Vaccines currently in the clinical use contain adjuvants stimulating preferably Th2 type of immune response associated with the production of specific antibodies, mostly of neutralizing isotypes. This kind of immune response is effective only against some types of pathogens and has limited effect against tumors and many viruses where parallel activation of antigen-specific humoral and cell-mediated immunity is required. One of the main objectives of the current vaccine research is the development of approaches leading to the induction of antigen-specific CD8(+) T cell response including cytotoxic T lymphocyte (CTL). Induction of antigen-specific CD8(+) T cell response to exogenously delivered antigen requires their cross-presentation by antigen presenting cells, especially dendritic cells. The cross-presentation principles seem to be crucial for effective activation of CTL. In this paper, we discuss some approaches to employing heat shock proteins for induction of antigen-specific CD8(+) T cells in the context of cross-presentation and cross-priming principles.

• Klíčová slova
• Cross-presentation, Dendritic cells, Heat shock protein (hsp),
• MeSH
• aktivace lymfocytů MeSH
• CD8-pozitivní T-lymfocyty imunologie   MeSH
• cytotoxicita imunologická MeSH
• dendritické buňky imunologie   transplantace   MeSH
• lidé MeSH
• nádory imunologie   terapie   MeSH
• nepřímá aktivace * MeSH
• proteiny teplotního šoku imunologie   MeSH
• protinádorové vakcíny * MeSH
• virové nemoci imunologie   terapie   MeSH
• virové vakcíny * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• proteiny teplotního šoku MeSH
• protinádorové vakcíny * MeSH
• virové vakcíny * MeSH

Cellular immune reactions against non-self-epitopes require activation of cytotoxic CD8+ T-cells via cross-presentation of MHC class I-restricted peptides by professional antigen presenting cells (pAPCs), with the consequent detection and elimination of cells expressing the same antigens via the endogenous (direct) pathway. The source of peptides for the endogenous pathway is constituted of alternative mRNA translation products; however, it is still unclear which source of peptides is used for cross-presentation. Furthermore, the presentation of non-canonical translation products, produced during a non-conventional translation event, on class I molecules of tumor cells has been reported but how these peptides are generated, presented to pAPCs, and their capacity to stimulate CD8+ T cells is still not known. Here, we report that pioneer translation peptides (PTPs) derived from intron or exon pre-mRNAs can serve as tumor-associated antigens (TA-PTPs) and are delivered from the producing tumor cells to pAPCs via exosomes where they are processed by the cytosolic pathway. Injection of TA-PTPs and tumor-derived exosomes efficiently induce CD8+ T-cell proliferation and prevent tumor growth in mice. Our results show that TA-PTPs represent an efficient source of antigenic peptides for CD8+ T cell activation and that full-length proteins are not required for cross-presentation. These findings can have interesting implications for generating tolerance and for designing vectors to generate vaccines.

• Klíčová slova
• Exosomes, MHC-I antigen cross presentation, pioneer translation products, tumor rejection, vaccines,
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The source of peptides that enter the major histocompatibility class I (MHCI) pathway has been intensively debated over the last two decades. The initial assumption that peptides are derived from degradation of full length proteins was challenged by a model in which alternative translation products are a source of peptides. This model has been tested and supported by scientific data. We now need new hypotheses on the physiological implications of different sources of peptides for the MHCI pathway. The aim of this overview is to give an up-to-date account of the source of antigenic peptide material for the MHCI pathway and to incorporate the more recent observations of alternative mRNA translation products into existing models of the direct and cross-presentation pathways.

• MeSH
• alternativní sestřih MeSH
• antigeny genetika   metabolismus   MeSH
• lidé MeSH
• MHC antigeny I. třídy metabolismus   MeSH
• nepřímá aktivace MeSH
• peptidy genetika   metabolismus   MeSH
• prezentace antigenu MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• antigeny MeSH
• MHC antigeny I. třídy MeSH
• peptidy MeSH

The activation of tumor-specific effector immune cells is key for successful immunotherapy and vaccination is a powerful strategy to induce such adaptive immune responses. However, the generation of effective anticancer vaccines is challenging. To overcome these challenges, a novel straight-forward strategy of adjuvant-induced tumor antigen assembly to generate nanovaccines with superior antigen/adjuvant loading efficiency is developed. To protect nanovaccines in circulation and to introduce additional functionalities, a biocompatible polyphenol coating is installed. The resulting functionalizable nanovaccines are equipped with a pH (low) insertion peptide (pHLIP) to facilitate endolysosomal escape and to promote cytoplasmic localization, with the aim to enhance cross-presentation of the antigen by dendritic cells to effectively activate CD8+ T cell. The results demonstrate that pHLIP-functionalized model nanovaccine can induce endolysosomal escape and enhance CD8+ T cell activation both in vitro and in vivo. Furthermore, based on the adjuvant-induced antigen assembly, nanovaccines of the clinically relevant tumor-associated antigen NY-ESO-1 are generated and show excellent capacity to elicit NY-ESO-1-specific CD8+ T cell activation, demonstrating a high potential of this functionalizable nanovaccine formulation strategy for clinical applications.

• Klíčová slova
• T cell activation, antigen/adjuvant codelivery, cancer nanovaccines, cross-presentation, endolysosomal escape,
• MeSH
• adjuvancia imunologická MeSH
• aktivace lymfocytů fyziologie   MeSH
• antigeny nádorové imunologie   MeSH
• buněčné linie MeSH
• CD8-pozitivní T-lymfocyty metabolismus   MeSH
• kinetika MeSH
• lidé MeSH
• polyfenoly chemie   MeSH
• protinádorové vakcíny imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adjuvancia imunologická MeSH
• antigeny nádorové MeSH
• polyfenoly MeSH
• protinádorové vakcíny MeSH

Heat shock proteins hsp70 and gp96 have been confirmed as adjuvants enabling induction of cell- and antibody-mediated immunity specific to associated protein or peptide antigens due to the activation of naive dendritic cells and supporting cross-presentation of associated antigen. An efficacious vaccine preventing HIV-1 infection should induce (1) antibodies neutralizing HIV-1 Env protein, preventing virus spreading and (2) CD4(+) Th1 and CD8(+) T cells specific to viral proteins, especially gag p24, important for elimination of HIV-1 infected cells. As p24 is relatively poorly recognized by dendritic cells, its targeting to DC is important for enhancement of vaccine efficacy. In this study, a p24 protein fused to the C- or N-terminus of murine hsp70 was produced as a recombinant protein and administered without any adjuvant to experimental BALB/c mice. Consequently, p24-specific cellular and humoral immune responses were measured. To minimize the effect of bacterial endotoxin, each protein was subjected to a repeated endotoxin phase extraction until each preparation contained less than 2.5 endotoxin unit (EU) per mg of antigen. In addition, endocytosis of p24 fused to hsp70 by dendritic cells and their activation were characterized. The fusion to hsp70 protein enhanced endocytosis of p24 as well as activation of dendritic cells in vitro. After immunization of mice, hsp70-p24 fusion protein induced the strongest p24-specific CD4(+) and CD8(+) T cells (IFN-γ production) and humoral (IgG2b) responses corresponding to Th1 type dominance, whereas p24-hsp70 or p24 itself induced weaker responses.

• Klíčová slova
• HIV, HIV-1 protein p24, Heat shock protein, Vaccine,
• MeSH
• antigeny virové imunologie   MeSH
• CD8-pozitivní T-lymfocyty imunologie   MeSH
• dendritické buňky imunologie   MeSH
• endocytóza imunologie   MeSH
• endotoxiny imunologie   MeSH
• HIV korový protein p24 imunologie   metabolismus   MeSH
• imunizace MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• nepřímá aktivace imunologie   MeSH
• proteiny tepelného šoku HSP70 imunologie   metabolismus   MeSH
• rekombinantní fúzní proteiny imunologie   MeSH
• Th1 buňky imunologie   MeSH
• vakcíny proti AIDS imunologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny virové MeSH
• endotoxiny MeSH
• HIV korový protein p24 MeSH
• proteiny tepelného šoku HSP70 MeSH
• rekombinantní fúzní proteiny MeSH
• vakcíny proti AIDS MeSH

It has been demonstrated that pterostilbene inhibits reactive oxygen species production in neutrophils in vitro. However, little is known about its effects on neutrophils during inflammation in vivo. In this study, the effect of pterostilbene on neutrophil activity was investigated in experimental arthritis model. Lewis rats were injected by a single intradermal injection of heat-killed Mycobacterium butyricum in Freund's adjuvant to develop arthritis. Another group of arthritic animals received pterostilbene 30 mg/kg, daily, p.o. The number and activity of neutrophils in blood were measured on a weekly basis during the whole experiment. Moreover, the total radical trapping potential in plasma was measured at the end of the experiment. In the pterostilbene treated arthritic group, the treatment significantly lowered the number of neutrophils in blood on days 14 and 21 without significant downregulation of neutrophil oxidative burst. Pterostilbene nonsignificantly increased total radical trapping potential in arthritic animals. These results indicate that the promising effects of pterostilbene on reactive oxygen species operate by different mechanisms in vitro and in the animal model of inflammation. In conclusion, the positive effects of pterostilbene in the model of arthritis may be attributed to regulation of neutrophil number.

• MeSH
• artritida experimentální farmakoterapie   patologie   MeSH
• down regulace účinky léků   MeSH
• krysa rodu Rattus MeSH
• modely nemocí na zvířatech MeSH
• nepřímá aktivace účinky léků   imunologie   MeSH
• neutrofily cytologie   účinky léků   patologie   MeSH
• peroxidy metabolismus   MeSH
• počet leukocytů MeSH
• potkani inbrední LEW MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• stilbeny chemie   farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• perhydroxyl radical MeSH Prohlížeč
• peroxidy MeSH
• pterostilbene MeSH Prohlížeč
• reaktivní formy kyslíku MeSH
• stilbeny MeSH

Dendritic cell (DC)-based vaccination for cancer treatment has seen considerable development over recent decades. However, this field is currently in a state of flux toward niche-applications, owing to recent paradigm-shifts in immuno-oncology mobilized by T cell-targeting immunotherapies. DC vaccines are typically generated using autologous (patient-derived) DCs exposed to tumor-associated or -specific antigens (TAAs or TSAs), in the presence of immunostimulatory molecules to induce DC maturation, followed by reinfusion into patients. Accordingly, DC vaccines can induce TAA/TSA-specific CD8+/CD4+ T cell responses. Yet, DC vaccination still shows suboptimal anti-tumor efficacy in the clinic. Extensive efforts are ongoing to improve the immunogenicity and efficacy of DC vaccines, often by employing combinatorial chemo-immunotherapy regimens. In this Trial Watch, we summarize the recent preclinical and clinical developments in this field and discuss the ongoing trends and future perspectives of DC-based immunotherapy for oncological indications.

• Klíčová slova
• DAMPs, Dendritic cells, T cell priming, TAAs, antigen cross-presentation, clinical trial, immune checkpoint blockers, tumor-infiltrating lymphocytes,
• MeSH
• antigeny nádorové MeSH
• dendritické buňky MeSH
• imunoterapie MeSH
• lidé MeSH
• nádory * farmakoterapie   MeSH
• protinádorové vakcíny * terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny nádorové MeSH
• protinádorové vakcíny * MeSH

The use of patient-derived dendritic cells (DCs) as a means to elicit therapeutically relevant immune responses in cancer patients has been extensively investigated throughout the past decade. In this context, DCs are generally expanded, exposed to autologous tumor cell lysates or loaded with specific tumor-associated antigens (TAAs), and then reintroduced into patients, often in combination with one or more immunostimulatory agents. As an alternative, TAAs are targeted to DCs in vivo by means of monoclonal antibodies, carbohydrate moieties or viral vectors specific for DC receptors. All these approaches have been shown to (re)activate tumor-specific immune responses in mice, often mediating robust therapeutic effects. In 2010, the first DC-based preparation (sipuleucel-T, also known as Provenge®) has been approved by the US Food and Drug Administration (FDA) for use in humans. Reflecting the central position occupied by DCs in the regulation of immunological tolerance and adaptive immunity, the interest in harnessing them for the development of novel immunotherapeutic anticancer regimens remains high. Here, we summarize recent advances in the preclinical and clinical development of DC-based anticancer therapeutics.

• Klíčová slova
• DC, dendritic cell, DC-based vaccination, FDA, Food and Drug Administration, IFN, interferon, MRC1, mannose receptor, C type 1, MUC1, mucin 1, TAA, tumor-associated antigen, TLR, Toll-like receptor, Toll-like receptor agonists, Treg, regulatory T cell, WT1, Wilms tumor 1, antigen cross-presentation, autophagy, iDC, immature DC, immunogenic cell death, mDC, mature DC, pDC, plasmacytoid DC, regulatory T cells,
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Fibroblastoid mouse L-cells are widely used in immunological models because when transfected with class II-coding genes they become efficient antigen presenting cells. Little is known, however, about the cell surface markers borne by L-cells and their putative involvement/Interference with the experimental models studied. Rats were immunized against DAP.3 cells (subclone of L-cells) and monoclonal antibodies (mAbs) were prepared. One of them, 4D4, was studied in detail. It recognizes an epitope which is neither cell lineage- nor strain- nor species-restricted since, in addition to DAP.3 cells, it binds, as determined by flow cytometry and immunohistochemistry, to various cells such as CD8+ T cells from thymus, spleen, lymph node or intestinal epithelium, mouse peritoneal B cells and various tissues such as renal, pulmonary or intestinal epithelia. 4D4 mAb immunoprecipitates an undescribed 68 kDa protein. Functionally, this mAb inhibits the IL-2 secretion of a T cell clone in response to its peptide presented by appropriate class II-transfected L-cells and induces a negative selection of double positive CD4+CD8+ thymocytes. Since the 4D4 ligand is found on cells which are submitted to selection (T cells) and on cells which mediate selection (epithelial and antigen presenting cells), we conclude that 4D4 mAb defines a cell surface antigen involved, as an accessory molecule, in a cell selection process.

• MeSH
• antigeny povrchové analýza   imunologie   MeSH
• epitopy imunologie   MeSH
• inbrední kmeny potkanů MeSH
• interleukin-2 metabolismus   MeSH
• křížení genetické MeSH
• krysa rodu Rattus MeSH
• kultivované buňky MeSH
• L buňky (buněčná linie) imunologie   MeSH
• lidé MeSH
• molekulová hmotnost MeSH
• monoklonální protilátky imunologie   MeSH
• myši inbrední BALB C MeSH
• myši inbrední C3H MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• nádorové buňky kultivované MeSH
• norek MeSH
• orgánová specificita MeSH
• podskupiny lymfocytů imunologie   MeSH
• potkani inbrední BN MeSH
• prezentace antigenu * MeSH
• specificita protilátek MeSH
• transfekce MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, U.S. Gov't, P.H.S. MeSH
• Názvy látek
• 4D4 antigen MeSH Prohlížeč
• antigeny povrchové MeSH
• epitopy MeSH
• interleukin-2 MeSH
• monoklonální protilátky MeSH

• MeSH
• HLA antigeny analýza   imunologie   MeSH
• HLA-A antigeny MeSH
• HLA-B antigeny MeSH
• HLA-C antigeny MeSH
• lidé MeSH
• zkřížené reakce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• Geografické názvy
• Československo MeSH
• Názvy látek
• HLA antigeny MeSH
• HLA-A antigeny MeSH
• HLA-B antigeny MeSH
• HLA-C antigeny MeSH