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Immunology of Allergic Diseases
Published in Pudupakkam K Vedanthan, Harold S Nelson, Shripad N Agashe, PA Mahesh, Rohit Katial, Textbook of Allergy for the Clinician, 2021
Airway epithelium influences DC function and thus T cell differentiation. Airway ECs produce CCL2 and CCL20 in response to house dust mite inhalation and attract monocytes and immature DCs to the lung. Triggering of TLR 4 on ECs by dust mite also induces production of thymic stromal lymphopoietin (TSLP), GM-CSF, IL-25 and Il-33. These innate cytokines have pleiotropic effects. They share the propensity to activate DCs and prime TH2 responses, by inducing chemokines that attract TH2 cells or upregulating expression of surface molecules such as OX40L that facilitates TH2 development (Lambrecht and Hammad 2012). In addition, TSLP inhibits the production of the Th1 polarizing cytokine IL-12. The expression of TSLP is increased in bronchial biopsies and sputum from humans who have asthma, particularly in severe disease (Ying et al. 2005, Semlali et al. 2010). Further; genetic polymorphisms in the promoter region of TSLP are associated with increased risk of asthma. Diesel exhaust fumes, cigarette smoke and proteolytic allergens induce epithelial cells to produce TSLP. TSLP activates not only DCs but also other innate cells such as basophils, mast cells, eosinophils and innate non-T and non-B cells called innate lymphoid cells or nuocytes (Neil et al. 2010, Saenz et al. 2010). Basophils are an early source of IL-4 and enhance TH2 development initiated by DCs. Nuocytes are IL-25 and IL-33 responsive and produce IL-5 and IL-13 and thus contributes to eosinophilia, goblet cell metaplasia and airway hyper responsiveness (Chang et al. 2011).
Mucosal vaccine strategies
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Nils Lycke, Jan Holmgren, Harry B. Greenberg
Today we have fairly precise information about signals necessary for the stimulation of adaptive immune responses. This involves the stepwise stimulation of naive T cells through recognition by the T-cell receptor of major histocompatibility complex (MHC) class I or II together with peptide, and the more complicated second signals that are provided by cytokines and costimulatory molecules on the membranes of antigen-presenting cells (APCs). Costimulatory molecules such as CD40, CD80, CD86, and OX40L have been found critical for driving T-cell–dependent immune responses. The linking of innate responses to the induction of adaptive immunity is the key to understanding how to construct effective mucosal vaccines. It is noteworthy that while we have a wealth of data relevant to the induction and preservation of an immune response (both systemic and mucosal) in animals, there is a significant lack of mechanistic data as to how this information pertains to the performance of licensed vaccines in humans (Table 30.1).
New Approaches for Optimizing Melanoma Vaccines
Published in Sanjiv S. Agarwala, Vernon K. Sondak, Melanoma, 2008
Nasreen Vohra, Shari Pilon-Thomas, James J. Mulé, Jeffrey Weber
The frequency of precursor T cells with antitumor activity is low in patients with advanced cancers, and those cells often have a naïve phenotype (4). The goal of current vaccination strategies against melanoma is to activate and expand tumor-reactive T cells as an effective means of immunity. Activation of tumor-specific T cells requires presentation of peptides derived from melanoma-associated antigens. Most melanoma-associated antigens such as tyrosinase, gp100, and MART-1 are nonmutated proteins expressed exclusively by melanocytes. For a vaccine to be effective, antigens must be taken up by professional antigen presenting cells (APC), such as dendritic cells (DC). Immature DC, which reside mainly in peripheral tissues, are characterized by the ability to efficiently internalize and process antigen, but demonstrate low T cell stimulatory capacity. The captured antigens are targeted either to the proteasome or endocytic pathway where they are degraded into peptides. The resulting peptides are bound to major histocompatibility complex (MHC) class I molecules and presented to CD8+CTL or MHC class II molecules and presented to CD4+ helper T cells. As immature DC acquire antigens at the vaccination site, they may also come in contact with vaccine-associated bacterial DNA or viral vectors, immune-stimulating adjuvants, or activated T cells. These interactions lead to DC maturation and migration to the draining lymph nodes. The process of DC maturation results in diminished antigen uptake, downregulation of chemokine receptor expression, and the enhanced ability to interact with naïve T lymphocytes through upregulation of MHC class I and class II and costimulatory molecules such as CD80 and CD86. After antigen uptake and migration to secondary lymphoid tissues, DC educate naïve T cells for the induction of effective primary immune responses and immunologic memory. Terminal maturation of the DC is completed by reciprocal interactions with activated T cells via cognate surface receptors such as 4-1BB/4-1BBL, CD40/CD40L, and OX40/OX40L (5–7).
Cutaneous leishmaniasis: multiomics approaches to unravel the role of immune cells checkpoints
Published in Expert Review of Proteomics, 2022
Yasaman Taslimi, Nasrin Masoudzadeh, Fariborz Bahrami, Sima Rafati
OX40 (a.k.a. TNFRSF4, CD134) and its ligand (OX40L; a.k.a. CD134L and CD252) are expressed on different lymphocytes such as activated B-cells, activated NK, macrophages, DC, mast cells, activated T-cells and Foxp3+ Treg, as well as endothelial and microglial cells; however, it is not expressed on the resting APC [52]. It has been reported that OX40/OX40L signaling can stimulate follicular helper T- cells (TFH) differentiation and survival. Furthermore, their signaling can enhance the function of TFH with respect to B-cells [53]. In addition, OX40/OX40L enhance T-cell expansion and proliferation while decreasing the immunosuppression effect of Treg which together shape an enhanced antigen-specific immune response [54]. An in-vivo study on CL due to L. major in a murine model has shown that OX40/OX40L can induce Th2 response but not during infections due to L. mexicana [55]. In another study, using OX40-Fc alone and together with anti-cytotoxic T lymphocyte attenuator 4 (CTLA-4) as therapeutic strategies for L. donovani-infected C57BL/6 mice have pointed to increased levels of granuloma maturation and CD4+ T-cell proliferation, leading to the parasite killing [56]. Although this pathway has been reported to have potentials for regulating the immune response against leishmaniasis, its mode of action in different Leishmania species requires further investigation [51].
Immune checkpoint inhibitors: a new landscape for extensive stage small cell lung cancer treatment
Published in Expert Review of Respiratory Medicine, 2021
Andrea Bianco, Vito D’Agnano, Maria Gabriella Matera, Luigi Della Gravara, Fabio Perrotta, Danilo Rocco
OX40 (TNFRSF4/CD134), another co-stimulatory TNF receptor superfamily member, has lately come into the focus of clinical research. Whilst the main sources of OX40 have been reported to be both activated CD4+ and CD8 + T cells, ligands of OX40 may be found on professional APCs. However, once stimulated by inflammatory mediators, other cell types, such as NK cells, mast cells or endothelial cells may express OX40L [81–83]. OX40/OX40L axis seems to play a crucial role in the activation and proliferation of T cells by enhancing expression of multiple cytokines, such as interleukin (IL)-2 and related receptors. Interestingly, in immune cell infiltrates of tumor samples from patients with surgically resected stage I–IIIA NSCLC, OX-40 protein expression detected by immunohistochemistry (IHC) has prognostic significance for improved OS [84]. In murine models, OX-40 agonists combined with other immunomodulating agents showed greater effects compared to agents alone [85].
Prolongation of allograft survival by artemisinin treatment is associated with blockade of OX40-OX40L
Published in Immunopharmacology and Immunotoxicology, 2021
Lihua Liu, Juanzhi Zhao, An Li, Xuan Yang, Ben Sprangers, Shengqiao Li
T cells play a dominant role in allograft rejection. In order to investigate the inhibitory effect of ART on T cell activation, we selectively studied the proportion of OX40+ T cells in this study. OX40-OX40L is a positive co-stimulatory pathway in T cell activation, which promotes T cell survival, increases effector and memory T cell differentiation and inhibits regulatory immune responses [42]. To our knowledge, this is the first study suggesting that the OX40-OX40L pathway is affected by ART-mediated immunosuppression. Data from our in vitro experiments demonstrate that use of ART results in a reduced expression of OX40+ on T cells in a dose-dependent manner. Moreover, in vivo ART treatment results in a reduced proportion of CD4+OX40+ cells among CD4+ cells although the difference with control mice was not significant possibly due to the low solubility of ART. We hypothesize that improving the solubility or bioactivity of ART derivatives will enhance the further development of ART as an immunosuppressive agent since a recent study demonstrated that the peak concentration in blood was 947 ng/mL (about 3.3 µmol/L) after ART oral administration with a dose of 100 mg/kg [43].