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Simvastatin Reduces Protection and Intestinal T cell Responses Induced by a Norovirus P Particle Vaccine in Gnotobiotic Pigs
Published in Lijuan Yuan, Vaccine Efficacy Evaluation, 2022
Simvastatin has been shown to reduce the severity of several other diseases, including rheumatoid arthritis (Cojocaru et al., 2013; Kanda et al., 2007; Leung et al., 2003), multiple sclerosis (Zhang et al., 2013b), and periodontitis (Dalcico et al., 2013; Nassar et al., 2014). These pleiotropic effects can be explained by simvastatin's role in the down-regulation of IFN-induced MHC II expression by inhibition of the CIITA gene (Kwak et al., 2000; Kwak et al., 2001). This down-regulation of induced MHC II has many downstream effects, including reduced NK cell cytotoxicity (Hillyard et al., 2004; Hillyard et al., 2007), reduced in vitro T cell proliferation (Hillyard et al., 2004), reduced production of IL-2 and IFN-γ (Okopien et al., 2004), reduced CD4/CD8 and Th1/Th2 ratios (Kanda et al., 2007), increased Tregs (Mausner-Fainberg et al., 2008; Meng et al., 2012), and impaired lymphocyte homing to secondary lymphoid organs (Ulivieri et al., 2008).
The maternal immune system during pregnancy
Published in Hung N. Winn, Frank A. Chervenak, Roberto Romero, Clinical Maternal-Fetal Medicine Online, 2021
In addition, there is an absence of expression of MHC class II antigens, which appears to be caused by hypermethylation of the IFNg-responsive promoter that regulates expression of the class II transactivator (CIITA) gene. In vitro introduction of exogenous CIITA can induce cell surface expression of HLA-DR, -DP, and -DQ, leading to an acquired capacity to present antigen to antigen-specific T-helper cells (170).
Treatment of Vulnerable Plaques: Current and Future Strategies
Published in Levon Michael Khachigian, High-Risk Atherosclerotic Plaques, 2004
Leonard Kritharides, David Brieger, S. Benedict Freedman, Harry C. Lowe
A particularly important recent finding was that statins directly regulate inducible major histocompatibility complex class II (MHC-II) response in vitro.106 MHC-II molecules are involved in the activation of T lymphocytes, and the expression of MHC-II in endothelial cells and monocytes is inducible by interferon (IFN)-. This inducible expression of MHC-II is prevented by statins by virtue of direct inhibition of the promoter of transactivator molecule CIITA. This effect is independent of the lowering of LDLc and of the mevalonate pathway, suggesting an entirely novel immunomodulatory mechanism. Although it is unclear whether this observation is an important contributor to the effects of statins in humans in vivo, the mechanism of this effect may reveal novel therapeutic or pharmaceutical targets.
Pembrolizumab in the treatment of refractory primary mediastinal large B-cell lymphoma: safety and efficacy
Published in Expert Review of Anticancer Therapy, 2021
Vincent Camus, Camille Bigenwald, Vincent Ribrag, Julien Lazarovici, Fabrice Jardin, Clémentine Sarkozy
In line with this immune privilege theory, C. Steidl group discovered a highly expressed gene fusion involving the major histocompatibility complex (MHC) class II transactivator (CIITA) associated with a marked reduction of CIITA protein expression, using RNA sequencing of HL cell lines. Moreover, transduction of DLBCL lymphoma cell lines with a lentiviral vector containing the CIITA fusion led to decreased MHC II expression. Because PMBL and HL share clinical and biological features, the authors also studied PMBL and found 38% of CIITA rearrangements [36] as opposed to only 3% in DLBLC. Importantly, the presence of a CIITA rearrangement significantly correlated with a shorter disease-specific survival. This is in line with previous observation where diminished expression of HLA class II in B-cell lymphomas was linked to reduced immunogenicity, escape from immunosurveillance and inferior survival [37,38]. In addition to MHC II expression downregulation, CIITA rearrangement was associated with PDL1 and PDL2 protein overexpression, suggesting that within this reciprocal translocation, CIITA promoter drives PDL1 and PDL2 expression [36]. Overexpression of these checkpoint molecules led to inhibition of T-cell activation in vitro. Furthermore, the MHC class II down expression was also correlated with a lower CD4 and CD8 T cell infiltration in PMBL tumor samples as assessed by immunohistochemistry [39]. Additionally, PMBL tumor cells present an MHC class I membranous loss of expression, a feature also described in cHL [40].
Immunomodulation via FGFR inhibition augments FGFR1 targeting T-cell based antitumor immunotherapy for head and neck squamous cell carcinoma
Published in OncoImmunology, 2022
Michihisa Kono, Hiroki Komatsuda, Hidekiyo Yamaki, Takumi Kumai, Ryusuke Hayashi, Risa Wakisaka, Toshihiro Nagato, Takayuki Ohkuri, Akemi Kosaka, Kenzo Ohara, Kan Kishibe, Miki Takahara, Akihiro Katada, Tatsuya Hayashi, Hiroya Kobayashi, Yasuaki Harabuchi
In this study, we demonstrated that FGFR-tyrosine kinase inhibitors (TKIs) exhibited synergistic activity with ICI in the mouse HNSCC model. FGFR-TKIs amplified the expression of MHC class I and MHC class II in HNSCC cells. The upregulation of MHC class II expression was induced by CIITA, subsequent to inhibition of the FGFR/MAPK pathway. Moreover, we identified a novel FGFR1-derived peptide epitope that could generate antigen-reactive and multiple HLA-DR-restricted CD4+ T cell antitumor responses in healthy donors and HNSCC patients. Notably, we found that FGFR-TKIs augmented the antitumor effects of FGFR-reactive T cells in vitro. Overall, these results suggest that FGFR blockade is a novel and suitable combination approach with T cell-based cancer immunotherapy.
CIITA expression is regulated by histone deacetylase enzymes and has a role in α-synuclein pre-formed fibril-induced antigen presentation in murine microglial cell line
Published in Immunopharmacology and Immunotoxicology, 2022
Caner Günaydın, Z. Betül Çelik, S. Sırrı Bilge
Our study observed that administration of CUDC-907 and TMP-195 together with α-synuclein for 6 h, increased MHC-II expression, and thus there was an increase in antigen presentation functions of microglial cells. Also, the fact that this effect is more in CUDC-907, which affects more HDAC subclasses, is consistent with the literature about the effects of these subclasses on antigen presentation and immune mechanisms. Based on this information, we investigated the agents' effect, whose application time and dose were determined, on Ciita, which is accepted as the genomic regulator of MHC-II and tried to elucidate how this effect changes at the transcription level. Our results show that increasing histone acetylation with pharmacological agents increases MHC-II expression. CIITA is a transcriptional coactivator that plays a role in the occurrence of structural and post-induction MHC-II gene expression and is considered essential in antigen presentation [37]. Studies on many cell types have shown that CIITA is important for MHC-II upregulation with immune factors [38]. It has been shown in previous studies that in vivo and in vitro silencing of CIITA with lentiviral shRNAs significantly reduces MHC-II expression [30,39]. After investigating the methylation properties of CIITA, it strengthens the idea that coactivator-associated methyl transferase-1 (CARM1), a methyltransferase, is required for the structural and interferon-induced MHC-II expression. Since it has been shown that IFN-γ plays a role in the regulation of CIITA, we also investigated IFN-γ levels in our study. Our results showed that α-synuclein increases IFN-γ levels, in line with previous studies. The increase of this finding with the application of histone deacetylase inhibitors is parallel evidence to explain this effect.