Crystal Formation in Inflammation.

The formation and accumulation of crystalline material in tissues is a hallmark of many metabolic and inflammatory conditions. The discovery that the phase transition of physiologically soluble substances to their crystalline forms can be detected by the immune system and activate innate immune pathways has revolutionized our understanding of how crystals cause inflammation. It is now appreciated that crystals are part of the pathogenesis of numerous diseases, including gout, silicosis, asbestosis, and atherosclerosis. In this review we discuss current knowledge of the complex mechanisms of crystal formation in diseased tissues and their interplay with the nutrients, metabolites, and immune cells that account for crystal-induced inflammation.

Downregulation of the PD-1/PD-Ls pathway in peripheral cells correlates with asbestosis severity.

BACKGROUND: Asbestosis and silicosis are characterized by diffuse or nodular interstitial lung fibrosis resulting from exposure to asbestos or silica dust, respectively. This study was designed to detect programmed cell death protein (PD-1)/programmed death ligands (PD-Ls) expression in patients with asbestosis and silicosis and to explore the possible clinical significance of PD-1/PD-Ls expression in patients with the two diseases. METHODS: Thirty patients with asbestosis, 23 patients with silicosis and 25 healthy controls were consecutively recruited and provided informed consent to participate in the study. Clinical data were collected from patients' clinical charts. PD-1/PD-Ls expression in peripheral blood (PB) was detected using flow cytometry. RESULTS: PD-1 was expressed at significantly lower levels on CD4+ or CD8+ peripheral T cells from patients with asbestosis and silicosis than on cells from healthy controls. Similarly, significantly lower PD-L1 and PD-L2 expression was detected on CD14+ monocytes from patients with asbestosis and silicosis than on cells from healthy controls. In addition, no significant differences in PD-1, PD-L1 and PD-L2 expression were observed between the asbestosis and silicosis groups. Moreover, the proportions of PD-1+ CD4+ T cells and PD-1+ CD8+ T cells in patients with asbestosis were positively correlated with the percentage of forced vital capacity predicted. CONCLUSIONS: Decreased PD-1 expression on CD4+ T or CD8+ T cells in PB was positively correlated with the asbestosis severity, implying that pulmonary fibrosis development in patients with asbestosis was positively correlated with the downregulation of the PD-1/PD-Ls pathway.

Search for biomarkers of asbestos exposure and asbestos-induced cancers in investigations of the immunological effects of asbestos.

The immunological effects of asbestos exposure on various lymphocytes such as the regulatory T cell (Treg), responder CD4+ T helper cell (Tresp), CD8+ cytotoxic T lymphocytes (CTL), and natural killer (NK) cells were investigated. Results show that asbestos exposure impairs antitumor immunity through enhancement of regulatory T cell function and volume, reduction of CXCR3 chemokine receptor in responder CD4+ T helper cells, and impairment of the killing activities of CD8+ cytotoxic T lymphocytes (CTL) and NK cells. These findings were used to explore biological markers associated with asbestos exposure and asbestos-induced cancers and suggested the usefulness of serum/plasma IL-10 and TGF-ß, surface CXCR3 expression in Tresp, the secreting potential of IFN-γ in Tresp, intracellular perforin level in CTL, and surface expression NKp46 in NK cells. Although other unexplored cytokines in serum/plasma and molecules in these immunological cells, including Th17, should be investigated by experimental procedures in addition to a comprehensive analysis of screening methods, biomarkers based on immunological alterations may be helpful in clinical situations to screen the high-risk population exposed to asbestos and susceptible to asbestos-related cancers such as mesothelioma.

Libby amphibole-induced mesothelial cell autoantibodies promote collagen deposition in mice.

Libby amphibole (LA) causes a unique progressive lamellar pleural fibrosis (LPF) that is associated with pulmonary function decline. Pleural fibrosis among the LA-exposed population of Libby, MT, has been associated with the production of anti-mesothelial cell autoantibodies (MCAA), which induce collagen production from cultured human mesothelial cells. We hypothesized that the progressive nature of LPF could be at least partially attributed to an autoimmune process and sought to demonstrate that LA-induced MCAA trigger collagen deposition in vivo. C57BL/6 mice were exposed to LA for 7 mo, and serum was tested for MCAA by cell-based ELISA on primary mouse mesothelial cells. When treated in vitro with serum from mice exposed to LA, mesothelial cells upregulated collagen matrix production. This effect was lost when the serum was cleared of IgG using protein G beads, implicating IgG autoantibodies. Using the peritoneal cavity as a surrogate for the pleural cavity, groups of naïve (non-asbestos-exposed) mice were injected intraperitoneally with 1) control serum, 2) one dose of serum from LA-exposed mice (LA serum), 3) two doses of LA serum, or 4) two doses of LA serum cleared of IgG. After 1 mo, analysis of collagen in peritoneal walls using two-photon confocal microscopy (SHG analysis) and a hydroxyproline assay demonstrated significant increases in collagen by LA serum but not control or cleared serum. These data support the hypothesis that MCAA in LA-exposed mice induce fibrotic responses in vivo, demonstrating that an autoimmune component may be contributing to the progressive pleural fibrosis seen in LA-exposed patients.

Environmental factors and human health: fibrous and particulate substance-induced immunological disorders and construction of a health-promoting living environment.

Among the various scientific fields covered in the area of hygiene such as environmental medicine, epidemiology, public health and preventive medicine, we are investigating the immunological effects of fibrous and particulate substances in the environment and work surroundings, such as asbestos fibers and silica particles. In addition to these studies, we have attempted to construct health-promoting living conditions. Thus, in this review we will summarize our investigations regarding the (1) immunological effects of asbestos fibers, (2) immunological effects of silica particles, and (3) construction of a health-promoting living environment. This review article summarizes the 2014 Japanese Society for Hygiene (JSH) Award Lecture of the 85th Annual Meeting of the JSH entitled "Environmental health effects: immunological effects of fibrous and particulate matter and establishment of health-promoting environments" presented by the first author of this manuscript, Prof. Otsuki, Department of Hygiene, Kawasaki Medical School, Kurashiki, Japan, the recipient of the 2014 JSH award. The results of our experiments can be summarized as follows: (1) asbestos fibers reduce anti-tumor immunity, (2) silica particles chronically activate responder and regulatory T cells causing an unbalance of these two populations of T helper cells, which may contribute to the development of autoimmune disorders frequently complicating silicosis, and (3) living conditions to enhance natural killer cell activity were developed, which may promote the prevention of cancers and diminish symptoms of virus infections.

Systemic autoimmune disease in asbestosis rapidly responding to anti-interleukin-1beta antibody canakinumab: a case report.

BACKGROUND: Asbestosis is characterized by lung and pleural fibrosis and by immune system dysregulation, with autoantibody production and systemic immune-mediated disease. No specific therapies are available for asbestosis. Recently, the pivotal pathogenic role exerted by interleukin-1beta has been recently reported. CASE PRESENTATION: We treated with anti-interleukin 1 beta targeted antibody canakinumab a 67 year old man with asbestosis and long lasting systemic autoimmune features. A dramatic improvement in clinical manifestations was observed at 1 week after the first injection, with complete clinical remission at 4 months. CONCLUSION: This case suggests new perspectives for the treatment of asbestosis and its systemic features.

Evaluation of the deposition, translocation and pathological response of brake dust with and without added chrysotile in comparison to crocidolite asbestos following short-term inhalation: interim results.

Chrysotile has been frequently used in the past in manufacturing brakes and continues to be used in brakes in many countries. This study was designed to provide an understanding of the biokinetics and potential toxicology following inhalation of brake dust following short term exposure in rats. The deposition, translocation and pathological response of brake dust derived from brake pads manufactured with chrysotile were evaluated in comparison to the amphibole, crocidolite asbestos. Rats were exposed by inhalation 6 h/day for 5 days to either brake dust obtained by sanding of brake-drums manufactured with chrysotile, a mixture of chrysotile and the brake dust or crocidolite asbestos. No significant pathological response was observed at any time point in either the brake dust or chrysotile/brake dust exposure groups. The long chrysotile fibers (>20 µm) cleared quickly with T(½) estimated as 30 and 33 days, respectively in the brake dust and the chrysotile/brake dust exposure groups. In contrast, the long crocidolite fibers had a T(½)>1000 days and initiated a rapid inflammatory response in the lung following exposure resulting in a 5-fold increase in fibrotic response within 91 days. These results provide support that brake dust derived from chrysotile containing brake drums would not initiate a pathological response in the lung following short term inhalation.

Altered functions of alveolar macrophages and NK cells involved in asbestos-related diseases.

Asbestos exposure causes asbestosis and malignant mesothelioma, disorders which remain difficult to cure. We focused on alveolar macrophages (AM) and natural killer (NK) cells in asbestosis and mesothelioma, respectively, and examined their functions upon exposure to asbestos or in patients with mesothelioma. Exposure to asbestos caused rat AM to exhibit high production of transforming growth factor-beta (TGF-ß) with prolonged survival in the absence of other cells, not simultaneously with the apoptosis caused by asbestos. The NK cell line showed impaired cytotoxicity with altered expression of activating receptors upon exposure to asbestos, and primary NK cells in culture with asbestos and peripheral blood NK cells in mesothelioma shared a decrease in expression of NKp46, a representative activating receptor. The AM finding indicates that AM contribute to asbestosis by playing a direct role in the fibrogenic response, as well as the inflammatory response. The response of NK cells indicates that exposure to asbestos has an immune-suppressive effect, as well as a tumorigenic effect. Our studies therefore reveal novel effects of asbestos exposure on AM and tumor immunity, which may represent valuable information for construction of a strategy for prevention and cure of asbestosis and malignant mesothelioma.

[Inflammasome--essential regulator of the inflammatory reaction]. / Inflammasomi--tulehdusreaktion keskeinen säätelijä.

The function of inflammasome in the cell is to sense intracellular danger signals and--perhaps as the last cry of distress of a cell invaded by a microorganism--at an emergency situation to release interleukins (IL) outside of the cell, causing an inflammatory reaction and fever and also leads to an elevation of CRP. In a hopeless situation inflammasome-regulated pyroptosis is started. Disturbed action of inflammasomes has been linked to the pathogenesis of various disorders such as gout, atherosclerosis, asbestosis and type 2 diabetes. As the pathogenetic mechanisms of such diseases become clear, improved treatments for them may also become available.

Asbestos-induced cellular and molecular alteration of immunocompetent cells and their relationship with chronic inflammation and carcinogenesis.

Asbestos causes lung fibrosis known as asbestosis as well as cancers such as malignant mesothelioma and lung cancer. Asbestos is a mineral silicate containing iron, magnesium, and calcium with a core of SiO(2). The immunological effect of silica, SiO(2), involves the dysregulation of autoimmunity because of the complications of autoimmune diseases found in silicosis. Asbestos can therefore cause alteration of immunocompetent cells to result in a decline of tumor immunity. Additionally, due to its physical characteristics, asbestos fibers remain in the lung, regional lymph nodes, and the pleural cavity, particularly at the opening sites of lymphatic vessels. Asbestos can induce chronic inflammation in these areas due to the production of reactive oxygen/nitrogen species. As a consequence, immunocompetent cells can have their cellular and molecular features altered by chronic and recurrent encounters with asbestos fibers, and there may be modification by the surrounding inflammation, all of which eventually lead to decreased tumor immunity. In this paper, the brief results of our investigation regarding reduction of tumor immunity of immunocompetent cells exposed to asbestos in vitro are discussed, as are our findings concerned with an investigation of chronic inflammation and analyses of peripheral blood samples derived from patients with pleural plaque and mesothelioma that have been exposed to asbestos.

Libby vermiculite exposure and risk of developing asbestos-related lung and pleural diseases.

PURPOSE OF REVIEW: The vermiculite ore formerly mined in Libby, Montana, contains asbestiform amphibole fibers of winchite, richterite, and tremolite asbestos. Because of the public health impact of widespread occupational and nonoccupational exposure to amphiboles in Libby vermiculite, numerous related studies have been published in recent years. Here we review current research related to this issue. RECENT FINDINGS: Excess morbidity and mortality classically associated with asbestos exposure have been well documented among persons exposed to Libby vermiculite. Excess morbidity and mortality have likewise been documented among persons with only nonoccupational exposure. A strong exposure-response relationship exists for many malignant and nonmalignant outcomes and the most common outcome, pleural plaques, may occur at low lifetime cumulative exposures. SUMMARY: The public health situation related to Libby, Montana, has led to huge investments in public health actions and research. The resulting studies have added much to the body of knowledge concerning health effects of exposures to Libby amphibole fibers specifically and asbestos exposure in general.

Decreased CXCR3 expression in CD4+ T cells exposed to asbestos or derived from asbestos-exposed patients.

Asbestos causes malignant tumors such as lung cancer and malignant mesothelioma (MM). To determine whether asbestos exposure causes reduction of antitumor immunity, we established an in vitro T-cell line model of low-dose and continuous exposure to asbestos using an human adult T-cell leukemia virus-1 immortalized human polyclonal T-cell line, MT-2, and revealed that MT-2 cells exposed continuously to asbestos showed resistance to asbestos-induced apoptosis. In addition, the cells presented reduction of surface CXCR3 chemokine receptor expression and IFN-γ production. In this study, to confirm that these findings are suitable for clinical translation, surface CXCR3 and IFN-γ expression were analyzed using freshly isolated human CD4(+) T cells derived from healthy donors and patients with pleural plaque (PP) or MM. The results revealed that CXCR3 and IFN-γ expression in the ex vivo model were reduced in some cases. Additionally, CXCR3 expression in CD4(+) T cells from PPs and MMs was significantly reduced compared with that from healthy donors, and CD4(+) T cells from patients with MMs exhibited a marked reduction in IFN-γ mRNA levels after stimulation in vitro. Moreover, CD4(+)CXCR3(+) T cells in lymphocytes from MMs showed a tendency for an inverse correlation with its ligand CXCL10/IP10 in plasma. These findings show reduction of antitumor immune function in asbestos-exposed patients and indicate that CXCR3, IFN-γ, and CXCL10/IP10 may be candidates to detect and monitor disease status.

Pulmonary inflammatory and fibrotic responses in Fischer 344 rats after intratracheal instillation exposure to Libby amphibole.

Increased incidences of asbestosis have been reported in workers from Libby, MT, associated with exposures to amphibole-contaminated vermiculite. In this study pulmonary and histopathological changes were investigated following Libby amphibole (LA) exposure in a rat model. Rat respirable fractions of LA and amosite (aerodynamic diameter <2.5 µm) were prepared by water elutriation. Male F344 rats were exposed to single doses of either saline (SAL), amosite (0.65 mg/rat), or LA (0.65 or 6.5 mg/rat) by intratracheal instillation. At times from 1 d to 3 mo after exposure, bronchoalveolar lavage (BAL) was performed and right and left lungs were removed for reverse-transcription polymerase chain reaction (RT-PCR) and histopathological analysis, respectively. Data indicated that 0.65 mg amosite resulted in a higher degree of pulmonary injury, inflammation, and fibrotic events than LA at the same mass dose. Exposure to either amosite or high dose LA resulted in higher levels of cellular permeability and injury, inflammatory enzymes, and iron binding proteins in both BAL fluid and lung tissue at most time points when compared to SAL controls. However, mRNA expression for some growth factors (e.g., platelet-derived growth factor [PDGF]-A and transforming growth factor [TGF]-1ß), which contribute to fibrosis, were downregulated at several time points. Furthermore, histopathological examination showed notable thickening of interstitial areas surrounding the alveolar ducts and terminal bronchioles. On a mass dose basis, amosite produced a greater acute and persistent lung injury for at least 3 mo after exposure. However, further testing and analysis of LA are needed with regard to the dose metric to fully evaluate its potential fibrogenicity and carcinogenicity.

Analysis on the co-localization of asbestos bodies and Fas or CD163 expression in asbestos lung tissue by in-air micro-pixe.

To prevent and control disease caused by exposure to various agents, it is necessary to determine the harmful level of intervention and to establish a method for measuring that level. In-air microparticle-induced X-ray emission (in-air micro-PIXE) analysis is based on irradiation of specimens with a proton ion microbeam, and has been modified for biological application. Two-dimensional analysis and quantitative analysis using the system confirmed that asbestos induced apoptosis by upregulating Fas expression and also revealed the accumulation of CD163-expressing macrophages in the lungs of patients with asbestosis. By quantitative comparison of the area of Fas or CD163 expression and the Fas- or CD163-negative area in asbestos lung tissue, the harmful levels which caused the expression of Fas or CD163 could be estimated on Silica, Ferrous iron, and Magnesium (the components of asbestos) deposition. These results indicate that the system could be useful for investigating the pathogenesis of inhaled particle-induced immune reactions and for determining harmful levels of exogenous agents.

[Immunological aspects of asbestos-related diseases]. / Imunoloski aspekti bolesti izazvanih azbestom.

Asbestos is a generic name for a group of silicate minerals. The most common are chrysotile, crocidolite, amosite, tremolite and anthophyllite. Exposure to asbestos may cause asbestos-related non-malignant diseases of the lung and pleura, including asbestosis, pleural plaques, diffuse pleural fibrosis, small airway disease, and malignant diseases such as lung cancer and malignant mesothelioma. Inhaled asbestos fibres deposit in the distal regions of the respiratory system where they interact with epithelial cells and alveolar macrophages, and trigger active immunological response which leads to a slowly progressing lung fibrosis. Asbestos may affect immunocompetent cells and induce malignant transformation of mesothelial cells. It is still not clear whether asbestos causes mesothelioma directly or indirectly. There is a general opinion that malignant mesothelioma is a complex tumour that results from the accumulation of multiple genetic alterations over many years. There is no specific antibody for malignant mesothelioma as yet which could act as a single diagnostic tool. Recent studies have demonstrated that asbestos acts on peripheral T cells as superantigen and that in malignant mesothelioma patients there is an overexpression of the Bcl-2 gene on peripheral CD4+ T cells. These findings contribute to better understanding of biological effects of asbestos in respect to the duration and intensity of exposure.

Induced sputum markers of fibrosis and decline in pulmonary function in asbestosis and silicosis: a pilot study.

OBJECTIVE: To evaluate the usefulness of fibrogenic cytokines and mediators in the analysis of induced sputum and determine if their levels correlated with previous decline in lung function in asbestosis and silicosis. DESIGN: In a pilot study for the evaluation of 19 workers with asbestosis and 15 with silicosis, all workers had chart reviews and records of previous lung function tests. Fourteen healthy control subjects were also included in the study. All subjects attended the laboratory for a clinical evaluation, pulmonary function tests and induced sputum sampling. Differential cell counts were performed and the following mediators and cytokines were measured: matrix metalloproteinase 9 (MMP-9), tissue inhibitor of metalloproteinases 1 (TIMP-1), fibronectin, interleukin 1 beta (IL-1beta), IL-6, IL-8, IL-12, transforming growth factor beta (TGF-beta) and tumor necrosis factor-alpha (TNF-alpha). RESULTS: Levels of IL-1beta were higher in the sputum of subjects with asbestosis and silicosis than in controls. Eosinophils, neutrophils and IL-1beta levels were significantly correlated with the rate of decline in pulmonary function. CONCLUSION: The induced sputum levels of certain inflammatory cells and IL-1beta correlate with the decline in pulmonary function associated with asbestosis and silicosis. It remains to be established if these markers can help predict the clinical outcome of workers exposed to these mineral particles or fibers in a prospective study.

[Interferon gamma (IFN-gamma) level in broncholaveolar lavage (BAL) fluid is positively correlated with CD4/CD8 ratio in selected interstitial lung diseases]. / Stezenie interferonu gamma (IFN-gamma) w plynie z plukania oskrzelowo-pqcherzykowego w wybranych chorobach sródmiaqszowych pluc--dodatnio skorelowane z wartoscia stosunku CD4/CD8.

UNLABELLED: IFN-gamma a potent antifibrotic activity in interstitial lung diseases (ILD). T cells, both Th1 and Tc1, are considered to be the main local source of IFN-gamma. MATERIAL AND METHODS: BAL fluids of 98 patients with ILD, incl. idiopathic pulmonary fibrosis (IPF/UIP), sarcoidosis, extrinsic allergic alveolitis (EAA), asbestosis and silicosis (n=16, 49, 7, 10, 16 resp.) were tested with ELISA for IFN-gamma levels. Results were compared with BAL cytoimmunology and patients' clinical data. RESULTS: Significantly increased IFN-gamma levels were found in non-treated patients with EAA (7.8 +/- 2.1), IPF (6.1 +/- 1.8), Loefgren's syndrome, LS (11.9 +/- 2.6) and progressive sarcoidosis, PS (6.4 +/- 1.2, p < 0.05 for all), whereas the results in pneumoconioses were comparable to those obtained in controls (2.0 +/- 1.1 pg/ml, median +/- SEM). IFN-gamma results were positively correlated with total number of CD4+ cells (r(s) = +0.38, p < 0.05), CD4+ cells percentage (r(s) = +0.32, p < 0.005) and CD4+/CD8+ ratio (r(s) = +0.38, p = 0.0007), but negatively correlated with CD8+ cell percentage (r(s) = -0.39, p < 0.0005). In IPF patients with CD4/CD8 < or =1 (n=9) IFN-gamma level was lower as compared with the group with CD4/CD8 >1 (n=7), 2.8 +/- 1.3 vs. 7.3 +/- 1.0 pg/ml. In sarcoidosis, IFN-gamma level did not seem to have a prognostic role, since values obtained in PS did not differ remarkably from those in stable sarcoidosis and LS. Moreover, subsequent steroid treatment in 7 patients with progressive sarcoidosis did not change significantly IFN-gamma levels in BAL fluid. CONCLUSIONS: Increased IFN-gamma level was found in non-treated patients with IPF, Loefgren's syndrome and progressive sarcoidosis. CD4+ (Th1), but neither CD8+ (Tc1) nor NK cells seem to be the main local source of IFN-gamma in ILD. Relatively low CD4/CD8 ratio in ILD may indicate the patients with increased risk of lung fibrosis.

Expression of the T cell receptor Vbeta repertoire in a human T cell resistant to asbestos-induced apoptosis and peripheral blood T cells from patients with silica and asbestos-related diseases.

To explore the effects of asbestos and silica on the human immune system, an experimental model of low-dose and long-term exposure was established using a human HTLV-1-immortalized polyclonal T cell line, MT-2 (MT-2Org). MT-2 cells were continuously exposed to asbestos at a concentration (10 microg/ml) which does not induce complete cell death during short-term exposure. After acquiring resistance to CB-induced apoptosis (designated MT-2Rst), an immunological comparison was made between the MT-2Org and MT-2Rst lines in terms of T cell receptor-Vbeta (TcR-Vbeta) expression. MT-2Rst cells showed excess expression of various TcR-Vbeta, although TcR-Vbeta-overpresenting cells were characterized as undergoing apoptosis due to first contact with CB. Patients with asbestos-related diseases (ARD), such as asbestosis and malignant mesothelioma, were compared with silicosis (SIL) patients as a disease control and with healthy donors (HD). SIL and ARD not only differed in their causative materials, silica and asbestos as mineral silicates, but also in terms of complications; autoimmune disorders in SIL and tumors in ARD. ARD patients showed a restricted overpresentation of TcR-Vbeta without clonal expansion, whereas SIL patients revealed significant overpresentation of TcR-Vbeta 7.2. These experimental and clinical analyses indicate the superantigenic and dysregulation of autoimmunity-inducing effects of asbestos and silica, respectively.

[Cytoimmunological changes in the bronchoalveolar lavage in asbestos exposure patients]. / Cytoimmunologiczna charakterystyka zmian w plucach wywolanych ekspozycja na pyly azbestu.

Bronchoalveolar lavage (BAL) fluid in the group of 19 patients with the confirmed exposure to asbestos was investigated. The cytological and immunocytochemical methods as well as computer morphometry were used in this study. In the groups studied the differences in cell numbers and BAL cell activity were found, especially in the monocytes and macrophages group of cells.

Mesothelioma and interferon-γ-dependent chemokine IP-10.

Recently it has been shown that interferon (IFN)-γ plays an important role in mesothelioma, mediated by the main IFN-γ dependent chemokines, chemokine (C-X-C motif) ligand (CXCL)10/IFN-γ- induced protein 10 (IP-10). IP-10 is up-regulated in malignant mesothelioma (MM), suggesting a relationship with development of these tumors. Nanoparticles containing nickel, that increase the risk for pleural diseases, induced increased levels of IP-10 in rat pleural mesothelial cells. Chemokine (C-X-C motif) receptor (CXCR)3 expression in CD4(+) T cells from pleural plaques and MMs was significantly decreased compared with that from healthy donors suggesting that CXCR3, IFN-γ, and IP-10 may be candidates to detect and monitor disease status. In a patient with asbestos-related malignant pleural mesothelioma the oncolytic adenovirus (ONCOS-102) induced prominent infiltration of CD8(+) lymphocytes to tumor, marked induction of systemic antitumor CD8(+) T-cells and expression of IP-10. Furthermore, increased IP- 10 concentrations were observed in the sera of the asbestos-exposed workers and were associated with the severity of asbestos-related diseases. These findings suggest that IP-10 chemokine may have a prognostic role in the progression of asbestos-related diseases and could be used for the health surveillance of either workers with an occupational history of asbestos exposure or patients affected by nonmalignant asbestos-related diseases.