can differentiate into several distinct mesenchymal cell lineages. We named this cell population monocyte-derived mesenchymal progenitor (MOMP). MOMPs were obtained in vitro from human peripheral blood mononuclear cells cultured on fibronectin in the presence of fetal bovine serum alone as a source of growth factors. MOMPs had a unique molecular phenotype-CD14+CD45+CD34+type I collagen+-and showed mixed morphologic and molecular features of monocytes and endothelial and mesenchymal cells. MOMPs were found to be derived from a subset of circulating CD14+ monocytes, and their differentiation required that they bind fibronectin and be exposed to one or more soluble factors derived from peripheral blood CD14- cells. MOMPs could be expanded in culture without losing their original phenotype for up to five passages. The induction of MOMPs to differentiate along multiple limb-bud mesodermal lineages resulted in the expression of genes and proteins specific for osteoblasts, skeletal myoblasts, chondrocytes, and adipocytes. Our findings represent the first evidence that human circulating CD14+ monocytes are a source of progenitors that exhibit mesenchymal cell differentiation.

Alkaline Phosphatase↗