Plasmacytoid dendritic cells (pDCs) are the most potent type I interferon-producing cells and play an important role in antiviral immunity. Tumor-infiltrating pDCs were shown to be predominantly pro-tumorigenic, with reduced ability to produce interferon alpha (IFNα) and confirmed capacity to prime regulatory T cells (Tregs) by the ICOS/ICOS-L pathway. Because a significant number of HNSCCs are induced by human papillomaviruses and show markedly different immune profiles than non-virally induced tumors, we compared the phenotype and functional capacity of HNSCC-infiltrating pDCs to the HPV status of the tumor. We observed a reduced capacity of pDCs to produce IFNα upon toll-like receptor activation in HPV-negative samples and a rather uncompromised functionality in HPV-associated tumors. Additionally, supernatants from non-virally induced but not HPV-associated tumor cell suspensions significantly inhibited IFNα production by peripheral blood-derived pDCs. We identified IL-10 and TNFα as the soluble pDC-suppressive factors with the highest variability between HPV-negative and HPV-positive tumor-derived supernatants. Additionally, we observed a positive correlation of tumor-infiltrating pDCs with Tregs in HPV-negative samples but not in virally induced tumors. Overall, our study indicates that the immunosuppressive cytokine milieu rich in IL-10 and TNFα in HPV-negative but not in HPV-positive HNSCC significantly affects the functional capacity of tumor-infiltrating pDCs, and such dysfunctional pDCs may further support the immunosuppressive tumor microenvironment by promoting the expansion of Tregs in the tumor tissue.
- MeSH
- biologické markery MeSH
- cytokiny metabolismus MeSH
- dendritické buňky imunologie metabolismus patologie MeSH
- dlaždicobuněčné karcinomy hlavy a krku etiologie metabolismus patologie MeSH
- exprese genu MeSH
- infekce papilomavirem komplikace virologie MeSH
- interferon alfa imunologie metabolismus MeSH
- lidé MeSH
- náchylnost k nemoci MeSH
- nádorové mikroprostředí * imunologie MeSH
- regulační T-lymfocyty imunologie metabolismus MeSH
- studie případů a kontrol MeSH
- T-lymfocyty - podskupiny imunologie metabolismus MeSH
- virová transformace buněk MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Recombinant interferon-α (IFN-α) treatment functionally cures chronic hepatitis B virus (HBV) infection in some individuals and suppresses virus replication in hepatocytes infected in vitro. We studied the antiviral effect of conditioned media (CM) from peripheral blood mononuclear cells (PBMCs) stimulated with agonists of Toll-like receptors (TLRs) 2, 7, 8 and 9. We found that CM from PBMCs stimulated with dual-acting TLR7/8 (R848) and TLR2/7 (CL413) agonists were more potent drivers of inhibition of HBe and HBs antigen secretion from HBV-infected primary human hepatocytes (PHH) than CM from PBMCs stimulated with single-acting TLR7 (CL264) or TLR9 (CpG-B) agonists. Inhibition of HBV in PHH did not correlate with the quantity of PBMC-produced IFN-α, but it was a complex function of multiple secreted cytokines. More importantly, we found that the CM that efficiently inhibited HBV production in freshly isolated PHH via various cytokine repertoires and mechanisms did not reduce covalently closed circular (ccc)DNA levels. We confirmed our data with a cell culture model based on HepG2-NTCP cells and the plasmacytoid dendritic cell line GEN2.2. Collectively, our data show the importance of dual-acting TLR agonists inducing broad cytokine repertoires. The development of poly-specific TLR agonists provides novel opportunities towards functional HBV cure.
- MeSH
- buňky Hep G2 MeSH
- chronická hepatitida B virologie MeSH
- cytokiny metabolismus MeSH
- hepatocyty virologie MeSH
- interferon alfa metabolismus MeSH
- kruhová DNA metabolismus MeSH
- kultivační média speciální farmakologie MeSH
- lékové transportní systémy MeSH
- leukocyty mononukleární metabolismus MeSH
- lidé MeSH
- přirozená imunita účinky léků MeSH
- replikace viru účinky léků MeSH
- toll-like receptory agonisté metabolismus MeSH
- virus hepatitidy B fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Studies on Huntington's disease (HD) demonstrated altered immune response in HD gene carriers. Using multiplexing immunoassay, we simultaneously investigated seven cytokines in secretomes of microglia and blood monocytes, cerebrospinal fluid (CSF) and serum collected from transgenic HD minipigs at pre-symptomatic disease stage. Decline in IFNα and IL-10 was observed in CSF and secretome of microglia whilst elevated IL-8 and IL-1β levels were secreted by microglia. Additionally, IL-8 was increased in serum. The proportion of mutant huntingtin in microglia may have causative impact on cytokine production. IFNα, IL-10, IL-8 and IL-1β represent promising biomarkers reflecting immuno-pathological mechanisms in porcine HD model.
- MeSH
- biologické markery metabolismus MeSH
- centrální nervový systém cytologie patologie MeSH
- cytokiny metabolismus MeSH
- DNA vazebné proteiny metabolismus MeSH
- geneticky modifikovaná zvířata MeSH
- Huntingtonova nemoc genetika metabolismus patologie MeSH
- interferon alfa metabolismus MeSH
- interleukin-10 metabolismus MeSH
- interleukin-1beta metabolismus MeSH
- interleukin-8 metabolismus MeSH
- kultivované buňky MeSH
- lidé MeSH
- lipopolysacharidy farmakologie MeSH
- mikroglie účinky léků metabolismus MeSH
- miniaturní prasata MeSH
- modely nemocí na zvířatech MeSH
- monocyty účinky léků metabolismus MeSH
- prasata MeSH
- proteiny nervové tkáně genetika metabolismus MeSH
- regulace genové exprese genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder of hematopoietic stem cells that has been recognized as a disease responsive to immunotherapy. Despite the huge success of the tyrosine kinase inhibitors (TKIs), CML remains for the most part incurable, probably due to treatment resistance of leukemic stem cells, which are responsible for rapid disease relapse after discontinuation of therapy. Only allogeneic stem cell transplantation enables disease eradication. In addition to the Bcr-Abl1 oncoprotein, TKIs also inhibit off-target kinases (e.g. c-kit, Src, Tec), some of them having physiological functions in immune responses. In vitro studies have implied immunomodulatory effects of TKIs and interferon-alpha (IFN-α), but comprehensive information from in vivo analyses is missing. This review summarizes the recent advances in the field of immunology of CML, including basic information about leukemia-associated antigens and peptide vaccines, that could lead to the incorporation of TKIs and IFN-α in future therapeutic, potentially curative, interventions for CML.
- MeSH
- antigeny nádorové chemie imunologie MeSH
- chronická myeloidní leukemie imunologie terapie MeSH
- imunitní systém účinky léků imunologie MeSH
- imunologické faktory terapeutické užití MeSH
- imunoterapie MeSH
- inhibitory proteinkinas terapeutické užití MeSH
- interferon alfa metabolismus terapeutické užití MeSH
- lidé MeSH
- protinádorové vakcíny imunologie terapeutické užití MeSH
- signální transdukce účinky léků MeSH
- subjednotkové vakcíny imunologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Treatments of non-small cell lung cancer (NSCLC), the most common form of lung cancer, still remain poor. Interferon alpha (IFN-alpha), an important physiological immunomodulator, possesses direct cytotoxic and cytostatic effects on tumour cells, antiangiogenic effects, and activates anti-tumour immunity. Recently, the IFN-alpha oncologic indications have included melanoma, renal carcinoma, and different types of leukaemia. However, the application of IFN-alpha in therapy of lung cancer has not been validated yet. Herein the human lung carcinoma cell line A549, a model of NSCLC in vitro, was used to pursue the effect of IFN-alpha on A549 cell proliferation and differentiation together with the effect on protein expression and activity of three ATP-transporters mediating multi-drug resistance (MDR). IFN-alpha significantly inhibited the proliferation of A549 cells which was not connected with arrest in a particular cell cycle phase. Further, IFN-alpha-mediated differentiation of A549 was observed based on an increase in alkaline phosphatase activity. Simultaneously, IFN-alpha increased the expression and activity of ATP-transporters mediating MDR. Thus, the IFN-alpha down-regulation of NSCLC cell proliferation was accompanied by a potential of cells to exclude potential therapeutic substances such as chemotherapeutic agents. These effects could have a significant impact on considerations of IFN-alpha as a therapeutic agent for NSCLC.
- MeSH
- ABC transportéry metabolismus MeSH
- alkalická fosfatasa metabolismus MeSH
- buněčná diferenciace fyziologie MeSH
- buněčný cyklus fyziologie MeSH
- fosforylace MeSH
- interferon alfa metabolismus MeSH
- karcinom enzymologie patofyziologie MeSH
- lidé MeSH
- mitogenem aktivované proteinkinasy p38 metabolismus MeSH
- nádorové buněčné linie MeSH
- nádory plic enzymologie patofyziologie MeSH
- proliferace buněk MeSH
- signální transdukce MeSH
- transkripční faktor STAT1 metabolismus MeSH
- viabilita buněk fyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- MeSH
- antivirové látky antagonisté a inhibitory MeSH
- buněčné linie MeSH
- interferon alfa antagonisté a inhibitory fyziologie metabolismus MeSH
- lidé MeSH
- neutralizační testy MeSH
- receptory interferonů genetika metabolismus MeSH
- virové proteiny metabolismus MeSH
- virus vakcinie genetika MeSH
- Check Tag
- lidé MeSH
