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Mucosal basophils, eosinophils, and mast cells
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Edda Fiebiger, Stephan C. Bischoff
Human mast cells also likely participate in regulating lymphocyte functions during the course of allergic inflammation. Upon IgE cross-linking, mast cells produce IL-13, a cytokine that supports the production of allergen-specific IgE by B cells. The release of IL-13 can be further increased by the presence of IL-4, which is known to shift the cytokine profile produced by human mast cells away from pro-inflammatory cytokines—such as TNF-α, IL-1β, and IL-6—to TH2 cytokines, including IL-13. Human mast cells can also regulate T-cell functions through other mediators, such as PGD2 that almost exclusively derives from activated mast cells, is released during allergic reactions, and is particularly important at the onset and in the perpetuation of asthma in young adults. This lipid mediator evokes airway hypersensitivity and chemotaxis of T cells, basophils, and eosinophils through interaction with two receptors: the prostanoid DP receptor (PTGDR) on granulocytes and smooth muscle cells; and CRTH2 (chemoattractant receptor-homologous molecule expressed on TH2 cells) on TH2 cells. Furthermore, PTGDR has been identified as an asthma-susceptibility gene. Apart from PGD2, other human mast-cell mediators, such as LTB4, CCL3, and CCL4; OX40 ligand; and TNF-α, are involved in recruiting T cells and triggering T-cell–mediated adaptive immune responses, including memory induction, that enhance and perpetuate allergic reactions.
Pathophysiology of Atopic Dermatitis and Atopiform Dermatitis
Published in Donald Rudikoff, Steven R. Cohen, Noah Scheinfeld, Atopic Dermatitis and Eczematous Disorders, 2014
The induction of inflammatory Th2 cells results from the production of OX40-ligand (OX40-L) by TSLP–DCs in the absence of IL-12. If IL-12 is present, the production of inflammatory Th2 cells is blocked. It has recently been demonstrated that TSLP also has a direct effect on activated CD4+ T lymphocytes (Rochman et al. 2007). Thus, TSLP that is released by epithelial cells in response to trauma, microbes, and inflammation links the innate immune response with a polarized adaptive immune response. In addition, TSLP induces mast cells to produce Th2 cytokines such as IL-13, further contributing to the Th2 microenvironment (Allakhverdi et al. 2007).
When topical therapy of atopic dermatitis fails: a guide for the clinician
Published in Expert Review of Clinical Immunology, 2021
Giuseppe Ingrasci, Zoe M. Lipman, Gil Yosipovitch
GBR 830 and KHK 4083 are monoclonal antibodies specific for OX40 (CD 135), a co-stimulatory molecule expressed on T cells. When bound by an inhibiting antibody, OX40 is unable to interact with OX40 ligand, which prevents the activation of T cells [120]. A recent phase IIa clinical trial of GBR 830 in patients with moderate-to-severe AD reported a clinical improvement in AD clinical lesions, a reduction in serum biomarkers of AD disease severity, and a similar distribution of adverse events compared to placebo [121]. A phase IIb clinical trial of GBR 830 with a secondary outcome measuring the proportion of patients with moderate-to-severe AD who achieve a peak pruritus NRS decrease of more than 4 from baseline is currently underway [122]. A phase II study of KHK 40483 for patients with moderate-to-severe AD measuring the percent change in peak pruritus from baseline as a secondary outcome was recently completed, but the results of the study are still pending [123].
Prognostic significance of OX40+ lymphocytes in tumor stroma of surgically resected small-cell lung cancer
Published in OncoImmunology, 2021
Hiroshi Yokouchi, Hiroshi Nishihara, Toshiyuki Harada, Toraji Amano, Takayuki Ohkuri, Shigeo Yamazaki, Hajime Kikuchi, Satoshi Oizumi, Hidetaka Uramoto, Fumihiro Tanaka, Masao Harada, Kenji Akie, Fumiko Sugaya, Yuka Fujita, Kei Takamura, Tetsuya Kojima, Mitsunori Higuchi, Osamu Honjo, Yoshinori Minami, Naomi Watanabe, Masaharu Nishimura, Hiroyuki Suzuki, Hirotoshi Dosaka-Akita, Hiroshi Isobe
OX40, also known as CD134, is a member of the tumor necrosis factor superfamily. It resides on the surface of various immunological cells such as activated T lymphocytes and regulatory T cells (Tregs). OX40 engagement via the OX40 ligand (OX40L) mediates antitumor immunity via anti-apoptotic protein induction, effector T cell stimulation, and Treg suppression.6 However, conflicting clinical observations have been reported in this regard. Specifically, the infiltration of OX40+ T cells in tumors was related to better survival in patients with colon cancer7 and non-small cell lung cancer (NSCLC),8 but worse survival was observed in patients with hepatocellular carcinoma.9 Investigators, including us, have attempted to enhance OX40 signaling using OX40L fusion proteins and anti-OX40 agonistic monoclonal antibodies (mAbs) either individually or in combination with ICIs, other immunotherapy, or radiotherapy to establish a novel immunotherapeutic strategy in pre-clinical and clinical settings.6,10–12 However, the OX40 expression profile in SCLC remains relatively unknown. In addition, searching ClinicalTrials.gov using the terms “SCLC” and “OX40” revealed just one ongoing clinical trial and another completed clinical trial that included patients with advanced solid tumors including SCLC who were administered agonistic anti-OX40 monoclonal antibodies (NCT02554812 and NCT03241173, respectively as of August 1st, 2021). The findings of these trials are yet to be reported.
Immune checkpoint-based therapy in myeloid malignancies: a promise yet to be fulfilled
Published in Expert Review of Anticancer Therapy, 2019
Jan Philipp Bewersdorf, Maximilian Stahl, Amer M. Zeidan
Boosting the immune response by activating co-stimulatory receptors such as 4-1BB (CD137) or OX-40 (CD134) is another promising treatment strategy. OX-40 has been shown to promote activation and proliferation of effector T-cells while suppressing the differentiation of regulatory T-cells [102,103]. In preclinical models, OX-40 agonists have been demonstrated to lead to tumor regression by stimulating cytotoxic T-cell and NK-cell activity [104]. OX40 is also expressed on AML cells, and its expression pattern varies between patients [36]. Application of tumor-necrosis factor in in vitro models could further increase OX40 expression [103]. Antibodies targeting OX40 have been successfully tested in various hematologic and solid malignancies [102,104]. A multi-arm phase I trial of the OX40 agonist PF-04518600 as monotherapy or in combination with 5-AZA, PD-1 inhibitors, or 4-1BB agonists in AML patients is currently ongoing (NCT03390296). However, OX40-ligand is highly expressed on other cells within the tumor microenvironment and the effect of this OX40–OX40L interaction needs to be further elucidated [103]. Additionally, stimulating the immune response by activating OX40 may lead to increased side effects especially when combined with other checkpoint inhibitors.