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Koh Nakata

Publications and source records attributed to Koh Nakata.

At least 19 recordsLinked to original sources
PubMed2006

Epidemiological and clinical features of idiopathic pulmonary alveolar proteinosis in Japan.

Idiopathic pulmonary alveolar proteinosis (IPAP) is a rare disease characterized by excessive amounts of lipoproteinaceous material in the alveolus. This report presents an interim analysis of nationwide epidemiological data from Japanese patients with pulmonary alveolar proteinosis, and the roles of serum markers for IPAP. (i) The nationwide demographic data from 166 Japanese patients with IPAP are shown. The female to male ratio was 1:2, and the average age was 51 +/- 14 years old (age range: 15-79 years) at registration or diagnosis. A total of 30% of patients with IPAP have a poor clinical course. In total, 30% of patients were treated with whole lung lavage therapy (WLL). Under WLL, the patients significantly improved in the short term, but 40% of the patients who underwent WLL worsened again. A new strategy such as granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy for intractable PAP is required. (ii) The correlation of serum KL-6, carcinoembryonic antigen, surfactant proteins D and A, and LDH with disease severity suggests their potential as disease markers. In contrast, serum anti-GM-CSF antibody did not correlate with disease severity, but is a specific marker for the diagnosis of IPAP. The combined measurements of the serum markers may well prove very useful for both the diagnosis and the management of IPAP patients.

Adolescent↗
PubMed2006

Granulocyte-macrophage colony-stimulating factor inhalation therapy for patients with idiopathic pulmonary alveolar proteinosis: a pilot study; and long-term treatment with aerosolized granulocyte-macrophage colony-stimulating factor: a case report.

Idiopathic pulmonary alveolar proteinosis (IPAP) is considered to be caused by an autoantibody to the granulocyte-macrophage colony-stimulating factor (GM-CSF), which neutralizes GM-CSF and therefore impairs the differentiation of alveolar macrophages. The authors have previously characterized the BAL fluid and alveolar macrophages obtained from three IPAP patients who were successfully treated with aerosolized GM-CSF and demonstrated restoration of the cell number, expression of surface marker, and phagocytic ability of the alveolar macrophages as well as a decrease in the autoantibody levels in the BAL fluid. The condition recurred in one of the patients after 20 months. This patient underwent a second and third course of GM-CSF inhalation therapy with the same dose and schedule as the first one. Since the second therapeutic intervention did not succeed in producing any improvement in the symptoms and disease markers, the authors used a new nebulizer and a liquid preparation of the drug instead of the lyophilized preparation for the third therapeutic session and this restored the respiratory function considerably. A 6-month maintenance therapeutic regimen with a lower GM-CSF inhalation frequency brought about a further improvement in the disease markers. The results suggest that the efficacy of GM-CSF inhalation therapy might be related to the drug preparation mode, choice of nebulizer, and duration of treatment.

Aerosols↗
PubMed2006

Why does the autoantibody against granulocyte-macrophage colony-stimulating factor cause lesions only in the lung?

OBJECTIVES: During the course of investigating the etiology of idiopathic pulmonary alveolar proteinosis (IPAP), the authors found that the autoantibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) was consistently present in both sera and the lung tissue. The autoantibody completely blocked bioactivity by direct binding with high specificity and avidity. Because of the existence of patients with congenital PAP who lack GM-CSF receptors and the development of PAP in GM-CSF and GM-CSF receptor knock-out mice, the autoantibody is likely to be the causative agent for IPAP. However, this finding posed the question as to why the autoantibody against GM-CSF caused lesions only in the lung. METHODOLOGY: To answer this question, the authors investigated, using immunohistochemistry, confocal laser microscopy, and immunoblotting, the expression of PU.1 in tissue macrophages. PU.1 is a critical transcription factor for terminal differentiation of alveolar macrophage (AM), as reported previously in the lung, liver, spleen, kidney, intestine and brain. RESULTS: PU.1 was consistently expressed in the nuclei of normal AM, but faintly or not at all in IPAP-AM. Moreover, it was not expressed in the nuclei of any other normal tissue macrophages tested. Blood monocytes expressed PU.1 in the cytosol but not in the nuclei. These results suggested that the differentiation pathway is different between AM and other tissue macrophages. PU.1 was not expressed in the nuclei of newborn rat lung AM but was gradually expressed during the first 10 days. CONCLUSIONS: The authors demonstrated that GM-CSF is crucial for terminal differentiation of AM, but not for that of other tissue macrophages.

Animals↗
PubMed2006

Successful treatment of congenital pulmonary alveolar proteinosis with intravenous immunoglobulin G administration.

The authors report a female patient with congenital pulmonary alveolar proteinosis (PAP). She had two brothers who died from the same disease. BAL did not improve her progressive respiratory failure. After intravenous immunoglobulin G (IVIG) administration for complicated hypogammaglobulinemia, she recovered from respiratory failure. The efficacy of IVIG was confirmed by recovery from deterioration in respiratory status and improvement in chest CT findings on two separate occasions. Subsequently, the patient remains free from respiratory symptoms for more than 3 years on an ongoing regimen of monthly IVIG. She had no surfactant protein (SP) B deficiency. Alveolar macrophages (AM) obtained from her BAL fluid were small and showed decreased phagocytotic activity. Immunostaining revealed weak expression of PU.1 in her AM, a key protein in AM maturation. All nucleotide sequences of granulocyte-macrophage colony stimulating factor (GM-CSF), GM-CSF-receptor and PU.1 were normal. Endotoxin-induced GM-CSF release from peripheral mononuclear cells (PMNC), and proliferation of PMNC in response to GM-CSF were normal. In addition, an antibody against GM-CSF, as seen in adult patients with idiopathic PAP, was not detected in the serum or BAL fluid. Although the patient's PMNC secreted only small amounts of IgG and IgM, an EB virus-derived cell line of her B cells secreted IgM as much as normal control cells. In a flow cytometric study, IgM was expressed on the cell surface. In conclusion, an abnormality in a single gene may have decreased secretion of immunoglobulin from the B cells and the AM phagocytotic activity in the patient.

Agammaglobulinemia↗
PubMed2006

Serum antibody against granulocyte/macrophage colony-stimulating factor and KL-6 in idiopathic pulmonary alveolar proteinosis.

Here we describe a case of idiopathic pulmonary alveolar proteinosis (I-PAP), in which anti-granulocyte/macrophage colony-stimulating factor (GM-CSF) antibody and high level of KL-6 were found in the serum. Anti-GM-CSF antibody is responsible for I-PAP, and KL-6 is a serum marker for the activity of diffuse interstitial lung disease. A 38-year-old woman, who had no symptoms, was found to have an abnormal shadow on chest radiograph 5 years previously at a health check up. Chest radiograph showed a patchy shadow in the left lower lung field. Thoracoscopic biopsy was performed because the shadow had gradually expanded during the 5 years. Histological examination revealed proteinous material filling the alveoli and positive staining by the PAS method, suggesting PAP. Anti-GM-CSF antibody and a high level of KL-6 were detected in the serum at the time of diagnosis. Three years later, the shadow disappeared spontaneously. During this period, the level of KL-6 dramatically decreased, although that of GM-CSF antibody remained unchanged. The present case suggests that the serum level of the anti-GM-CSF antibody represents a useful marker for the diagnosis but not for follow-up of the clinical course. On the contrary, KL-6 is an excellent marker for the assessment of the clinical course of I-PAP.

Adult↗
PubMed2005

Variations of the CFTR gene in the Hanoi-Vietnamese.

In order to investigate polymorphic backgrounds of the cystic fibrosis transmembrane conductance regulator gene (CFTR) in the Vietnamese, we analyzed 495 blood samples of randomly selected healthy individuals in Hanoi for the delta F508 mutation and TG-repeats, poly-T, and M470V polymorphisms. We compared their distributions with those of Caucasians and other Asian populations. No delta F508 mutation was found, being consistent with the extremely low incidence of cystic fibrosis (CF) in Vietnam. Allele frequency of the T5 allele promoting exon 9 skipping was 0.037. Greater number of TG-repeats, which is known to facilitate this aberrant splicing, was a predominant trend in the Vietnamese and other Asians. A "T5-TG12-V470" haplotype was most common (29/37) among T5-bearing haplotypes. Three major haplotypes, T7-TG12-M470, T7-TG11-V470, and T7-TG12-V470, estimated by PHASE program, related to 92% of the population. This is the first study of the CFTR gene among the Vietnamese.

Adolescent↗
PubMed2005

Granulocyte-macrophage colony-stimulating factor and lung immunity in pulmonary alveolar proteinosis.

The anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibody is inferred to cause idiopathic pulmonary alveolar proteinosis (iPAP): the antibody neutralizes GM-CSF and thereby impairs differentiation of alveolar macrophages. Administration of GM-CSF improves respiratory function of patients with iPAP, as confirmed in this study using aerosolized GM-CSF. To elucidate its mechanism, we characterized bronchoalveolar lavage fluid and alveolar macrophages obtained from three patients with iPAP who were treated successfully with aerosolized GM-CSF. Cell number, expressions of surface mannose receptor and the transcription factor PU.1, and phagocytic ability of alveolar macrophages were all restored to control levels. With treatment, the neutralizing capacity of GM-CSF activity was reduced markedly, concomitant with the decreasing autoantibody levels. Interestingly, the amount of GM-CSF autoantibody complex also decreased. In one case in which the complex was analyzed, the majority of GM-CSF binding the complex was endogenous protein, suggesting that the complex is removed immediately from the lung after treatment. Our study shows that GM-CSF administration engenders a decrease in the neutralizing capacity against the protein in the lungs. Thereby, it facilitates restoration of the normal function of alveolar macrophages.

Administration, Inhalation↗
PubMed2005

Promoter analysis and aberrant expression of the MUC5B gene in diffuse panbronchiolitis.

Diffuse panbronchiolitis (DPB) is a chronic inflammatory airway disease predominantly affecting Asian populations. DPB is considered to be a complex genetic disease. Considering the mucous hypersecretion of the disease, we hypothesized that the transcriptional activity of mucin genes may be altered in DPB. We analyzed nucleotide sequences of regulatory region of six mucin genes--MUC1, MUC2, MUC4, MUC5AC, MUC5B, and MUC7--and detected their promoter polymorphisms. Among them, the insertion/deletion polymorphism identified in the MUC5B gene was significantly associated with the disease (p = 0.0001). Transcriptional activity observed in the three major promoter haplotypes corresponded to the strength of the disease association in which these haplotypes are involved. Immunohistochemistry of the lung tissues of DPB revealed that MUC5B was abundantly expressed not only in bronchial glands but also in increased numbers of goblet cells on the bronchial surface, where MUC5AC is predominant and MUC5B expression is generally scarce in the normal lung. Marked mucous hypersecretion observed in DPB may be partly explained by increased and aberrant expression of MUC5B. The possible involvement of MUC5B gene in DPB was demonstrated. A further role of the MUC5B polymorphism in its pathogenesis should be studied in the future.

Aged↗
PubMed2005

Propionibacterium acnes is the most common bacterium commensal in peripheral lung tissue and mediastinal lymph nodes from subjects without sarcoidosis.

BACKGROUND: In studies of the unknown etiology of sarcoidosis, Propionibacterium acnes (a possible agent) was found in the lungs and lymph nodes of many sarcoidosis patients and some control subjects. P. acnes might be commensal not only to the skin, conjunctivae, and intestine, but also to the lungs and lymph nodes of individuals without sarcoidosis. METHODS: We cultured peripheral lung tissue and various lymph nodes obtained from patients with diseases other than sarcoidosis. DNA of 45 isolates of P. acnes from these patients, 67 isolates from normal skin, conjunctiva, and intestine, and 39 isolates from sarcoid lymph nodes were compared by random amplified polymorphic DNA analysis. RESULTS: P. acnes was isolated from half of 43 lungs and 8 of 11 mediastinal lymph nodes, mostly in pure culture. P. acnes was isolated from half of 20 gastric and 3 of 12 intestinal lymph nodes; intestinal bacteria were also numerous. In general, fewer than 500 colony-forming units of P. acnes per gram tissue were isolated, but 4 lung tissue specimens, 2 of which had a few granulomas, had many more. P. acnes strains from a particular site (lung, lymph node, skin or conjunctivae, and intestine) were genetically similar, more than isolates obtained from different sites. Lymph-node isolates from subjects with and without sarcoidosis differed little. CONCLUSION: These results suggest that P. acnes normally resides in peripheral lung tissue and mediastinal lymph nodes and that the strains of P. acnes isolated from sarcoid lymph nodes were not specific to sarcoidosis.

Adult↗
PubMed2004

BCL-6 mutations in pulmonary lymphoproliferative disorders: demonstration of an aberrant immunological reaction in HIV-related lymphoid interstitial pneumonia.

We used a PCR and sequence procedure to analyze the Ig V(H) gene and the mutations in the 5' regulatory regions of BCL-6 genes in pulmonary lymphoproliferative disorders (mucosa-associated lymphoid tissue (MALT) lymphoma, HIV-related, EBV-related, and virus-negative lymphocytic interstitial pneumonia (LIP)). Eight of 20 (40%) pulmonary MALT lymphoma and 10 of 20 LIP (5 of 5 (100%) HIV-related, 2 of 5 (40%) EBV-related, and 3 of 10 (30%) virus-negative LIP) cases showed BCL-6 gene mutations. Intraclonal heterogeneity of the BCL-6 mutations was observed only in pulmonary MALT lymphoma cases whose Ig V(H) genes also showed intraclonal heterogeneity. Ongoing BCL-6 mutations might reflect re-entry into a germinal center pathway to further mutations. BCL-6 mutations in pulmonary MALT lymphoma and HIV-negative LIP showed some features (high transition to transversion ratio, standard polarity, and RGYW/WRCY bias) of Ig V(H) gene hypermutation, leading to the view that pulmonary MALT lymphomas and HIV-negative LIP are under the influence of germinal center hypermutation mechanisms. Because BCL-6 mutations in HIV-related LIP cases did not demonstrate features of Ig V(H) gene hypermutation, immunological reactions in HIV-related LIP are the result of a process different from that found in HIV-negative pulmonary lymphoproliferative disorders.

Adult↗
PubMed2004

Pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) has been recognized for almost half a century. At least three separate pathophysiologic mechanisms may lead to the characteristic feature of PAP: the excessive accumulation of surfactant lipoprotein in pulmonary alveoli, with associated disturbance of pulmonary gas exchange. The prognosis for adult patients with PAP varies, but disease-specific survival rate exceeds 80% at 5 years. The survival rates for adult PAP patients seem to have increased progressively in the four decades since the initial clinical description of this condition. The last decade has brought new advances in laboratory and clinical research that are lifting a veil not only on PAP but also on general aspects of pulmonary surfactant biology and innate immune defense.

Algorithms↗
PubMed2004

Serum neutralizing capacity of GM-CSF reflects disease severity in a patient with pulmonary alveolar proteinosis successfully treated with inhaled GM-CSF.

Existence of anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) neutralizing antibody and treatment with recombinant GM-CSF are new topics in idiopathic pulmonary alveolar proteinosis (PAP). We have hypothesized inhaled GM-CSF is effective and neutralizing capacity of GM-CSF, not concentration of anti-GM-CSF antibody in serum reflect disease severity. A 57-year-old female smoker with idiopathic PAP was treated with inhaled GM-CSF. The response to the treatment was evaluated by diffusing capacity for carbon monoxide (DLCO), alveolar-arterial oxygen gradient ([A-a]DO2). Conventional serum markers, including KL-6, surfactant apoprotein (SP)-A, SP-D, carcino-embryonic antigen and cytokeratin fragment 19 (CYFRA), and concentration of anti-GM-CSF antibody were examined. The neutralizing capacity of GM-CSF in serum was evaluated using a GM-CSF dependent cell line, TF-1. Ground glass opacity disappeared at the end of the treatment. Her DLCO, [A-a]DO2 remarkably improved after treatment. The neutralizing capacity of GM-CSF declined in line with disease remission and it correlated significantly with DLCO (P = 0.0137). The concentration of anti-GM-CSF antibody had no significant relation with disease severity and serum markers including neutralizing capacity. Conventional serum markers other than CYFRA showed no significant correlation with Inhaled GM-CSF was effective for idiopathic PAR Serial measurement of neutralizing capacity of GM-CSF was useful to evaluate disease severity and the anti-GM-CSF antibody was proved to be a causative factor for PAR In the future, inhaled GM-CSF may replace whole lung lavage and response to GM-CSF and its optimal amount may be decided by the capacity.

Administration, Inhalation↗
PubMed2004

Direct determination of MUC5B promoter haplotypes based on the method of single-strand conformation polymorphism and their statistical estimation.

Haplotype-based human genome research is important in identifying disease susceptibility genes efficiently. Although haplotype reconstruction by statistical methods is widely used, direct haplotype determination by molecular techniques has also been developed as a complementary method for statistical estimation. In this study, we demonstrate a molecular haplotyping method making use of single-strand conformation polymorphism (SSCP) gels. We identified 10 common SNPs and a dinucleotide insertion/deletion polymorphism within 2-kb region upstream of the transcription initiation site of MUC5B and determined haplotype structure, dividing the region into two DNA fragments. Real haplotypes were determined unambiguously by our SSCP-based analysis with fragments longer than 1 kb. Haplotypes reconstructed from diploid genotypes in the same region by the statistical methods including EM algorithm were also evaluated. Direct comparison between statistical estimation and direct determination of haplotypes revealed that major haplotypes containing multiple marker sites showing strong LD are estimated in great accuracy but that a variety of haplotypes reflecting weak LD are not reconstructed precisely enough. Our data can be helpful in implementing molecular haplotyping or statistical estimation, since usage of these methods may be determined depending on the haplotype structures.

Base Sequence↗
PubMed2004

Evaluation of choroidal perfusion of the new central macular area by dilution analysis of indocyanine green angiography after macular translocation.

PURPOSE: To evaluate the possible long-term alterations of choroidal perfusion parameters in the new central macular area after macular translocation surgery. METHODS: Eleven subjects with subfoveal neovascular membrane secondary to age-related macular degeneration or degenerative myopia underwent indocyanine green angiography by using a scanning laser ophthalmoscope before and after macular translocation (mean, 10 months after surgery). Fluorescence intensity of the new central macular area over time was evaluated. Parameters derived from the intensity curves included 10% filling time, ascending slope, and maximal intensity of brightness. The 10% filling time reflects the rapidity of the early choroidal filling phase, whereas the slope of the filling of the curve shows the speed of blood entrance into the choroid. Maximal intensity of brightness indicates vascular density of the area. RESULTS: No statistical difference was encountered before or after macular translocation in 10% filling time (14.25 +/- 2.09 seconds versus 16.20 +/- 2.95 seconds), slope of the ascending portion of the curve (0.12 +/- 0.04 versus 0.11 +/- 0.04), and maximal intensity of brightness (0.89 +/- 0.09 versus 0.88 +/- 0.07) in the new central macular area. The rotational degree of the retina against the retinal pigment epithelium did not show any significant correlation with 10% filling time, slope, or maximal intensity of brightness. CONCLUSION: Choroidal perfusion parameters in the new foveal region do not change after macular translocation surgery.

Aged↗
PubMed2004

A case of idiopathic pulmonary alveolar proteinosis accompanied by T-cell receptor gene rearrangement in bronchoalveolar lavage fluid cells.

We describe a case of a patient with idiopathic pulmonary alveolar proteinosis (PAP), who had an elevated serum level of antigranulocyte-macrophage colony stimulating factor (anti-GM-CSF) antibody accompanied by T-cell receptor gene rearrangements in BAL fluid cells. Histopathological examination of the lung excluded lymphoma but revealed PAP and silicosis. There was no detectable serum anti-GM-CSF antibody in 50 outpatients with advanced silicosis who did not have PAP, suggesting that anti-GM-CSF antibody is directly linked to PAP but not to silicosis. We speculate that monoclonal expansion of a T-cell population may play a role in the production of anti-GM-CSF antibody and the development of PAP.

Aged↗
PubMed2004

[Molecular pathogenesis in tuberculosis complicated with AIDS].

HIV-1 infection is a major cause of worldwide epidemic of tuberculosis. There is increasing clinical evidence that coinfection with M. tuberculosis accelerates progression of AIDS. We found that, in vivo, HIV-1 load and mutation increase in involved lung segments in patients with pulmonary tuberculosis. We also reported that Mycobacterium tuberculosis stimulates HIV-1 replication by enhancing transcription on the 5' LTR in a macrophage cell line, THP-1, in vitro. In contrast, HIV-1 replication is suppressed by M. tuberculosis infection of monocytes derived macrophages (MDM) or differentiated monocytic THP-1 cells. We observed that HIV-1 5' LTR function was repressed in PMA differentiated THP-1 cells after co-infection with M. tuberculosis. Point mutations in C/EBP beta binding domains of the HIV-1 LTR negative regulatory element (NRE) abolished promoter repression. Monocyte-derived macrophages and differentiated THP-1 cells increased expression of the 16kDa inhibitory form of C/EBP after M. tuberculosis co-infection. Bronchoalveolar lavage cells obtained from normal controls and alveolar macrophages from uninflamed lung of tuberculosis patients also expressed the 16kDa inhibitory form of C/EBP. However, alveolar macrophages from lung segments involved with pulmonary tuberculosis had markedly reduced C/EBP expression. These data suggest that 16kDa isoform of C/EBP plays an important role for the control of HIV-1 replication in macrophages. We propose derepression of HIV-1 LTR mediated transcription as one mechanism for enhanced HIV-1 replication observed in pulmonary tuberculosis. Since the cellular immune response in pulmonary tuberculosis requires lymphocyte/macrophage interaction, a model system was developed in which lymphocytes were added to AM. Contact between lymphocytes and AM reduced inhibitory C/EBP beta, activated NF-kappaB and enhanced HIV-1 replication. If contact between lymphocytes and macrophages was prevented, inhibitory C/EBP beta expression was maintained and the HIV-1 long terminal repeat (LTR) was not maximally stimulated although NF-kappaB was activated. Antibodies which cross-linked macrophage expressed B-7, VCAM and CD-40 were used mimic lymphocyte contact. Cross-linking antibodies abolished inhibitory C/EBP beta expression; however, the HIV-1 LTR was not maximally stimulated and NF-kappaB was not activated. Maximal HIV-1 LTR stimulation required both lymphocyte derived soluble factors and cross-linking of macrophage expressed co-stimulatory molecules. These results demonstrate that neither contact nor soluble factor(s) are sufficient to maximally enhance HIV-1 LTR activity in macrophages. Contact between activated lymphocytes and macrophages is necessary to downregulate inhibitory C/EBP beta, thereby derepressing the HIV-1 LTR. Lymphocyte derived soluble factor(s) activate NF-kappaB, further enhancing the HIV-1 LTR.

AIDS-Related Opportunistic Infections↗
PubMed2003

High-affinity autoantibodies specifically eliminate granulocyte-macrophage colony-stimulating factor activity in the lungs of patients with idiopathic pulmonary alveolar proteinosis.

Deficiency of granulocyte-macrophage colony-stimulating factor (GM-CSF) in mice results in pulmonary alveolar proteinosis (PAP) from impaired surfactant catabolism by alveolar macrophages (AMs). Recently, we have shown that neutralizing anti-GM-CSF autoantibodies develop specifically in patients with idiopathic pulmonary alveolar proteinosis (iPAP). Analogous to murine PAP models, it is plausible that the autoantibodies reduce GM-CSF activity, resulting in AM dysfunction and surfactant accumulation. To examine this hypothesis, we estimated the neutralizing activity of the autoantibodies in the lungs of patients and characterized their biologic properties. GM-CSF bioactivity was completely abrogated in the bronchoalveolar lavage fluid (BALF) of patients with iPAP but not in healthy subjects. Autoantibodies were present in the alveoli in high concentrations and colocalized with GM-CSF. They recognized human GM-CSF with high avidity (K(AV) = 20.0 +/- 7.5 pM) and high specificity, reacting with its superstructure and neutralizing GM-CSF activity to a level 4000 to 58 000 times the levels of GM-CSF normally present in the lung. Although target epitopes varied among patients, GM-CSF amino acids 78 to 94 were consistently recognized. Thus, autoantibodies bind GM-CSF with high specificity and high affinity, exist abundantly in the lung, and effectively block GM-CSF binding to its receptor, inhibiting AM differentiation and function. Our data strengthen the evidence associating anti-GM-CSF autoantibodies with the pathogenesis of this disease.

Adult↗