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Mechanotransduction Mechanisms of Hypertrophy and Performance with Resistance Exercise
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Andrew C. Fry, Justin X. Nicoll, Luke A. Olsen
Immune cell response and acute elevations of inflammatory proteins contribute to regulation of skeletal muscle adaptations to exercise. Cytokines secreted from skeletal muscle during muscular contractions are called myokines (160). Although numerous myokines have been described in the literature, interleukin (IL)-6, IL-8, IL-10, and IL-15 and tumour necrosis factor-α (TNF-α) are most frequently investigated. Some cytokines such as IL-6 are released from muscle independent of the degree of muscle disruption or damage (23), and the IL-6 response to resistance exercise remains preserved following chronic training (172). Others, such as IL-15, appear to play an important role in anabolism after resistance exercise (138, 146). Indeed, recent data indicate the post-exercise response of IL-15 signalling was associated with post-exercise myofibrillar protein synthesis rates, and IL-15 receptor protein content was significantly related to leg press maximal strength (138).
Intraepithelial T cells: Specialized T cells at epithelial surfaces
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Additional local factors produced by the epithelial cells, such as IL-7 and IL-15, further expand and adapt the nIETs. In the absence of IL-15 or IL-15Rα, there is a preferential loss of CD8αα+ nIETs. IL-15 operates by an unusual mechanism of trans-presentation in which IL-15 is bound to IL-15Rα intracellularly, transported to the cell surface, and presented to responding cells expressing the IL-15β and common γ-receptor chains. This mechanism is important for IET development since both IL-15 and IL-15Rα expression by the intestinal epithelium is essential for nIET development and maintenance. Notch receptor signaling and activation of c-Myc also contribute to the homeostasis of CD8αα+ nIETs, at least in part through the IL-15 receptor pathway. Stem cell factor (SCF), produced by epithelial cells, also plays an important role in their homeostasis, and most nIETs, but not iIETs, express c-Kit. While early TCRγδ nIET development is normal in SCF or SCF-receptor (c-Kit) mutant mice, this population is gradually lost with time.
Management of noncicatricial circumscribed alopecia
Published in Pierre Bouhanna, Eric Bouhanna, The Alopecias, 2015
New drug treatment opportunities, based on the results of genome-wide association studies that implicate T cell and natural killer cell activation pathways, are paving the way to new approaches in future clinical trials for alopecia areata. Currently, there are ongoing studies with the CTLA4-Ig fusion protein abatacept (blocks costimulation of T cells), anti-IL15Rβ monoclonal antibodies (blocks activation of CD8+ T cells), and the Janus Kinase (JAK) 3 inhibitor tofacitinib and JAK 1/3 inhibitor ruxolitinib (block signal transduction at the IL-15 receptor).11
Anti-CD122 antibody restores specific CD8+ T cell response in nonalcoholic steatohepatitis and prevents hepatocellular carcinoma growth
Published in OncoImmunology, 2023
Stéphanie Lacotte, Florence Slits, Beat Moeckli, Andrea Peloso, Stéphane Koenig, Matthieu Tihy, Sofia El Hajji, Quentin Gex, Laura Rubbia-Brandt, Christian Toso
Our study had some limitations, as we assessed a strong antigenic immune response far from the tumor-associated antigens. The sequences of epitopes and the levels of antigens play a crucial role in the development of the hepatic immune response.8,35 However, we were able to detect T cells with an exhausted phenotype and the tolerogenicity of ovalbumin in the context of liver immunity has been described in previous studies.35,36 Another limitation was the use of the HCC recurrence model, where the implantation of high number of cells is different of what is observed during carcinogenesis. The targeting of CD122, also known as IL-2Rb or IL-15Rb, in cancer treatment should be considered cautiously and limited to the case of underlying inflammatory liver diseases. The signaling through CD122 as a component of the high-affinity IL-15 receptor is critical for costimulation-independent memory CD8+ T cell recall.37 The clinical use of anti-CD122 in the case of tumors requiring the promotion of antigen-specific T cell response is challenging and would require more investigations. Altogether, the presented data reinforce the hypothesis that NASH alters the antitumor cytotoxic immune response through CD44+ CXCR6+ CD8+ T cells with high expression of PD-1. The antitumor response may be restored through the depletion of these cells with an anti-CD122 antibody, without worsening the underlying NASH disease.
Combination immunotherapy for pancreatic cancer: challenges and future considerations
Published in Expert Review of Clinical Immunology, 2022
Gustavo C. L. Gössling, David B. Zhen, Venu G. Pillarisetty, E. Gabriela Chiorean
NK cells which innately recognize cancer antigens even in the absence of MHC proteins, have been tested in multiple clinical trials, both as CAR-NK cell therapies and off-the-shelf allogeneic NK cells. Allogeneic NK cells exhibit greater cytotoxicity compared to autologous NK cells thus, they have been used preferentially in clinical trials. Given its role in the expansion and activation of NK cells and memory CD8 + T cells expansion, IL-15 and the IL-15 receptor α chain (IL-15:IL-15 R α) have been tested both in preclinical and clinical trials. Allogeneic PD-L1 targeting NK cells in combination with recombinant super-agonist IL-15 fusion protein N-803, GnP or liposomal irinotecan/5-FU, and stereotactic radiotherapy are being studied in advanced pretreated PDA patients (NCT04390399). Preliminary results noted OS of 6.3 months for patients treated in third line (n = 30), and 5.8 months for all patients treated in third line and beyond (n = 61) [92]. Another study is testing allogeneic NK cells in combination with PD-1/PD-L1 inhibitors with and without IL-2 in solid tumors, including PDA patients (NCT03841110).
Inhibition of urothelial carcinoma through targeted type I interferon-mediated immune activation
Published in OncoImmunology, 2019
Devin Plote, Woonyoung Choi, Sharada Mokkapati, Debasish Sundi, James E Ferguson, Jon Duplisea, Nigel R. Parker, Seppo Yla-Herttuala, SUO CTC Bladder Committee, David McConkey, Kimberly S. Schluns, Colin P. Dinney
We also examined the roles for IL-15 and inducible nitric oxide synthase (iNOS) in the IFN-I response due to the central role for IL-15 in driving IFN-mediated T cell and NK cell responses,28 and the reported use of iNOS as an anti-tumor effector produced by Ly6G+ neutrophils.29 In IL-15 receptor α deficient mice (IL15Rα-/-), both PBS and poly(I:C) treatments had similar anti-tumor effects as in WT mice indicating a minimal role for IL-15 in the poly(I:C) response (Supplementary Figure 4A). Drug-mediated inhibition of iNOS by N-iminoethyl-l-lysine (L-NIL) had no effect on tumor growth when animals were treated with poly(I:C) however, in PBS-treated mice, inhibition of iNOS reduced tumor growth (Supplementary Figure 4B). Because activation of innate cells can lead to production of IL-12, a cytokine important in the Th1 immune response and IFNγ induction,30,31 we looked at the gene expression of both IL-12 isoforms and their heterodimeric receptor and found that poly(I:C) does significantly increase IL-12p40 and IL-12Rb1 expression within tumors (Supplementary Figure 4C). Collectively these results suggest that the regulation of IL-15 or iNOS by IFN-I are not critical to the antitumor response of poly(I:C) in this model system, but there may be a role for IL-12 influencing the IFN-I induced Th1 response.