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Overview of Immune Tolerance Strategies
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Charles J. Hackett, Helen Quill
Lymphocytes leaving the thymus or bone marrow and circulating in the body are not activated until called into action by a process that involves a series of signaling steps in response to foreign antigens. For T cells, binding of the TCR to peptide-MHC alone is insufficient; a simultaneous signal from another group of cell-surface molecules, termed costimulatory molecules, must also be present.6These costimulatory molecules include B7-1 (CD80) and B7-2 (CD86), which are expressed on surfaces of activated APC. B cells require sufficient antigen to aggregate their BCRs, and most B cells also require signals from activated “helper” T cells in order to develop into potent antibody secreting cells.1
Alternative skin sensitization prediction and risk assessment using proinflammatory biomarkers, interleukin-1 beta (IL-1β) and inducible nitric oxide synthase (iNOS)
Published in Journal of Toxicology and Environmental Health, Part A, 2019
Min Kook Kim, Kyu-Bong Kim, Hyung Sik Kim, Byung-Mu Lee
In this regard, the Organization for Economic Co-operation and Development (OECD) designed the adverse outcome pathway (AOP) to classify the process of skin sensitization into individual steps and described the mechanism of skin sensitization for each step (OECD 2012a, 2012b). First, the skin sensitizer penetrates the stratum corneum of the skin and undergoes haptenation processes where it covalently binds to the skin protein of the epidermis (Reisinger et al. 2015). Haptenation is a characteristic molecular event attributed to skin sensitizers (Aptula and Roberts 2006). Based upon this skin sensitization potency might be initially predicted by measuring peptide reactivity of test substances and synthetic peptides such as synthetic lysine and synthetic cysteine (Gerberick et al. 2009, 2004, 2007). The direct peptide reactivity assay (DPRA) and the peroxidase peptide reactivity assay (PPRA) are representative methods. Secondly, haptenated skin sensitizers activate keratinocytes (KC) and dendritic cells (DC) (Reisinger et al. 2015). Activated KC and DC trigger an immune response that leads to activation of pro-inflammatory cytokines such as interleukin (IL)-18, and costimulatory molecules such as cluster of differentiation (CD) 54 and CD 86 (Novak et al. 1999; Roggen 2014; Toebak et al. 2009). As a result, another method of predicting skin sensitization potency involves measuring the degree of change in levels of cytokines and costimulatory molecules induced by a test substance in an appropriate cell line (Ade et al. 2006; Bauch et al. 2012; Corsini et al. 2009; Galbiati et al. 2011; Nukada et al. 2012; Reuter et al. 2011; Sakaguchi et al. 2009). The NCTC 2544 IL-18 assay, human cell line activation test (h-CLAT), myeloid U937 skin sensitization test (MUSST), and peripheral blood monocyte-derived dendritic cell assay (PBMDC) are representative methods. Thirdly, the DC activated by skin sensitizers acts as antigen-presenting cells (APCs), which migrate to the lymph nodes and induce proliferation of T cells (Kim et al. 2018a; Reisinger et al. 2015). With reference to this mechanism, there is a method of predicting skin sensitization potency, which involves determining the degree of proliferation of T cells induced by the test substance and oxidative stress (Corsini et al. 2013; Vocanson et al. 2008). Finally, activated T cells produce immune reactions when the skin sensitizer is re-exposed to the body, resulting in skin sensitization reactions such as inflammation (Banchereau and Steinman 1998).