Browsing by Subject "toll-like receptors"

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  • Cerullo, Vincenzo; Capasso, Cristian; Vähä-Koskela, Markus; Hemminki, Otto; Hemminki, Akseli (2018)
    Adenovirus is one of the most commonly used vectors for gene therapy and it is the first approved virus-derived drug for treatment of cancer. As an oncolytic agent, it can induce lysis of infected cells, but it can also engage the immune system, promoting activation and maturation of antigen-presenting cells (APCs). In essence, oncolysis combined with the associated immunostimulatory actions result in a "personalized in situ vaccine" for each patient. In order to take full advantage of these features, we should try to understand how adenovirus interacts with the immune system, what are the receptors involved in triggering subsequent signals and which kind of responses they elicit. Tackling these questions will give us further insight in how to manipulate adenovirus-mediated immune responses for enhancement of anti-tumor efficacy. In this review, we first highlight how oncolytic adenovirus interacts with the innate immune system and its receptors such as Toll-like receptors, nucleotide-binding and oligomerization domain (NOD)-like receptors and other immune sensors. Then we describe the effect of these interactions on the adaptive immune system and its cells, especially B and T lymphocytes. Finally, we summarize the most significant preclinical and clinical results in the field of gene therapy where researchers have engineered adenovirus to manipulate the host immune system by expressing cytokines and signal-ingmediators.
  • Ehrnrooth, Ninja (Helsingin yliopisto, 2018)
    Allograft hud är kadaverhud som används som ett tillfälligt skydd på det brända och opererade hudområdet. Den tillfälliga allograften vaskulariseras i det rena sårbottnet inom några dagar och stöts bort efter 1-4 veckor. Förvaringen i glycerol dödar cellerna och har antibakteriella och antivirala egenskaper, men man vet inte om allografthudens immunogenicitet minskar om förvaringstiden i glycerol förlängs. Blodtransfusioner och användning av allograft hud är de vanligaste orsakerna till HLA-sensitisering hos brännskadepatienter. I denna avhandling utreder vi allograft hudens immunopositivitet med immunohistokemiska metoder, för att kunna förstå oss bättre på hud allograftens immunogenicitet. Vi vill utreda om lagringstiden i glycerol eller donatorns livslängd ändrar den glycerolförvarade allograftens immuniserande egenskaper. Vi analyserade fem Toll-lika receptorer (TLR2, 4, 5, 7 och 9) och cd45 receptorer i glycerolförvarad allograft hud för att se om det fanns ett samband mellan immunopositiviteten och förvaringstiden i glycerol och donatrons livslängd. Analysen gjordes för att kunna ge direktiv om förvaring och användning av glycerolförvarad allograft hud i hopp om att minska patientens immunisering. Vårt begränsade material minskade på möjligheterna att påvisa de samband, som var målsättningen för studien. Vi fann inte ett samband, men vi kunde se immunopositivitet i allograften, vilket tyder på att det finns proteiner i allograften som kan aktivera immunförsvaret.
  • Barreto, Goncalo; Manninen, Mikko; Eklund, Kari K. (2020)
    Osteoarthritis (OA) has long been viewed as a degenerative disease of cartilage, but accumulating evidence indicates that inflammation has a critical role in its pathogenesis. In particular, chondrocyte-mediated inflammatory responses triggered by the activation of innate immune receptors by alarmins (also known as danger signals) are thought to be involved. Thus, toll-like receptors (TLRs) and their signaling pathways are of particular interest. Recent reports suggest that among the TLR-induced innate immune responses, apoptosis is one of the critical events. Apoptosis is of particular importance, given that chondrocyte death is a dominant feature in OA. This review focuses on the role of TLR signaling in chondrocytes and the role of TLR activation in chondrocyte apoptosis. The functional relevance of TLR and TLR-triggered apoptosis in OA are discussed as well as their relevance as candidates for novel disease-modifying OA drugs (DMOADs).
  • Hasnat, Shrabon; Hujanen, Roosa; Nwaru, Bright I.; Salo, Tuula; Salem, Abdelhakim (2020)
    Head and neck squamous cell carcinoma (HNSCC) is a group of tumours which exhibit low 5 year survival rates. Thus, there is an urgent need to identify biomarkers that may improve the clinical utility of patients with HNSCC. Emerging studies support a role of toll-like receptors (TLRs) in carcinogenesis. Therefore, this systematic review and meta-analysis was performed to assess the prognostic value of TLR immunoexpression in HNSCC patients. We compiled the results of thirteen studies comprising 1825 patients, of which six studies were deemed qualified for quantitative synthesis. The higher immunoexpression of TLR-1 to 5 and 9 was associated with a worsening of the clinical parameters of patients with HNSCC. Furthermore, induced levels of TLR-3, 4, 5, 7 and 9 were found to predict the patients' survival time. The meta-analysis revealed that TLR-7 overexpression is associated with a decreased mortality risk in HNSCC patients (HR 0.51; 95%CI 0.13-0.89; I2 34.6%), while a higher expression of TLR-5 predicted shorter, but non-significant, survival outcome. In conclusion, this review suggests that TLRs may represent some prognostic value for patients with HNSCC. However, due to small sample sizes and other inherent methodological limitations, more well designed studies across different populations are still needed before TLRs can be recommended as a reliable clinical risk-stratification tool.