Effect of IL-15 addition on asbestos-induced suppression of human cytotoxic T lymphocyte induction.

BACKGROUND: Asbestos fibers possess tumorigenicity and are thought to cause mesothelioma. We have previously reported that exposure to asbestos fibers causes a reduction in antitumor immunity. Asbestos exposure in the mixed lymphocyte reaction (MLR) showed suppressed induction of cytotoxic T lymphocytes (CTLs), accompanied by a decrease in proliferation of CD8+ T cells. Recently, we reported that asbestos-induced suppression of CTL induction is not due to insufficient levels of interleukin-2 (IL-2). In this study, we continue to investigate the mechanism responsible for the effect of asbestos fibers on the differentiation of CTLs and focus on interleukin-15 (IL-15) which is known to be a regulator of T lymphocyte proliferation. METHODS: For MLR, human peripheral blood mononuclear cells (PBMCs) were cultured with irradiated allogenic PBMCs upon exposure to chrysotile B asbestos at 5 µg/ml for 7 days. After 2 days of culture, IL-15 was added at 1 ng/ml. After 7 days of MLR, PBMCs were collected and analyzed for phenotypic and functional markers of CD8+ T cells with fluorescence-labeled anti-CD3, anti-CD8, anti-CD45RA, anti-CD45RO, anti-CD25, and anti-granzyme B antibodies using flow cytometry. To examine the effect of IL-15 on the expression level of intracellular granzyme B in proliferating and non-proliferating CD8+ lymphocytes, PBMCs were stained using carboxyfluorescein diacetate succinimidyl ester (CFSE) and then washed and used for the MLR. RESULTS: IL-15 addition partially reversed the decrease in CD3+CD8+ cell numbers and facilitated complete recovery of granzyme B+ cell percentages. IL-15 completely reversed the asbestos-induced decrease in percentage of granzyme B+ cells in both non-proliferating CFSE-positive and proliferating CFSE-negative CD8+ cells. The asbestos-induced decrease in the percentage of CD25+ and CD45RO+ cells in CD8+ lymphocytes was not reversed by IL-15. CONCLUSION: These findings indicate that CTLs induced upon exposure to asbestos possess dysfunctional machinery that can be partly compensated by IL-15 supplementation, and that IL-15 is more effective in the recovery of proliferation and granzyme B levels from asbestos-induced suppression of CTL induction compared with IL-2.

The Effects of Asbestos Fibers on Human T Cells.

Asbestos exposure causes malignant tumors such as lung cancer and malignant mesothelioma. The effects of asbestos fibers on immunocompetent cells, however, have not been well studied. Asbestos physically comprises a fibrous substance, which differs from silica particles which are a particulate substance, although chemically it is a mineral silicate. Since silicosis patients previously exposed to silica particles often suffer from lung and autoimmune diseases, it is clear that silica exposure impairs immune tolerance. Similarly, asbestos may alter the immune system in asbestos-exposed individuals. Given that malignant tumors can result following exposure to asbestos, the attenuation of anti-tumor immunity in cases of asbestos exposure is an important area of investigation. We observed the effect of asbestos fibers on T lymphocytes, such as CD8+ cytotoxic T lymphocytes (CTLs), CD4+ helper T (Th), and regulatory T (Treg) cells, and showed that anti-tumor immunity was attenuated, as demonstrated in a system that stimulates fresh cells isolated from peripheral blood in vitro and a system that is continuously exposed to a cell line. In this manuscript, we introduce the experiments and results of studies on CTLs, as well as Th and Treg cells, and discuss how future changes in immunocompetent cells induced by asbestos fibers can be clinically linked.

Effect of asbestos exposure on differentiation and function of cytotoxic T lymphocytes.

Asbestos exposure is known to cause malignant mesothelioma, which is associated with poor prognosis. We focused on and examined the effect of asbestos exposure on the differentiation and function of cytotoxic T lymphocytes (CTLs). CTLs have the ability to specifically attack tumor cells after being differentiated from naïve CD8+ T cells following antigen stimulation. Exposure to chrysotile B asbestos suppressed the differentiation of CTLs during the mixed lymphocyte reaction (MLR) and was associated with a decrease in proliferation of CD8+ T cells. Additionally, in an effort to investigate the mechanism associated with suppressed CTL differentiation upon exposure to asbestos, we focused on IL-2, a cytokine involved in T cell proliferation. Our findings indicated that insufficient levels of IL-2 are not the main cause for the suppressed induction of CTLs by asbestos exposure, although they suggest potential improvement in the suppressed CTL function. Furthermore, the functional properties of peripheral blood CD8+ lymphocytes from asbestos-exposed individuals with pleural plaque (PP) and patients with malignant mesothelioma (MM) were examined. MM patients showed lower perforin levels in CD8+ lymphocytes following stimulation compared with PP-positive individuals. The production capacity of IFN-γ in the MM group tended to be lower compared with healthy volunteers or PP-positive individuals. In an effort to determine whether chronic and direct asbestos exposure affected the function of CD8+ T cells, cultured human CD8+ T cells were employed as an in vitro model and subjected to long-term exposure to chrysotile (CH) asbestos. This resulted in decreased levels of intracellular perforin and secreted IFN-γ. Those findings underlie the possibility that impaired CD8+ lymphocyte function is caused by asbestos exposure, which fail to suppress the development of MM. Our studies therefore reveal novel effects of asbestos exposure on CTLs, which might contribute towards the development and implementation of an effective strategy for the prevention and cure of malignant mesothelioma.

Role of Nephronectin in Pathophysiology of Silicosis.

Silicosis is a typical form of pneumoconiosis and is characterized as a type of lung fibrosis. Silica particles are captured and recognized upon by alveolar macrophages via the macrophage receptor with collagenous structure (MARCO) scavenger receptor, and thereafter the inflammasome is activated. Thereafter, various chemokines/cytokines play their roles to eventually form fibrosis. Additionally, silica particles chronically activate T helper cells which sets the background for the formation of silicosis-associated autoimmune disturbances. The occurrence and progression of lung fibrosis, the extracellular matrix-related molecules such as integrins and their ligands including fibronectin, vitronectin, laminin, and collagens, all play important roles. Here, the roles of these molecules in silicosis-related lung fibrosis are reviewed from the literature. Additionally, the measurement of serum nephronectin (Npnt), a new member of the integrin family of ligands, is discussed, together with investigations attempting to delineate the role of Npnt in silica-induced lung fibrosis. Serum Npnt was found to be higher in silicosis patients compared to healthy volunteers and seems to play a role in the progression of fibrosis with other cytokines. Therefore, serum Npnt levels may be employed as a suitable marker to monitor the progression of fibrosis in silicosis patients.

Decrease in Serum Amyloid a Protein Levels Following Three-month Stays in Negatively Charged Particle-dominant Indoor Air Conditions.

OBJECTIVE: The changes in serum adipokines and cytokines related to oxidative stress were examined during 3 months 'Off to On' and 'On to Off' periods using negatively charged particle-dominant indoor air conditions (NCPDIAC). METHODS: Seven volunteers participated in the study, which included 'OFF to 3 months ON' periods (ON trials) for a total of 16 times, and 'ON to 3 months OFF' (OFF trials) periods for a total of 13 times. RESULTS: With the exception of one case, serum amyloid A (SAA) levels decreased significantly during the ON trials. CONCLUSION: Considering that SAA is an acute phase reactive protein such as C reactive protein (CRP), this observed decrease might indicate the prevention of cardiovascular and atherosclerotic changes, since an increase in high-sensitive CRP is associated with the subsequent detection of these events.

Inflammatory Alteration of Human T Cells Exposed Continuously to Asbestos.

Asbestos is a known carcinogen and exposure can lead to lung cancer and malignant mesothelioma. To examine the effects of asbestos fibers on human immune cells, the human T cell leukemia/lymphoma virus (HTLV)-1 immortalized human T cell line MT-2 was employed. Following continuous exposure to asbestos fibers for more than eight months, MT-2 sublines showed acquisition of resistance to asbestos-induced apoptosis with decreased death signals and increased surviving signals. These sublines showed various characteristics that suggested a reduction in anti-tumor immunity. On the other hand, inflammatory changes such as expression of MMP7, CXCR5, CXCL13 and CD44 was found to be markedly higher in sublines continuously exposed to asbestos compared with original MT-2 cells. All of these molecules contribute to lung inflammation, T and B cell interactions and connections between mesothelial cells and T cells. Thus, further investigation focusing on these molecules may shed light on the role of chronic inflammation caused by asbestos exposure and the occurrence of malignant mesothelioma. Finally, regarding peripheral T cells from healthy donors (HD) and asbestos-exposed patients with pleural plaque (PP) or malignant pleural mesothelioma (MPM), following stimulation of CD4+ T cells, T cells from MPM patients showed reduced potential of interferon (IFN)-γ expression. Moreover, levels of interleukin (IL)-6, one of the most important cytokines in chronic inflammation, in cultured supernatants were higher in PP and MPM patients compared with HD. Overall, asbestos-induced chronic inflammation in the lung as well as the pleural cavity may facilitate the onset of asbestos-induced cancers due to alterations in the interactions among fibers, immune cells such as T and B cells and macrophages, and mesothelial and lung epithelial cells. Further investigations regarding chronic inflammation caused by asbestos fibers may assist in identifying molecular targets for preventive and therapeutic strategies related to the effects of asbestos exposure.

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.

Biological Effects of Cloth Containing Specific Ore Powder in Patients with Pollen Allergy.

OBJECTIVE: The custom-homebuilding company, Cosmic Garden Co. Ltd., located in Okayama City, Japan was established in 1997 and uses specific natural ore powder (SNOP) in wall materials and surveys customers in order to improve allergic symptoms. METHODS: To investigate the biological effects of SNOP, patients with a pollen allergy were recruited to stay in a room surrounded by cloth containing SNOP (CCSNOP), and their symptoms and various biological parameters were compared with those of individuals staying in a room surrounded by control non-woven cloth (NWC). Each stay lasted 60 min. Before and immediately after the stay, a questionnaire regarding allergic symptoms, as well as POMS (Profile of Mood Status) and blood sampling, was performed. Post-stay minus pre-stay values were calculated and compared between CCSNOP and NWC groups. RESULTS: Results indicated that some symptoms, such as nasal obstruction and lacrimation, improved, and POMS evaluation showed that patients were calmer following a stay in CCSNOP. Relative eosinophils, non-specific Ig E, epidermal growth factor, monocyte chemotactic protein-1, and tumor necrosis factor-α increased following a stay in CCSNOP. CONCLUSION: This ore powder improved allergic symptoms, and long-term monitoring involving 1 to 2 months may be necessary to fully explore the biological and physical effects of SNOP on allergic 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.

Silica exposure and altered regulation of autoimmunity.

Silica particles and asbestos fibers, which are known as typical causatives of pneumoconiosis, induce lung fibrosis. Moreover, silicosis patients often complicate with autoimmune diseases, and asbestos-exposed patients suffer from malignant diseases such as pleural mesothelioma and lung cancer. We have been conducting experimental studies to investigate altered regulation of self-tolerance caused by silica exposure, including analyses using specimens such as plasma and immunocompetent cells obtained from silicosis patients, as a means of examining the supposition that silica exposure induces molecular and cellular biological alterations of immune cells. These approaches have resulted in the detection of several specific autoantibodies, alterations of CD95/Fas and its related molecules, and evidence of chronic activation of responder T cells and regulatory T cells following silica exposure. In this review, we present details of our investigations as an introduction to scientific approaches examining the immunological effects of environmental and occupational substances.

Anti-fatigue activity of methyl dihydrojasmonate and linalool in a rat model evaluated by a novel index for neuro-immune and oxidative stress interactions.

Avoiding fatigue is a long-standing challenge in both healthy and diseased individuals. Establishing objective standard markers of fatigue is essential to evaluate conditions in spatiotemporally different locations and individuals and identify agents to fight against fatigue. Herein, we introduced a novel method for evaluating fatigue using nervous system markers (including dopamine, adrenaline, and noradrenaline), various cytokine levels (such as interleukin [IL]-1ß, tumor necrosis factor [TNF]-α, IL-10, IL-2, IL-5 and IL-17A), and oxidative stress markers (such as diacron-reactive oxygen metabolites [d-ROMs] and biological antioxidant potential [BAP]) in a rat fatigue model. Using this method, the anti-fatigue effects of methyl dihydrojasmonate (MDJ) and linalool, the fragrance/flavor compounds used in various products, were assessed. Our method evaluated the anti-fatigue effects of the aforementioned compounds based on the changes in levels of the nerves system markers, cytokines, and oxidative stress markers. MDJ exerted more potent anti-fatigue effects than linalool. In conclusion, the reported method could serve as a useful tool for fatigue studies and these compounds may act as effective therapeutic agents for abrogating fatigue symptoms.

Effect of asbestos exposure on differentiation of cytotoxic T lymphocytes in mixed lymphocyte reaction of human peripheral blood mononuclear cells.

Asbestos fibers are associated with tumorigenicity, and are thought to cause mesothelioma. However, their effect on immune response remains unclear. We examined the effect of asbestos exposure on differentiation of cytotoxic T lymphocytes (CTLs) in mixed lymphocyte reactions (MLR) of human peripheral blood mononuclear cells (PBMCs) upon exposure to chrysotile B (CB) or crocidolite (CR) asbestos at 5 µg/ml for 7 days. Exposure to CB during MLR suppressed increases in the percentage and number of CD8⁺ T cells in response to allogenic cells. The cytotoxicity for allogenic targets decreased in PBMCs exposed to CB, but not CR, when compared with PBMCs without any exposure during MLR. Exposure to CB during MLR resulted in suppression of increases in granzyme B⁺ cells and IFN-γ⁺ cells. CB exposure also resulted in suppression of increases in CD45RO⁺ effector/memory cells and CD25⁺-activated cells in CD8⁺ lymphocytes, and a decrease in CD45RA⁺ cells. CB exposure suppressed the proliferation of CD8⁺ lymphocytes without an increase in annexin V⁺ apoptotic cells in CD8⁺ lymphocytes. Moreover, the production of IL-10, IFN-γ, and TNF-α, but not IL-2, decreased in the presence of CB. These results suggest that exposure to asbestos potentially suppresses the differentiation of cytotoxic T lymphocyte, accompanied by decreases in IFN-γ and TNF-α.

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.

Respiratory disease in workers handling cross-linked water-soluble acrylic acid polymer.

Eight workers involved in packing cross-linked water-soluble acrylic acid polymer, an organic substance, developed pulmonary fibrosis, and the upper lobe was the most affected. The dust concentration in the polymer packing workstation was measured. Chest computed tomography (CT) was obtained for 82 individuals, including the 8 workers mentioned above. Three workers were histopathologically examined. In six of these eight workers, central pulmonary fibrosis and secondary bulla formation caused pneumothorax. Histopathologically, multiple centrilobular fibrotic foci were observed. Chest CT revealed centrilobular nodular opacity and interlobular septal thickening, suggesting early lesions in the workers because the dust concentration was remarkably high. Although the pathogenesis of the disease is unclear, we reported the occurrence of pulmonary fibrosis caused by the exposure to cross-linked water-soluble acrylic acid polymers in humans as it has not been reported earlier.

[Allergy and immunotoxicology in preventive and clinical medicine from theory to practice: Occupational allergy and isocyanate-induced asthma].

Genetic and environmental factors and their interactions cause diseases and deteriorate health (Genetic and Environmental Interaction). Exposure to environmental factors plays a major role in the deterioration of health in the workplace.Occupational asthma (OA) is a common disorder in the workplace. Approaches to OA are well described and discussed in "Japanese Guideline for Diagnosis and Management of Occupational Allergic Diseases" by the Japanese Society of Occupational and Environmental Allergy. According to the guideline, OA and work-aggravated asthma comprise work-related asthma, and OA can be further divided into two disease entities: sensitizer-induced OA and irritant-induced OA. The guidelines also describe diagnostic and therapeutic strategies for OA. Since a definitive diagnosis of OA requires a comprehensive decision based on a detailed interview on clinical symptoms related to employment status and clinical tests, including inhalation tests of suspected substances as needed, the possibility of OA should be considered as the first step toward diagnosis of the patient. Otherwise, OA may not be diagnosed. Therapeutic strategies include exposure avoidance, environmental arrangements in the workplace, utilization of social resources for workers, and conventional pharmacotherapy for asthma.Artificially synthesized small compounds are used in various industries and can cause allergies. For example, isocyanates are small compounds in the -NCO group, which have been toxicologically studied. It was later shown that isocyanate could cause various nontoxic adverse health effects, including allergic reactions. Since small agents with low molecular weights bind to proteins, detecting their specific immunoglobulin E (IgE) antibodies targeting small compounds is generally difficult. In contrast, isocyanate-specific IgE antibodies are detectable in individuals with isocyanate allergies.Suspecting OA is essential in cases exposed to newly synthesized compounds, or to those that are already known but applied to new uses, which can be better understood and predicted by studying the health effects of isocyanates.Academic interest in various issues related to allergies, immunology, and toxicology in the workplace includes clinical medicine, epidemiology, and epigenetics related to environmental exposure. Further advanced research in these areas is necessary and promising.

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.

Identification of anti-SARS-CoV-2 agents based on flavor/fragrance compositions that inhibit the interaction between the virus receptor binding domain and human angiotensin converting enzyme 2.

Coronavirus disease 2019 (COVID-19) pandemic poses a threat to human beings and numerous cases of infection as well as millions of victims have been reported. The binding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor binding domain (RBD) to human angiotensin converting enzyme 2 (hACE2) is known to promote the engulfment of the virus by host cells. Employment of flavor/fragrance compositions to prevent SARS-CoV-2 infection by inhibiting the binding of viral RBD (vRBD) to hACE2 might serve as a favorable, simple, and easy method for inexpensively preventing COVID-19, as flavor/fragrance compositions are known to directly interact with the mucosa in the respiratory and digestive systems and have a long history of use and safety assessment. Herein we report the results of screening of flavor/fragrance compositions that inhibit the binding of vRBD to hACE2. We found that the inhibitory effect was observed with not only the conventional vRBD, but also variant vRBDs, such as L452R, E484K, and N501Y single-residue variants, and the K417N+E484K+N501Y triple-residue variant. Most of the examined flavor/fragrance compositions are not known to have anti-viral effects. Cinnamyl alcohol and Helional inhibited the binding of vRBD to VeroE6 cells, a monkey kidney cell line expressing ACE2. We termed the composition with inhibitory effect on vRBD-hACE2 binding as "the molecularly targeted flavor/fragrance compositions". COVID-19 development could be prevented by using these compositions with reasonable administration methods such as inhalation, oral administration, and epidermal application.

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.

Reduction of CXC chemokine receptor 3 in an in vitro model of continuous exposure to asbestos in a human T-cell line, MT-2.

Because patients with silicosis who are chronically exposed to silica particles develop not only pulmonary fibrosis, but also complications involving autoimmune diseases such as rheumatoid arthritis and systemic sclerosis, exposure to asbestos may affect the human immune system. This immunologic effect may impair antitumor immune function because cancer complications such as lung cancer and malignant mesothelioma are found in patients exposed to asbestos. To elucidate the antitumor immune status caused by CD4(+) T cells exposed to asbestos, an in vitro T-cell model of long-term and low-level exposure to chrysotile asbestos was established from a human adult T-cell leukemia virus-1-immortalized human polyclonal T cell line, MT-2, and the resulting six sublines showed resistance to asbestos-induced apoptosis after more than 8 months of continuous exposure. The results of DNA microarray analysis showed that the expression of 139 genes was altered by long-term and low-level exposure to asbestos, and the profile was almost similar among the six sublines when compared with the original MT-2 cells that had never been exposed to asbestos. Pathway and network analysis indicated a down-regulation of IFN-γ signaling and expression of CXC chemokine receptor 3 (CXCR3) in the sublines, whereas ELISA and flow cytometry analysis demonstrated a reduction in Th1-related IFN-γ production and cell-surface CXCR3 expression. These findings suggest that chronic exposure to asbestos may reduce antitumor immune status in CD4(+) T cells, and that an in vitro T-cell model may be useful in identifying molecules related to the impairment of antitumor immune function.

Asbestos induces reduction of tumor immunity.

Asbestos-related cancers such as malignant mesothelioma and lung cancer are an important issue in the world. There are many conflicts concerning economical considerations and medical evidence for these cancers and much confusion regarding details of the pathological mechanisms of asbestos-induced cancers. For example, there is uncertainty concerning the degree of danger of the iron-absent chrysotile compared with iron-containing crocidolite and amosite. However, regarding bad prognosis of mesothelioma, medical approaches to ensure the recognition of the biological effects of asbestos and the pathological mechanisms of asbestos-induced carcinogenesis, as well as clinical trials to detect the early stage of mesothelioma, should result in better preventions and the cure of these malignancies. We have been investigating the immunological effects of asbestos in relation to the reduction of tumor immunity. In this paper, cellular and molecular approaches to clarify the immunological effects of asbestos are described, and all the findings indicate that the reduction of tumor immunity is caused by asbestos exposure and involvement in asbestos-induced cancers. These investigations may not only allow the clear recognition of the biological effects of asbestos, but also present a novel procedure for early detection of previous asbestos exposure and the presence of mesothelioma as well as the chemoprevention of asbestos-related cancers.