Immunologically Mediated Diseases and Allergic Reactions
Julius P. Kreier in Infection, Resistance, and Immunity, 2022
Upon reexposure to the allergen, the Langerhans′ cells again process and present the antigen to the primed T cells, which initiate the elicitation phase of DTH in the skin. Activated, memory T cells release a number of soluble mediators termed cytokines. In particular, interferon gamma (IFNγ) activates macrophages and enhances their ability to eliminate the antigen. IFNy increases phagocytosis, antigen presenting efficiency, and microbicidal activity. Because it is a potent macrophage activating cytokine, IFNy is the most potent mediator of DTH reactions. IFNγ also increases the expression of adhesion molecules on endothelial cells and potentiates the release of proinflammatory cytokines and chemokines. This complex cascade of events results in the recruitment and activation of many T cells and macrophages in the local inflammatory site. Upon gross examination of the DTH reaction site, the area is erythematous and “indurated” or hard to the touch. Resolution of DTH reactions occurs after forty-eight to seventy-two hours, and the mechanism of suppression involves secretion of prostaglandin E2 and downregulatory cytokines, such as TGFβ and IL-10. Both TGFβ and PGE2 have inhibitory effects on IL-1 and IL-2 synthesis; whereas, IL-10 downregulates Class II molecules and inhibits antigen-specific proliferation of IFNy-secreting T cells.
Vaginal Immunology
William J. Ledger, Steven S. Witkin in Vulvovaginal Infections, 2017
Macrophages possess multiple TLRs and nonspecifically recognize a variety of microbial pathogens. They also possess membrane-bound receptors for complement and immunoglobulins and opsonize and destroy microorganisms that contain these components on their surface. The association of TLRs with its appropriate ligand results in activation of macrophage genes that code for proinflammatory cytokines and chemokines. Their release leads to the recruitment of T lymphocytes and the induction of pathogen-specific immunity. Once within the macrophage, ingested microorganisms are degraded, and their components become available for induction of antigen-specific acquired immunity, similar to what occurs in dendritic cells. In the lymph nodes, T lymphocytes also become activated to release the cytokine, interleukin 2 (IL-2). IL-2 induces the replication of T and B lymphocytes, resulting in the formation of a large number of lymphocytes that can recognize and respond to a specific microbial invader. Interferon gamma is also released by the activated T cells and stimulates macrophages to become more efficient in engulfing and processing microorganisms. A repertoire of T and B lymphocytes is generated (memory cells) that will recognize the specific microorganism if it should ever reappear in the future and quickly activate a cell-mediated and/or antibody-mediated immune response to prevent its proliferation and ability to cause disease.
The Role of Interferons in the Therapy of Melanoma
Ronald H. Goldfarb, Theresa L. Whiteside in Tumor Immunology and Cancer Therapy, 2020
Combinations of interferon alpha and other cytokines such as interleukin-2, tumor necrosis factor, and interferon gamma have been pursued on the basis of known immunomodulatory pathways of these cytokines. The use of combined modality therapy with interferon alpha has been of recent interest, based on the suggestion that interleukin-2 mediated effects on the host response tumor might be augmented if interferon could induce tumor cell surface antigen expression to higher levels. Early trials of interferon alfa-2 in combination with interleukin-2 suggested increased responses in melanoma and renal cell carcinoma (50–52), but toxicity of the combination was significant, and the level of ≈25% clinical activity for this regimen may not represent synergism, but subadditive activity. Given the observation that interferon response rates do not appear to be compromised by prior patient therapy, one may require synergism rather than additive effects to argue for combinations unless a survival advantage is evident.
Promising predictors of checkpoint inhibitor response in NSCLC
Published in Expert Review of Anticancer Therapy, 2020
Friedlaender Alex, Addeo Alfredo
Gene expression profiles (GEPs) can allow for a more complex and accurate analysis of the tumor microenvironment in a more precise manner than a single protein, such as PD-L1. Interferon gamma is key cytokine in the T-cell mediated immune response. However, it is also responsible for negative feedback, downregulating the inflammatory response by enabling upregulation of PD-L1 in tumor, immune and stromal cells. Cancer cells take advantage of this balance to survive. A T-cell inflamed GEP comprising 10 genes directly associated with IFN-gamma signaling was able to predict response to PD-1 blockade in melanoma [55]. In a recent GEP in NSCLC, 395 genes involved in the function of lymphocyte regulation, cytokine signaling, immune checkpoints, and tumor characterization were used to predict response to ICPIs. A composite predictive biomarker with peripheral T cell signatures (HLA-DOA, GPR18, STAT1) and the ‘’M1 signature” (CBLB, CCR7, CD27, CD48, FOXO1, FYB, HLA-B, HLA-G, IFIH1, IKZF4, LAMP3, NFKBIA, and SAMHD1), showed high sensitivity and specificity in predicting response and was able to identify patients with a median OS of 42 months, compared to 14 months in patients without these profiles [56]. These early results are promising but require prospective validation.
Biodistribution and targeting properties of iron oxide nanoparticles for treatments of cancer and iron anemia disease
Published in Nanotoxicology, 2019
Second, another application of IONP is the treatment of cancer by protein therapy. IONP can be associated or linked to proteins to favor the antitumor mechanisms such as: (i) the blocking of cell surface receptors by using for example III (EGFRvIII) antibody that inhibit the cellular receptor EGFRvIII (Hadjipanayis et al. 2010), (ii) Cyclophosphamide that decreases tumor cell proliferation (Veiseh 2009), (iii) Cytochrome c that favors tumor cell apoptosis (Santra, Kaittanis, and Perez 2010), (iv) interferon gamma (IFNγ) that triggers an anti-tumor immune activity (Mejias et al. 2008). Compared with the use of free proteins (without IONP), proteins associated with IONP should be less easily metabolized or cleared, be delivered more efficiently to cancer cells, be protected from protease degradation, or more efficiently interact with parts of cancer cells such as cell receptors by being located on IONP surface.
Aluminum hydroxide nebulization-induced redox imbalance and acute lung inflammation in mice
Published in Experimental Lung Research, 2020
Erika Tiemi Kozima, Ana Beatriz Farias de Souza, Thalles de Freitas Castro, Natália Alves de Matos, Nicole Elizabeth Philips, Guilherme de Paula Costa, André Talvani, Sílvia Dantas Cangussú, Frank Silva Bezerra
Inflammatory responses consist of coordinated activation of signaling pathways, expression and production of inflammatory mediators, and activation and trapping of inflammatory cells to the site of inflammation.43 In this study, we performed immunoenzymatic assays to verify the involvement of chemokines (CCL2) and cytokines (TNF and IFN) in the pulmonary inflammatory process. In our study, IFN-γ concentration was higher in the group exposed to aluminum hydroxide. Interferon gamma is recognized as the major cytokine involved in the activation of macrophages and is produced by lymphocytes, particularly natural killer (NK) cells, and by subsets of T cells.44–46 Davis et al. observed an increase in IFN production by different lymphocyte phenotypes in mice with silicosis.47 In our study, the increase in IFN may be related to a greater presence of lymphocytes in the pulmonary parenchyma and suggest that this cytokine is involved in the inflammatory response triggered by exposure to aluminum.
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