Suppressed Immune System Caused by Exposure to Asbestos and Malignant Mesothelioma

Mesothelioma is the most serious of the asbestos-related diseases. It is caused by exposure to relatively low doses of asbestos and takes a long period to develop, which suggests the enactment of gradual adverse effects other than cellular toxicity. The immune system, which can play a role in tumor prevention, is a presumable target of asbestos by accumulation in lymph nodes and then slowly affecting functions of immune cells. Here, we describe key findings obtained from our studies concerning the immune-suppressive effects of asbestos and functional alteration in immune cells of patients with mesothelioma as well as plaque-positive subjects. Asbestos exposure of cell cultures resulted in decreased natural and acquired cytotoxicity exerted by NK cells and CTLs and the ability of Th1 cells to activate and support antitumor immunity. In contrast, asbestos exposure augmented Treg cell function and generation of fibrogenic/suppressive macrophages. Mesothelioma patients also showed similar characteristics in certain alterations caused by asbestos exposure. Additionally, our recent study established immunological screening devices for mesothelioma and asbestos exposure on the basis of comprehensive analysis of peripheral blood. Those findings underscore the importance of the immunological effects of asbestos and should assist further understanding of the mechanism and early detection of mesothelioma

Immune Alteration Caused by Fibrous and Particulate Environmental Substances

Fibrous and particulate environmental substances such as asbestos fibers and silica particles cause not only lung fibrosis but also various health disturbances. Asbestos induce malignant tumors such as pleural mesothelioma and lung cancer. Silicosis patients exposed to silica particles show complications of various autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, and antineutrophil cytoplasmic antibody (ANCA)-related vasculitis/nephritis. The causative alteration of immune cells exposed to these environmental substances may form baseline modification of human immune system not only localized pulmonary lesions, alteration of alveolar macrophages, and others but also general immune system and changes of function in effector, regulatory, and cytotoxic T cells and natural killer cells. In this review, both (localized and generalized) immune alterations caused by environmental fibrous and particulate substances are summarized and reported

A New Method to Determine Natural Killer Cell Activity Without Target Cells

Natural killer (NK) cell activity is a conventional parameter used to determine the performance lytic activity against tumor as well as virus-infected cells in innate immunity. However, use of this parameter has several problems related to bioassay measurements. To measure NK cell activity, target cells and cell culture equipment are required and adequate pre-culture of target cells is needed to maintain constant sensitivity for NK cells. NK cell-activating receptors play an important role in the recognition of targets, which transduce the signals necessary for cellular machinery to induce target injury and cytokine production. We statistically examined the parameters related to the NK cell activity of human peripheral blood mononuclear cells (PBMCs) by multiple regression analysis, and obtained a formula with NK cell % and RNA levels of two genes in isolated NK cells. The score calculated using this formula with the three measured values showed significant correlation with NK cell activity. This prediction score, named the non-incubating natural killer (NINK) score, which is independent of target cells, is not affected by inappropriate preparation of those targets, and allows us to accurately compare the performance of NK cell activity among specimens

Alteration of Various Lymphocytes by Particulate and Fibrous Substances

Various occupational and environmental substances alter the cellular and molecular function of the human lymphoid system. For example, silicosis patients who have been chronically exposed to silica particles often complicate with autoimmune diseases such as rheumatoid arthritis and systemic sclerosis. From our investigations, silica particles affect CD4+ responder T cells and regulatory T cells (Tregs), which results in the disruption of autoimmunity. Asbestos fibers are a type of mineral silicate, and patients exposed to asbestos fibers revealed cancers such as mesothelioma and lung cancer. In these cases, asbestos fibers may reduce antitumor immunity. Our results investigating the effect of asbestos on cytotoxic T lymphocyte, natural killer (NK) cells, CD4+ cells, and Tregs revealed a reduction in antitumor immunity. To date, the effects of silica and asbestos on Th17 cells and antigen-presenting cells such as dendritic cells and macrophages remain unclear. Based on these findings, it will be possible to generate earlier detection methods to identify the occurrence of immune alterations in silicosis as well as the appearance of a decreased antitumor immunity in asbestos-exposed populations. Additionally, research efforts should also be directed at discovering and identifying physiological substances from foods, plants, and other sources that can restore the immune status in people exposed to particulate and fibrous substances

Toxicity of Titanate Nanosheets on Human Immune Cells

Titanium oxide is regarded as a bio-inert material, but studies concerning the toxic effects of titanium dioxide (TiO2), particularly nano-scaled TiO2 particles, have been accumulating that indicate nano-scaled TiO2 particles show more harm and cause greater alteration of immune functions compared with large particles. Inorganic nanosheets have been the focus of increasing interest because of their ultrathin structure, as well as diversity of compounds and structures leading to various functions. Oxide nanosheets are included in the group comprising inorganic nanosheets, and titanate nanosheets (TiNSs) represent a form of oxide nanosheets. We therefore examined the toxicity of nano-scaled 2D materials of TiNSs on human immune cells. Our study revealed that TiNSs have the potential to cause harm through caspase-dependent apoptosis of human peripheral blood mononuclear cells (PBMCs) to the same degree as asbestos. Furthermore, isolated monocytes developed marked vacuoles prior to cell death upon exposure to TiNSs, which were found in the vacuoles and indicated engulfment of TiNSs. A consideration of these findings with the co-localization of vacuoles with endocytosed fluorescence-labeled dextran indicates that TiNSs entered the endosomal pathway, leading to the formation of vacuoles in monocytes and subsequent cell death. TiNSs might therefore affect immune functions through interference of endo-lysosomal functions

Biological Effects of Negatively Charged Particle-Dominant Indoor Air Conditions

To identify health-promoting indoor air conditions, we developed negatively charged particle-dominant indoor air conditions (NCPDIAC). Experiments assessing the biological effects of NCPDIAC comprised (1) 2.5-h stays in NCPDIAC or control rooms, (2) 2-week nightly stays in control followed by NCPDIAC rooms, (3) 3-month OFF to ON and ON to OFF trials in individual living homes equipped with NPCDIAC in their sleeping or living rooms, and (4) in vitro assays comparing the immune effects between negatively charged particle-dominant and control cell culture incubators. The most significant difference examined between NCPDIAC and control rooms in the 2.5-h stays was an increase in interleukin (IL)-2 with occupancy of the NCPDIAC room. For the 2-week nightly stay experiments, natural killer (NK) cell activity increased with occupancy of the NCPDIAC room. The 3-month OFF to ON trial showed an increase in NK cell activity, while the ON to OFF trial yielded a decrease in NK cell activity. Additionally, the in vitro assays also showed an increase in NK cell activity. The use of NCPDIAC resulted in increased NK cell activity, which has the effect of enhancing immune surveillance for the occurrence of cancer and improving symptoms associated with viral infections

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

Cytotoxicity Caused by Asbestos Fibers and Acquisition of Resistance by Continuous Exposure in Human T Cells

The cytotoxic effects of asbestos fibers on human T cells and the acquisition of resistance against asbestos-induced apoptosis have been studied. These analyses are based on the establishment of a continuous and relatively low-dose exposure model of human immune cells exposed to asbestos that resembles actual exposure in the human body. The MT-2 T cell line was selected as the candidate for the investigations. A transient and high-dose exposure to chrysotile resulted in apoptosis with production of reactive oxygen species (ROS) and activation of the mitochondrial apoptotic pathway. However, sublines continuously exposed to low dose of asbestos exhibited resistance to asbestos-induced apoptosis. The mechanism of resistance acquisition involved excess production of IL-10, activation of STAT3, and enhanced expression of Bcl-2 located downstream of STAT3. These changes were also found in a subline continuously exposed to crocidolite. Furthermore, sublines showed a marked decrease in the expression of forkhead box O1 (FoxO1) transcription factor. FoxO1 is known to regulate apoptosis and various other cellular processes. Regarding apoptosis, sublines continuously exposed to asbestos showed reduction of FoxP1-driven proapoptotic genes. This pathway is also considered one of the mechanisms that result in resistance to asbestos-induced apoptosis in sublines. These sublines also exhibited several characteristics suggesting reduction of antitumor immunity

Immunological Risks Caused by Fibrous and Particulate Substances

The immunological risks caused by fibrous and particulate substances, especially the effects caused by asbestos fibers and silica particles, are discussed in this chapter. Patients with silicosis often suffer from autoimmune diseases, such as rheumatoid arthritis, systemic sclerosis, and antineutrophil cytoplasmic antibody–related vasculitis. Silica particles, SiO2, may influence directly various immune cells resulting in the production of many autoantibodies and imbalance between responder and regulatory T cells. The core chemical content of asbestos fibers is Si and O, although the physical feature is different. Considering the complications in asbestos-exposed patients, malignant tumors, such as lung cancer and malignant mesothelioma, are the most important. To think about these situations, asbestos fibers may cause the reduction of antitumor immunity. The experimental findings and measurements of various immunological parameters in silicosis patients, as well as asbestos-exposed population, such as patients with pleural plaque and mesothelioma, are demonstrated and discussed in this chapter