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Biological characteristics of polysccharide based contrast agents for cancer diagnostics
Křivánková, Markéta ; Jirák, Daniel (advisor) ; Shapoval, Oleksandr (referee) ; Vannucci, Luca Ernesto (referee)
Despite all the progress made in the treatment of cancer in recent years, it is still necessary to continue with the research of more effective and specific drugs. In recent years, there has been a growing interest in personalized medicine and its application through drug delivery systems, which could help increase the specificity of cancer treatment and subsequently its effectiveness. Drug delivery systems can use different platforms for their design, whether they are liposomes, micelles, nano crystals or others. A very interesting platform for the construction of drug delivery systems are polysaccharides, which were, as carriers of contrast agents in order to effectively display tumours, characterized in this doctoral thesis. But polysaccharides are interesting for more reasons. Both by its availability, and by its biocompatibility and non-toxic character. In this doctoral thesis we deal with two types of polysaccharides conjugates with linked contrast agents for magnetic resonance and fluorescent imaging. The first type of polysaccharide is glycogen, the second is mannan. Both constructs - glycogen and mannan based, were synthesized in a version with and without polymethyloxazolin, which should prolong their circulation in the organism. Both types of polysaccharide conjugates used passive...
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Toll like receptors and myeloid cells in development and disease
Balounová, Jana ; Filipp, Dominik (advisor) ; Špíšek, Radek (referee) ; Vannucci, Luca Ernesto (referee)
Toll like receptors (TLRs) are germline-encoded pattern recognition receptors (PRRs) that play a central role in host cell recognition and responses to pathogens. Primarily they are responsible for induction and regulation of the innate and adaptive immune responses whereby the effector function is executed chiefly by differentiated myeloid cells. Somewhat unexpectedly, TLRs have been also shown to be involved in direct pathogen sensing by bone marrow-derived hematopoietic stem cells (HSCs) and hematopoietic progenitors when, under inflammatory conditions, the rapid generation of innate immune effector cells that effectively combat the infection is of utmost priority. While it has been recognized that the release of inflammatory cytokines from inflamed tissues along with the changes in proportions of differentiating cells in the bone marrow (BM) as well as the BM niche can nudge the differentiation of adult BM-derived cells towards myeloid cells and granulocytes, a direct role of TLRs expressed by HSCs in this process has been demonstrated only recently. However, whether a similar mechanism operates also during embryonic hematopoiesis is unknown. Here we show that TLRs and their adaptor proteins are functionally expressed during early stages of embryogenesis by short-lived maternally-transferred...
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Inflammation and cancer in germ-free vs. conventionally reared animals
Čaja, Fabián ; Vannucci, Luca Ernesto (advisor) ; Tlaskalová - Hogenová, Helena (referee) ; Smrž, Daniel (referee)
Inflammation is considered as one of the main defence mechanisms of the immune system against threats that occur in the body. When present in its acute form, minimal or no detectable subsequent damage of original affected tissue exists. The more pathological form, chronic inflammation, is associated with permanent damage of the tissue and typically a hallmark of various diseases such as ulcerative colitis or colon carcinogenesis. These two pathologies are evolving in the unique colon microenvironment, where intensive interaction between the host cells and bacteria is present. The aim of our study was to investigate the immunological (ELISA, FACS, RT-PCR) and structural (histology, confocal microscopy) changes in the colon mucosa of Wistar-AVN rats induced by dextran sodium sulphate (DSS) to produce colon colitis and by azoxymethane (AOM) to produce colon carcinogenesis. Conventional (CV) and also germ-free (GF) reared animals were used to investigate the effects of the mucosal inflammation activated by the administered inducers as well as the role of colon microbiota - as promoters of a continuous immune activation - in the modulation of immunity and collagen scaffold remodelling. Our results showed that even in the early period after the induction, both inducers produced a smouldering...
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Tumor-infiltrating T cells and their role in adoptive cell immunotherapy of cancer
Střížová, Zuzana ; Smrž, Daniel (advisor) ; Vannucci, Luca Ernesto (referee) ; Posová, Helena (referee)
Cancer immunotherapy has become a leading treatment modality in metastatic diseases. Although this novel therapy has changed the therapeutic algorithms and patients' outcomes in multiple malignancies, certain proportions of patients still fail to respond to these approaches. In our studies, we aimed to address the main mechanisms of tumor resistance to cancer immunotherapy. We have systematically defined the main challenges in adoptive cell transfer. We have focused on two key mechanisms of the tumor resistance to immunotherapy: poor trafficking of adoptively transferred immune cells into tumors, and the death receptor-induced apoptosis of the tumor-infiltrating immune cells. In our work, we have gone beyond the tumor tissue and searched for the immune cell populations and novel targets that would help to challenge the two mechanisms of resistance. Our data uncovered the therapeutic potential of the paratumoral tissue compartments and, thus, provided new avenues on how to challenge solid tumors by immunotherapy.
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Anticancer immunity in animal models and experimental immunotherapy with glycodendrimers specific for the lectin-like receptor NKR-P1
Vannucci, Luca Ernesto ; Fišerová, Anna (advisor) ; Bubeník, Jan (referee) ; Apte, Ron Nathan (referee)
5 SUMMARY Anticancer immunity is a complex network in which innate immunity play an critical role. The immune system can control the onset of tumors by recognizing the changed phenotype of the transformed cells as a non-self phenotype. The active control against cells not presenting self characters is defined by the paradigm of immune surveillance. In recent years, various studies have shown that the immune response against transformed cells start as a localized acute inflammatory response. The cooperation of natural-killer cells (NK) and phagocytes attracted by so-called "danger signals" (pro-inflammatory molecules and chemo-attractants delivered by stressed cells) can lead to total ablation of the harmful cell clone. If the intervention is not completely efficient, immunoediting of the tumor can follow with stimulation of chronic inflammatory responses, mainly mediated by macrophages. The systemic immunity attempt to terminate the uncontrolled inflammation stimulates the intervention of regulatory T lymphocytes and the shift from an antitumor cytotoxic Th1 response to a Th2 inhibitory response. This regulatory mechanism paradoxically assists the tumor development. All the described events needs the interplay and cooperation of both tumor cells and host cells and stromal elements, that altogether form the...
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Therapeutic Nanoparticles and Immunotoxicity
Lehutová, Daniela ; Vannucci, Luca Ernesto (advisor) ; Grobárová, Valéria (referee)
Nanočastice sú submikroskopické štruktúry vyhotovené z rôznych materiálov s obrovským terapeutickým potenciálom. Rovnako predstavujú nový nástroj pre lepšie cielenie a podávanie liečiv do jednotlivých tkanív. Bolo vynaložených mnoho pokusov pre vyvinutie terapeutík, ktoré budú lepšie kompatibilné v organizme a zároveň by zlepšili účinnosť moderných liekov. Na rozdiel od bežne používaných spôsobov pre podávanie liečiv, enkapsulovaná forma predstavuje obrovskú výhodu pri znižovaní vedľajších účinkov oproti bežne používaných liekoch. V tejto práci sú porovnávané výhody použitia nanočastíc spolu s ich možným rizikom, najmä na ich munitný systém. Vzhľadom k tomu, že toxicita sa líši v závislosti na chemicko fyzikálnych vlastnostiach a tkanivách, v ktorých sa akumulovali, musí byť zvolená vhodná stratégia, aby sa predišlo možných nežiaducim účinkom. Z tohto dôvodu je potrebné zvážiť preventívne opatrenia a správne upraviť dané nanočástice predtým, než budú použité v organizme, rovnako ako spôsobená odpoveď organizmu a jej dôsledok musia byť vhodne monitorované. Zvýšená pozornosť musí byť venovaná príprave nanočastíc, aby sa predišlo prípadnej kontaminácii a nebezpečenstvu pre laboratórny personál. Kľúčové slová nanočástice, podávanie liečiv, imunita, toxicita, teranostika
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Toll like receptors and myeloid cells in development and disease
Balounová, Jana ; Filipp, Dominik (advisor) ; Špíšek, Radek (referee) ; Vannucci, Luca Ernesto (referee)
Toll like receptors (TLRs) are germline-encoded pattern recognition receptors (PRRs) that play a central role in host cell recognition and responses to pathogens. Primarily they are responsible for induction and regulation of the innate and adaptive immune responses whereby the effector function is executed chiefly by differentiated myeloid cells. Somewhat unexpectedly, TLRs have been also shown to be involved in direct pathogen sensing by bone marrow-derived hematopoietic stem cells (HSCs) and hematopoietic progenitors when, under inflammatory conditions, the rapid generation of innate immune effector cells that effectively combat the infection is of utmost priority. While it has been recognized that the release of inflammatory cytokines from inflamed tissues along with the changes in proportions of differentiating cells in the bone marrow (BM) as well as the BM niche can nudge the differentiation of adult BM-derived cells towards myeloid cells and granulocytes, a direct role of TLRs expressed by HSCs in this process has been demonstrated only recently. However, whether a similar mechanism operates also during embryonic hematopoiesis is unknown. Here we show that TLRs and their adaptor proteins are functionally expressed during early stages of embryogenesis by short-lived maternally-transferred...
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New ferritin nanoparticles for specific targeting of experimental melanoma in mice: in vitro and in vivo tests.
Rajsiglová, Lenka ; Vannucci, Luca Ernesto (advisor) ; Šírová, Milada (referee)
Cancer diseases represent second most frequent cause of death after cardiovascular diseases in Europe. Nowadays used medical treatments like chemotherapy and radiotherapy are nonspecific and cause huge side effects. Various systems to deliver therapy directly inside the tumour microenvironment and reduce side effects are under development. Protein nanoparticles seem to be very promising strategy to achieve that goal. Our group in cooperation with CNR in Rome tested nanoparticles based on heavy chain of human ferritine. These constructs, modified to expose the tumor targeting molecule, were able to be specifically internalised by B16F10 melanoma cells in vitro. They also specifically target and localise at the sites of primary melanoma and lung metastases of different size in mouse in vivo model. These nanoparticles can carry either therapeutic or diagnostic molecules. Thus they represent a suitable candidate for further studies for potential use in clinical praxis as a diagnostic and/or therapeutic agents (theranostics). Powered by TCPDF (www.tcpdf.org)
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