Strong immunity Dotaz Zobrazit nápovědu
There is no doubt that immunotherapy lies in the spotlight of current cancer research and clinical trials. However, there are still limitations in the treatment response in certain types of tumors largely due to the presence of the complex network of immunomodulatory and immunosuppressive pathways. These limitations are not likely to be overcome by current immunotherapeutic options, which often target isolated steps in immune pathways preferentially involved in adaptive immunity. Recently, we have developed an innovative anti-cancer immunotherapeutic strategy that initially elicits a strong innate immune response with subsequent activation of adaptive immunity in mouse models. Robust primary innate immune response against tumor cells is induced by toll-like receptor ligands and anti-CD40 agonistic antibodies combined with the phagocytosis-stimulating ligand mannan, anchored to a tumor cell membrane by biocompatible anchor for membrane. This immunotherapeutic approach results in a dramatic therapeutic response in large established murine subcutaneous tumors including melanoma, sarcoma, pancreatic adenocarcinoma, and pheochromocytoma. Additionally, eradication of metastases and/or long-lasting resistance to subsequent re-challenge with tumor cells was also accomplished. Current and future advantages of this immunotherapeutic approach and its possible combinations with other available therapies are discussed in this review.
- MeSH
- adaptivní imunita MeSH
- fagocytóza účinky léků imunologie MeSH
- imunitní systém imunologie metabolismus MeSH
- imunomodulace MeSH
- imunoterapie * metody MeSH
- kombinovaná terapie MeSH
- lidé MeSH
- ligandy MeSH
- nádorové mikroprostředí účinky léků genetika imunologie MeSH
- nádory etiologie metabolismus patologie terapie MeSH
- přirozená imunita MeSH
- protinádorové látky imunologicky aktivní farmakologie terapeutické užití MeSH
- toll-like receptory metabolismus MeSH
- výsledek terapie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Research Support, N.I.H., Intramural MeSH
BACKGROUND: Using killed microorganisms or their parts to stimulate immunity for cancer treatment dates back to the end of 19(th) century. Since then, it undergone considerable development. Our novel approach binds ligands to the tumor cell surface, which stimulates tumor phagocytosis. The therapeutic effect is further amplified by simultaneous application of agonists of Toll-like receptors. We searched for ligands that induce both a strong therapeutic effect and are safe for humans. METHODS: B16-F10 murine melanoma model was used. For the stimulation of phagocytosis, mannan or N-formyl-methionyl-leucyl-phenylalanine, was covalently bound to tumor cells or attached using hydrophobic anchor. The following agonists of Toll-like receptors were studied: monophosphoryl lipid A (MPLA), imiquimod (R-837), resiquimod (R-848), poly(I:C), and heat killed Listeria monocytogenes. RESULTS: R-848 proved to be the most suitable Toll-like receptor agonist for our novel immunotherapeutic approach. In combination with covalently bound mannan, R-848 significantly reduced tumor growth. Adding poly(I:C) and L. monocytogenes resulted in complete recovery in 83% of mice and in their protection from the re-transplantation of melanoma cells. CONCLUSION: An efficient cancer treatment results from the combination of Toll-like receptor agonists and phagocytosis stimulating ligands bound to the tumor cells.
- MeSH
- cytokiny metabolismus MeSH
- fagocytóza MeSH
- imidazoly farmakologie MeSH
- imunoterapie * metody MeSH
- infiltrace neutrofily imunologie MeSH
- ligandy MeSH
- mannany imunologie MeSH
- melanom experimentální MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- nádory imunologie metabolismus patologie terapie MeSH
- neutrofily imunologie metabolismus MeSH
- poly I-C imunologie MeSH
- přirozená imunita * MeSH
- respirační vzplanutí imunologie MeSH
- toll-like receptory agonisté metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Ticks are important vectors of serious human and animal disease-causing organisms, but their innate immunity can fight invading pathogens and may have the ability to reduce or block transmission to mammalian hosts. Lectins, sugar-binding proteins, can distinguish between self and non-self-oligosaccharide motifs on pathogen surfaces. Although tick hemolymph possesses strong lectin activity, and several lectins have already been isolated and characterized, little is known about the implementation of these molecules in tick immunity. Here, we have described and functionally characterized fibrinogen-related protein (FReP) lectins in Ixodes ticks. We have shown that the FReP family contains at least 27 genes (ixoderins, ixo) that could, based on phylogenetic and expression analyses, be divided into three groups with differing degrees of expansion. By using RNA interference-mediated gene silencing (RNAi) we demonstrated that IXO-A was the main lectin in tick hemolymph. Further, we found that ixoderins were important for phagocytosis of Gram-negative bacteria and yeasts by tick hemocytes and that their expression was upregulated upon injection of microbes, wounding, or after blood feeding. However, although the tick hemocytes could swiftly phagocytose Borrelia afzelii spirochetes, their transmission and burst of infection in mice was not altered. Our results demonstrate that tick ixoderins are crucial immune proteins that work as opsonins in the tick hemolymph, targeting microbes for phagocytosis or lysis.
- MeSH
- fagocytóza MeSH
- hemocyty imunologie MeSH
- hemolymfa imunologie MeSH
- klíště genetika imunologie MeSH
- lektiny genetika metabolismus MeSH
- přirozená imunita * MeSH
- proteiny členovců genetika metabolismus MeSH
- RNA interference MeSH
- umlčování genů MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Recognition of pathogen-associated molecular patterns (PAMPs) is crucial for plant defence against pathogen attack. The best characterized PAMP is flg22, a 22 amino acid conserved peptide from flagellin protein. In Arabidopsis thaliana, flg22 is recognized by the flagellin sensing 2 (FLS2) receptor. In this study, we focused on biotic stress responses triggered by flg22 after exposure to temporary heat stress (HS). It is important to study the reactions of plants to multiple stress conditions because plants are often exposed simultaneously to a combination of both abiotic and biotic stresses. Transient early production of reactive oxygen species (ROS) is a well-characterized response to PAMP recognition. We demonstrate the strong reduction of flg22-induced ROS production in A. thaliana after HS treatment. In addition, a decrease in FLS2 transcription and a decrease of the FLS2 presence at the plasma membrane are shown after HS. In summary, our data show the strong inhibitory effect of HS on flg22-triggered events in A. thaliana. Subsequently, temporary HS strongly decreases the resistance of A. thaliana to Pseudomonas syringae. We propose that short exposure to high temperature is a crucial abiotic stress factor that suppresses PAMP-triggered immunity, which subsequently leads to the higher susceptibility of plants to pathogens.
- MeSH
- alarminy metabolismus MeSH
- Arabidopsis účinky léků genetika imunologie mikrobiologie MeSH
- flagelin farmakologie MeSH
- genetická transkripce účinky léků MeSH
- imunita rostlin * účinky léků MeSH
- nemoci rostlin imunologie mikrobiologie MeSH
- odolnost vůči nemocem imunologie MeSH
- proteiny huseníčku genetika metabolismus MeSH
- Pseudomonas syringae účinky léků fyziologie MeSH
- reakce na tepelný šok * účinky léků MeSH
- regulace genové exprese u rostlin účinky léků MeSH
- respirační vzplanutí účinky léků MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
In this paper we address the issue of how to think about immunity. Many immunological writings suggest a straightforward option: the view that the immune system is primarily a system of defense, which naturally invites the talk of strong immunity and strong immune response. Despite their undisputable positive role in immunology, such metaphors can also pose a risk of establishing a narrow perspective, omitting from consideration phenomena that do not neatly fit those powerful metaphors. Building on this analysis, we argue two things. First, we argue that the immune system is involved not only in defense. Second, by disentangling various possible meanings of 'strength' and 'weakness' in immunology, we also argue that such a construal of immunity generally contributes to the distortion of the overall picture of what the immune system is, what it does, and why it sometimes fails. Instead, we propose to understand the nature of the immune system in terms of contextuality, regulation, and trade-offs. We suggest that our approach provides lessons for a general understanding of the organizing principles of the immune system in health and disease. For all this to work, we discuss a wide range of immunological phenomena.
- Publikační typ
- časopisecké články MeSH
Previous investigations proposed a link between the Epstein-Barr virus (EBV) and lung cancer (LC), but the results are highly controversial largely due to the insufficient sample size and the inherent limitation of the traditional viral screening methods such as PCR. Unlike PCR, current next-generation sequencing (NGS) utilizes an unbiased method for the global assessment of all exogenous agents within a cancer sample with high sensitivity and specificity. In our current study, we aim to resolve this long-standing controversy by utilizing our unbiased NGS-based informatics approaches in conjunction with traditional molecular methods to investigate the role of EBV in a total of 1127 LC. In situ hybridization analysis of 110 LC and 10 normal lung samples detected EBV transcripts in 3 LC samples. Comprehensive virome analyses of RNA sequencing (RNA-seq) data sets from 1017 LC and 110 paired adjacent normal lung specimens revealed EBV transcripts in three lung squamous cell carcinoma and one lung adenocarcinoma samples. In the sample with the highest EBV coverage, transcripts from the BamHI A region accounted for the majority of EBV reads. Expression of EBNA-1, LMP-1 and LMP-2 was observed. A number of viral circular RNA candidates were also detected. Thus, we for the first time revealed a type II latency-like viral transcriptome in the setting of LC in vivo. The high-level expression of viral BamHI A transcripts in LC suggests a functional role of these transcripts, likely as long non-coding RNA. Analyses of cellular gene expression and stained tissue sections indicated an increased immune cell infiltration in the sample expressing high levels of EBV transcripts compared to samples expressing low EBV transcripts. Increased level of immune checkpoint blockade factors was also detected in the sample with higher levels of EBV transcripts, indicating an induced immune tolerance. Lastly, inhibition of immune pathways and activation of oncogenic pathways were detected in the sample with high EBV transcripts compared to the EBV-low LC indicating the direct regulation of cancer pathways by EBV. Taken together, our data support the notion that EBV likely plays a pathological role in a subset of LC.
- Publikační typ
- časopisecké články MeSH
Deciphering the mechanisms that allow the induction of strong immune responses is crucial to developing efficient vaccines against infectious diseases and cancer. Based on the discovery that the adenylate cyclase from Bordetella pertussis binds to the CD11b/CD18 integrin, we developed a highly efficient detoxified adenylate cyclase-based vector (CyaA) capable of delivering a large variety of Ags to the APC. This vector allows the induction of protective and therapeutic immunity against viral and tumoral challenges as well as against transplanted tumors in the absence of any added adjuvant. Two therapeutic vaccine candidates against human papilloma viruses and melanoma have been developed recently, based on the CyaA vector, and are currently in clinical trials. We took advantage of one of these highly purified vaccines, produced under good manufacturing practice-like conditions, to decipher the mechanisms by which CyaA induces immune responses. In this study, we demonstrate that CyaA binds both human and mouse CD11b(+) dendritic cells (DCs) and induces their maturation, as shown by the upregulation of costimulatory and MHC molecules and the production of proinflammatory cytokines. Importantly, we show that DCs sense CyaA through the TLR4/Toll/IL-1R domain-containing adapter-inducing IFN-β pathway, independent of the presence of LPS. These findings show that CyaA possesses the intrinsic ability to not only target DCs but also to activate them, leading to the induction of strong immune responses. Overall, this study demonstrates that Ag delivery to CD11b(+) DCs in association with TLR4/Toll/IL-1R domain-containing adapter-inducing IFN-β activation is an efficient strategy to promote strong specific CD8(+) T cell responses.
- MeSH
- adaptorové proteiny vezikulární transportní imunologie MeSH
- adenylátcyklasový toxin imunologie MeSH
- antigeny CD11b imunologie MeSH
- antigeny CD80 biosyntéza MeSH
- antigeny CD86 biosyntéza MeSH
- Bordetella pertussis imunologie MeSH
- buněčná diferenciace imunologie MeSH
- cytotoxické T-lymfocyty imunologie MeSH
- dendritické buňky cytologie imunologie MeSH
- interferon beta imunologie MeSH
- interleukin-1beta biosyntéza MeSH
- interleukin-6 biosyntéza MeSH
- kultivované buňky MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- receptor interferonu alfa-beta genetika MeSH
- receptory interleukinu-1 imunologie MeSH
- signální transdukce imunologie MeSH
- TNF-alfa biosyntéza MeSH
- toll-like receptor 4 imunologie MeSH
- tyrosin genetika MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Background: Multiple Life and health directly depend on food and normal digestive system functions, as well as eating habits. Absorbed essential and beneficial nutrients from food are used by all human organic systems to maintain their functions for the purpose of maintaining health. The immune system resists harmful agents from the environment and increases level of its activity during infection. Such activity requires more energy sources and specific substrates from food to activate cellular and biochemical elements of immune defense. Adequate food choices and a wide range of nutrients are necessary to maintain optimal immune system function. In the fight against the COVID-19 pandemic, little attention is paid to strengthening the natural abilities of the human body and its immune system to prevent COVID-19. Objectives: The goal of this article is to evaluate new findings on the impact of food, specific nutrients and eating habits on immune system function during the COVID-19 pandemic. Methods: The available literature was analyzed using the key words: food, immune system, COVID-19, and the results of studies that have scientific evidence (EBM) for the positive impact of food on the activity of the immune system during this disease were summarized. Results and discussion: Food, diet and digestive function play the most important role in the overall immune response to viral infections. It has been proven that the active ingredients of food can strengthen or weaken the immune system (immunomodulation or immunosuppression). Organic balanced food adapted to each person (personal diet) is the first condition for creating an adequate natural defense system. Conclusion: There is evidence that many nutrients have key roles in boosting immune system. Strong immune system with adequate response can stop virus entering deeply in human body („to stop virus on the gate“).
Virtual memory T cells are foreign antigen-inexperienced T cells that have acquired memory-like phenotype and constitute 10-20% of all peripheral CD8+ T cells in mice. Their origin, biological roles, and relationship to naïve and foreign antigen-experienced memory T cells are incompletely understood. By analyzing T-cell receptor repertoires and using retrogenic monoclonal T-cell populations, we demonstrate that the virtual memory T-cell formation is a so far unappreciated cell fate decision checkpoint. We describe two molecular mechanisms driving the formation of virtual memory T cells. First, virtual memory T cells originate exclusively from strongly self-reactive T cells. Second, the stoichiometry of the CD8 interaction with Lck regulates the size of the virtual memory T-cell compartment via modulating the self-reactivity of individual T cells. Although virtual memory T cells descend from the highly self-reactive clones and acquire a partial memory program, they are not more potent in inducing experimental autoimmune diabetes than naïve T cells. These data underline the importance of the variable level of self-reactivity in polyclonal T cells for the generation of functional T-cell diversity.
High hydrostatic pressure (HHP) has been shown to induce immunogenic cell death of cancer cells, facilitating their uptake by dendritic cells (DC) and subsequent presentation of tumor antigens. In the present study, we demonstrated immunogenicity of the HHP-treated tumor cells in mice. HHP was able to induce immunogenic cell death of both TC-1 and TRAMP-C2 tumor cells, representing murine models for human papilloma virus-associated tumors and prostate cancer, respectively. HHP-treated cells induced stronger immune responses in mice immunized with these tumor cells, documented by higher spleen cell cytotoxicity and increased IFNγ production as compared to irradiated tumor cells, accompanied by suppression of tumor growth in vivo in the case of TC-1 tumors, but not TRAMP-C2 tumors. Furthermore, HHP-treated cells were used for DC-based vaccine antigen pulsing. DC co-cultured with HHP-treated tumor cells and matured by a TLR 9 agonist exhibited higher cell surface expression of maturation markers and production of IL-12 and other cytokines, as compared to the DC pulsed with irradiated tumor cells. Immunization with DC cell-based vaccines pulsed with HHP-treated tumor cells induced high immune responses, detected by increased spleen cell cytotoxicity and elevated IFNγ production. The DC-based vaccine pulsed with HHP-treated tumor cells combined with docetaxel chemotherapy significantly inhibited growth of both TC-1 and TRAMP-C2 tumors. Our results indicate that DC-based vaccines pulsed with HHP-inactivated tumor cells can be a suitable tool for chemoimmunotherapy, particularly with regard to the findings that poorly immunogenic TRAMP-C2 tumors were susceptible to this treatment modality.
- MeSH
- antigeny nádorové metabolismus MeSH
- cytotoxicita imunologická MeSH
- dendritické buňky cytologie MeSH
- experimentální nádory farmakoterapie terapie MeSH
- hydrostatický tlak MeSH
- imunitní systém MeSH
- imunoterapie metody MeSH
- infekce papilomavirem farmakoterapie terapie MeSH
- interferon gama metabolismus MeSH
- interleukin-12 metabolismus MeSH
- lidé MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory prostaty farmakoterapie metabolismus terapie MeSH
- protinádorové látky aplikace a dávkování MeSH
- protinádorové vakcíny chemie MeSH
- slezina imunologie MeSH
- taxoidy aplikace a dávkování MeSH
- toll-like receptor 9 metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
