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Enzymes for Prodrug-Activation in Cancer Therapy
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Higher generation CARs are additionally equipped with costimulatory molecules such as CD27, CD 28 or CD137. Co-stimulation is essential for T cell proliferation, differentiation, and survival and determines significantly the result of a T cell’s encounter with an antigen. Co-stimulation signals are generated from the interaction of receptors on the T cells’ surface with ligands on antigen-presenting cells. T cell stimulation by CD28 (the receptor for CD80 (B7.1) and CD86 (B7.2) proteins) is among others involved in the production of various interleukins (e.g., IL-2, IL-6). CD80 expression is upregulated in antigen presenting cells (APCs) via Toll-like receptors, whereas CD86 expression on APCs is constitutive. However, CD80 and CD 86 are missing in many cancer cells with the consequence to fail to respond to their specific antigen (T cell anergy) so that co-stimulation is indispensable for full T-cell activation which is achieved by combining the intracellular signaling domain of CD28 to CD3ζ in one polypeptide chain of the same second-generation CAR. In addition, costimulatory molecules like CD 137, a member of the tumor necrosis factor receptor (TNFR) superfamily family expressed on activated CD8+ T cells can be integrated in first- or second-generation CARs to give a third-generation one. Altogether these CAR-modifications serve to preserve survival and prolong polyclonal expansion of engineered T cells contributing to an increased amplification which results in prolonged T-cell persistence and an improved anti-tumor attack (Chmielewski et al., 2013). According to Sommermeyer et al. (2016) chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ (T helper cells) subsets confer superior antitumor reactivity in vivo.
Effects of life-stage and passive tobacco smoke exposure on pulmonary innate immunity and influenza infection in mice
Published in Journal of Toxicology and Environmental Health, Part A, 2022
Lei Wang, Maya Rajavel, Ching-Wen Wu, Chuanzhen Zhang, Morgan Poindexter, Ciara Fulgar, Tiffany Mar, Jasmine Singh, Jaspreet K. Dhillon, Jingjing Zhang, Yinyu Yuan, Radek Abarca, Wei Li, Kent E. Pinkerton
The resistance of the FA+IAV adult group, but not neonates, to virally-induced inflammation (Figure 3) might be a result of the immature immune systems of the neonates. You et al. (2008) concluded in their study that the adaptive immune system of younger mice was far weaker than that in older mice. Due to exposure to fewer pathogens, neonates, who have not been exposed to as many diseases, have immature adaptive immune systems, notably with fewer developed adaptive T cells (Simon, Hollander, and McMichael 2015; You et al. 2008). This is supported in the present study by the innately skewed immune response, in which a lower number of influxing lymphocytes and higher number of resident macrophages in the BALF were detected in neonatal mice compared to adults (Figure 3). Coates et al. (2015) demonstrated that antigen-presenting cells (e.g., macrophages) in the pediatric innate immune system tend to be less stimulatory when challenged with Toll-like receptor (TLR) agonists, which dampened responses leading to decreased antigen presentation and T cell co-stimulation relative to adults. Neutrophil generation of reactive oxygen species (ROS) and extracellular traps, which enable neutrophils to bind and kill pathogens, was also noted to be reduced in neonates compared to adults (Lawrence, Corriden, and Nizet 2017). These immature adaptive responses characteristic of a developing immune system also contribute to the increased morbidity of children upon infection with influenza. Overall, the outcomes indicate that because the neonatal adaptive immune system lacks some of the benefits of successfully combating prior pathogenic challenges (e.g., memory T cells and B cells), immune responses to viral (e.g., IAV) infection are compensatively skewed toward nonspecific innate defenses. In adult mice, perhaps prior ETS exposure weakened the immune system and enhanced susceptibility, inducing as large an influx of immune cells as seen in the neonates (Figures 3 and 4).