National Institute of Radiological SciencesJapan
Part of the book: Malignant Mesothelioma
Part of the book: Immune Response Activation
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.
Part of the book: Natural Killer 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.
Part of the book: Cytotoxicity
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.
Part of the book: Asbestos-related Diseases