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Host Response to Biomaterials
Published in Claudio Migliaresi, Antonella Motta, Scaffolds for Tissue Engineering, 2014
Sangeetha Srinivasan, Julia E. Babensee
TCRs recognize peptide fragments of antigens bound to MHC molecules. Naive TH cells require a second signal for generation of protective effector functions post TCR stimulation.95109 This second signal is provided by ligation of costimulatory molecules with B7 molecules on APCs. Upon APC maturation, CD80 and CD86 expressions are upregulated, thus supporting their immunostimulatory ability.111 The third signal of the cytokine environment polarizes T-cells responses. Absence of the second signal leads to T-cell anergy. T-cell polarization, for example, toward TH1 or TH2 phenotypes is achieved in response to secreted IL-12 or IL-4. Regulatory T-cells or Tregs with CD4+ CD25+ CTLA4+ or TGF-^-induced CD4+ CD25- FoxP3+112 have the ability of resolving immunity and promoting tolerance with specificity to antigen. The T-lymphocyte antigen 4 (CTLA4), a molecule homologous to CD28, binds to costimulatory B7 molecules.113114
Cellular and Molecular Basis of Human Biology
Published in Lawrence S. Chan, William C. Tang, Engineering-Medicine, 2019
Dendritic Cells. These are the “professional” APCs, responsible for “presenting” part of the antigen they digested and formatted on their cell surface through a MHC class I or II receptor, leading to proliferation and the T cells that would subsequently attack the antigen-barring invaders. Dendritic cells that possess MHC Class II receptor would present antigen to CD4+ T cells (or helper T cells), whereas those possess MHC Class I receptor would only present antigen to CD8+ T cells (or cytotoxic T cells). Figure 2 illustrate schematically the interaction of a CD4+ T-cell with a MHC Class II-barring APC. Dendritic cells first engulf and digest the antigen inside their cells before they present a processed antigen on their cell surface through their surface MHC class II molecule. The T cell interacts through their surface T cell receptor (TCR) with MHC molecule of dendritic cell. This interaction is followed by co-stimulatory molecules by the dendritic cells to T cells, by ways of surface receptors CD28:CD80/CD86 and CD40L:CD40 interaction and cytokine release, leading to T cell proliferation and development into long-term memory immune responses (Fig. 2). The recent medical advancements in utilizing artificially engineered APCs to stimulate T cells for immunotherapeutic and for generation of tailored vaccine purposes underscore the significant role of dendritic cells in human medicine (Butler and Hirano 2014, Perica et al. 2014, Gornati et al. 2018). There are now 6 classified subsets of dendritic cells, each with slightly different functional characteristics (Gornati et al. 2018, Table 1). More discussions of the APCs will be included in the Precision chapter (Chapter 12).
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.
Advances of engineered extracellular vesicles-based therapeutics strategy
Published in Science and Technology of Advanced Materials, 2022
Hiroaki Komuro, Shakhlo Aminova, Katherine Lauro, Masako Harada
Immune cell-derived EVs can induce either immunostimulatory or immunosuppressive responses [93,94]. EVs isolated from various immune cells, such as dendritic cells (DC), macrophages, natural killer cells (NK), and T-cells, have reported to perform different functions in the body. Therefore, several immune cell-derived EVs are known for having therapeutic potential against immunologic diseases. For example, DC-derived EVs play a key role in adaptive immunity through CD86, CD80, MHC-I, and MHC-II presented on the EV membrane [95]. Also, T-cells-derived EVs exhibit effects of immune activation, and several studies report the inhibition of tumor progression, whereas EVs derived from regulatory T cells (Treg) do not have such functions [96]. NK cells-derived EVs carry NK-cell specific molecules such as FasL and perforin, inducing apoptosis in tumors [97]. Mature DCs-derived EVs have been shown to induce endothelial inflammation and atherosclerosis [98]. Thus, additional knowledge is needed for the selection of immune cells in EV generation for therapeutics.
IL-1α and IL-1β as alternative biomarkers for risk assessment and the prediction of skin sensitization potency
Published in Journal of Toxicology and Environmental Health, Part A, 2018
Min Kook Kim, Kyu-Bong Kim, Kyungsil Yoon, Sam Kacew, Hyung Sik Kim, Byung-Mu Lee
Keratinocytes are known to secrete cytokines including tumor necrosis factor alpha (TNF-α), interleukin (IL)-18, and interferon (IFN)-γ, in response to hapten sensitization and to stimulate DC and T cells (Roggen 2014). Dendritic cells play an important role in the process of skin sensitization through the capture of haptens and release of prostaglandin E2 (PGE2) and reactive oxygen species (ROS), both of which act as Toll-like receptor (TLR) ligands (Christensen and Haase 2012; Erkes and Selvan 2014). These ligands bind to TLR2 and TLR4 and activate the nuclear factor kappa beta (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, which induce the expression of costimulatory molecules such as cluster of differentiation (CD)54, CD80, and CD86 on the cell surface, cytokines IL-1α, IL-1β, and TNF-α, and chemokines (Corsini et al. 2013; Kim et al. 2018; Lee and Kim 2018; Novak et al. 1999; Toebak et al. 2009). Therefore, DC function as antigen-presenting cells (APC) and induce T cell activity. Activated T cells induce ACD at hapten-exposed sites through proliferative and inflammatory responses (Banchereau and Steinman 1998); that is to say, skin sensitization is the consequence of immune responses by T cells. However, the use of DC obtained from the spleen and blood cells for testing of materials is limited owing to their low acquisition rates and high cost (Van Helden, Van Leeuwen, and Figdor 2008). In addition, a long time (typically 6–9 days) is required to induce the differentiation of DC precursors to DC (Van Helden, Van Leeuwen, and Figdor 2008). Further, experiments utilizing these primary cells demonstrated variations in expression of cytokines, cell surface molecules, and T cell activation (Van Helden, Van Leeuwen, and Figdor 2008). In contrast, RAW264.7 cells are known to play a role similar to that of DC in processing external antigens and are easy to culture (Van Helden, Van Leeuwen, and Figdor 2008). To circumvent the problems associated with DC, RAW264.7 cells were selected for our investigations.
Assessing the in vitro toxicity of airborne (nano)particles to the human respiratory system: from basic to advanced models
Published in Journal of Toxicology and Environmental Health, Part B, 2023
Maria João Bessa, Fátima Brandão, Fernanda Rosário, Luciana Moreira, Ana Teresa Reis, Vanessa Valdiglesias, Blanca Laffon, Sónia Fraga, João Paulo Teixeira
As indicated previously, MucilAir™ cultures might also be established from diseased tissues, which offers the possibility to investigate the effects of (nano)particles in primary cultures from individuals with respiratory diseases. In this context, Chortarea et al. (2017) evaluated the pulmonary toxicity of occupationally relevant doses (10 μg/cm2 for 5 weeks/5 days per week) aerosolized multiwalled carbon nanotubes (MWCNT) in MucilAir™ bronchial cultures from healthy and asthmatic donors. Although no cytotoxicity or morphological changes were observed, chronic MWCNT exposure induced a pro-inflammatory and oxidative stress response in both types of cultures, accompanied by elevated cilia beating frequency and alterations in mucociliary clearance. However, the magnitude and duration of the observed effects were higher in the asthmatic compared to healthy cells, suggesting that individuals with asthma may be more susceptible to adverse effects from chronic MWCNT exposure (Chortarea et al. 2017). Donor variability is an important aspect that needs to be considered when designing and interpreting data of primary culture-based studies. In this regard, Kooter et al. (2017) examined the toxicity of aerosolized CuO NP bronchial airway MucilAir™ cultures obtained from 4 donors. Despite no major cytotoxicity occurrence, an increase in levels of IL-6 and Monocyte Chemoattractant Protein (MCP)-1 release after 24 hr exposure was found. Dankers et al. (2018) also investigated the pro-inflammatory potential of 6 metal oxide NPs (CeO2, Mn2O3, CuO, ZnO, Co3O4, and WO3; 27–108 μg/mL) in MucilAir™ cultures and dendritic cells (DC). In MucilAir™ cultures, higher secretion of IL‐6, IL‐8, and MCP-1 pro-inflammatory cytokines was found after 24 hr incubation with CuO NP droplets, while only exposure for 48 hr to Mn2O3 NP upregulated all examined DC maturation biomarkers (HLA‐DR, CD80, CD83, and CD86). Interestingly, Dankers et al. (2018) addressed the potential interaction between epithelial cells and DC by exposing the latter to MucilAir™-exposed cultures media, and found that only Mn2O3 NP triggered DC maturation, suggesting the process was not dependent upon epithelial cells stimulation (Dankers et al. 2018).