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Cytokine/anti-cytokine mAb complexes and their biological activity
Hnízdilová, Tereza ; Kovář, Marek (advisor) ; Grobárová, Valéria (referee)
biologická aktivita některých cytokinů může být paradoxně zvýšena tvorbou komplexu některými svými monoklonálními protilátkami (mAb) rozpoznávajícími tento cytokin. Prodloužení poločasu eliminace z 2 mAb komplexy, neboť v použitém klonu mAb dochází k selektivní stimulaci buď CD25 2/S4B6 komplex) buněk. Díky výrazné stimulaci NK buněk a paměťových CD8 lymfocytů a pouze mírné stimulaci Treg buněk by IL nahradit konvenční IL vysoce selektivní stimulací Treg buněk naopak mohly uplatnit při léčbě autoimunitních onemocnění a transplantacích. Potenciálně klinicky využitelné jsou dále IL stimulaci žírných buněk, IL plazmatickými buňkami či IL proliferaci a přežívání T lymfocytů. Imunokomplexy mohou být tvořeny také cytokinem a jeho 15Rα komplexy představují generaci IL onistů, které mohou být díky stimulaci expanze NK buněk a paměťových CD8 T lymfocytů využity jako Klíčová slova 15Rα komplexy
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IL-15/IL-15Rα complexes as IL-15 superagonist
Honzírková, Lucie ; Kovář, Marek (advisor) ; Javorková, Eliška (referee)
Interleukin 15 binds to its hight-afinity receptor IL-15Rα and forms stable IL-15/IL-15Rα complexes. IL-15Rα presents IL-15 in trans to target CD122/CD132 cells, where initiates signal transduction. Interleukin 15 has important role in immune system as it - regulates the homeostatic proliferation of memory CD8+ T cells and it is an essential for function, development and homeostasis of NK and NKT cells. Cell surface-expressed IL-15/IL15Rα complexes can be completely substituted by soluble recombinant IL-15/IL-15Rα-Fc complexes, which have substantially higher biological activity in composition to free IL-15 and behave as IL-15 superagonist. Il-15/IL-15Rα-Fc complexes are thus promising tool for some clinical use, i.e. cancer immune therapy, treatment of HIV or improvement of vaccination.
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Biodegradable high molecular weight polymeric conjugates for efficient delivery of cytostatic drugs into solid tumors.
Černý, Viktor ; Kovář, Marek (advisor) ; Palich Fučíková, Jitka (referee)
Cancer remains one of the most pressing issues of contemporary science and medicine. Incidence of malignant diseases is rising worldwide and they represent a major problem for the society due to both economic and ethical issues they cause. Although the progress in cancer biology, therapy and immunology has led to the introduction of many novel therapeutic protocols, approaches and drugs with specificity defined on a molecular level into clinical practice, many malignancies retain their poor prognosis. Therefore, intense research into new ways to increase our therapeutic options is warranted. Unfortunately, bringing a completely novel drug into clinical use takes extremely high amounts of time and money and entails a high risk of failure. Therefore, a promising approach has been recently adopted which lies in repurposing compounds already used in human medicine for cancer treatment. This form of research can advance through clinical trials for a new indication much easier, faster and cheaper than researching completely new drugs. The aim of this study was to examine the anticancer potential of one such drug, mebendazole. An anthelminthic from the family of benzimidazoles, mebendazole has been in common clinical use from the 1970s and is marked by its low toxicity as well as its very low solubility....
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Biological activity of IL-2/anti-IL-2 mAb immunocomplexes in vivo and their terapeutical potential
Hnilicová, Šárka ; Kovář, Marek (advisor) ; Grobárová, Valéria (referee)
IL-2 belongs to the family of c cytokines (IL-2, 4, 7, 9, 15, and 21) which are key regulators of lymphocyte homeostasis and function. They have the potential to promote lymphocyte proliferation and survival and thus overall enhance dominantly adaptive immune response. IL-2 is an autocrine/paracrine soluble factor produced mainly by activated T cells. Interestingly, the in vivo biological activity of IL-2 can be dramatically increased through complexing with certain anti-IL-2 mAbs and such IL-2/anti-IL-2 mAbs immunocomplexes selectively stimulate proliferation of distinct population of immune cells, depending on the clone of anti-IL-2 mAb used. IL-2/S4B6 mAb immunocomplexes are highly stimulatory for CD122high populations (memory CD8+ T and NK cells) and intermediately also for CD25+ populations (Treg and activated T cells), while IL-2/JES6-1 mAb immunocomplexes enormously expand solely CD25+ cells. Thus, IL-2 immunocomplexes possess a broad spectrum of potential therapeutic applications like tumor immunotherapy, vaccination, autoimmune diseases or transplantology.
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Local production of cytokines after treatment with stem cells of damaged ocular surface
Kössl, Jan ; Holáň, Vladimír (advisor) ; Kovář, Marek (referee)
The damage of ocular surface represents one of the most common causes of decreased quality of vision or even blindness. If the injury is extensive and includes the region of limbus, niche of limbal stem cells (LSC), LSC deficiency occurs and the natural corneal regeneration is stopped. Conjunctival epithelium migrates into the injured area. Neovascularization, local inflammation and corneal opacity occur. Corneal transplantation is an insufficient treatment in such case. If the injury is bilateral, the allogenic limbal graft or LSC transplantation is required. In such cases systemic immunosuppressive drugs with many negative side-effects must be administered. The search for an adequate autologous substitution is important for avoid immunosuppressive medication. Mesenchymal stem cells (MSC) represent a perspective substitution for the reason of their immunomodulatory properties and the capability to differentiate in many cell types. There is possibility to isolate sufficient number of these cells from adipose tissue or bone marrow which are relatively easily accessible. Our goal was to observe local production of cytokines and other molecules which are present in inflammatory reaction after the chemical burn of the murine cornea and after the treatment with stem cells growing on nanofiber scaffold....
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Polymeric conjugates for deliveryof cytostatic drugs and ABC transporter inhibitors in multi drug resistant tumors.
Sivák, Ladislav ; Kovář, Marek (advisor) ; Truksa, Jaroslav (referee)
Significant problem and important cause of failure of the cancer chemotherapy is that even originally very sensitive tumors become resistant to effects of cytostatic drugs. Loss of sensitivity to specific chemotherapeutics agent may not directly cause the loss of sensitivity to other chemotherapeutics. However, it have been described that tumors resistant to one type of chemotherapeutics were found to be resistant to several other anticancer drugs that are different in both structure and mode of action. This phenomenon has been described as multidrug resistance (MDR). MDR can develop in several ways, with the predominant mechanism being the overexpression of ATP- binding cassette (ABC) transporters, such as P-glycoprotein. These transporters acts as energy driven pumps and which, maintain intracellular drug concentration below toxic levels. The aim of this study was to examine the potential of novel polymeric therapeutics based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers bearing either anticancer drug, inhibitor of ABC transporters or both, for overcoming MDR mediated by P-glycoprotein in doxorubicin (Dox) resistant murine monocytic leukemia cell line P388/MDR. Series of low-molecular weight inhibitors reversin 121 (R121), reversin 205 (R205) and ritonavir (RIT) and their derivatives...
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Immunocomplexes of IL-2 and anti-IL-2 mAbs as a novel class of selective and extremely potent immunostimulators
Tomala, Jakub ; Kovář, Marek (advisor) ; Smetana, Karel (referee) ; Špíšek, Radek (referee)
vi ABSTRACT IL-2 has been used in cancer therapy and also for other applications like treatment of chronic viral infections or as an adjuvant for vaccines. However, treatment with IL-2 is rather difficult due to its severe side effects. These toxicities, associated with high-dose treatment necessary for IL-2 to function, have been found the most limiting factor for IL- 2 applications. Further, particular anti-IL-2 monoclonal antibodies (mAb) can actually increase biological activity of IL-2 rather than block it. Binding of IL-2 to anti-IL-2 mAb creates a superagonistic immunocomplexes which have dramatically higher and selective biological activity in comparison to free IL-2 in vivo. Such approach may finally over- come the difficulties associated with administration of IL-2, thus opening brand new scopes for IL-2 and its application not only in the field of tumor therapy. We have shown that IL-2 immunocomplexes composed of IL-2 and anti-IL-2 mAb S4B6 (IL-2/S4B6) stimulate predominantly cells expressing CD122 and CD132 (dimeric IL-2 receptor), i.e. NK and MP CD8+ T cells, with Treg, T and NKT cells being expanded as well. IL-2/S4B6 are able to drive the expansion of activated naive CD8+ T cells into functional memory-like CD8+ T cells. Moreover, these immunocomplexes exert therapeu- tical potential alone...
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Depletion of Treg cells for potentiation of cancer treatment with HPMA copolymer-bound cytostatic drug conjugates"
Dvořáková, Barbora ; Kovář, Marek (advisor) ; Reiniš, Milan (referee)
Tumor diseases are severe problem worldwide with increasing number of patients suffering from various types of malignancies. Many of approved therapeutics cause serious side toxicities. Therefore, there are intensive efforts to improve cancer treatment protocols. The aim of this study was to deplete regulatory T (Treg) cells without affecting other immunocompetent cells playing a positive role in tumor eradication. Treg cells were reported to hamper anti-tumor immunity and promote tumor growth and survival. Thus, their selective elimination could lead to induction of anti-tumor responses and tumor rejection if combined with chemotherapy with selected N-(2- hydroxypropyl)methacrylamide (HPMA) copolymer-bound drug conjugates. Original approach was to deplete of Treg cells without the use of anti-CD25 mAb that has been widely exploited for Treg cell elimination; however, its long-term persistence in circulation together with inhibitory effect on activated effector cells (CD25+ ) are its main disadvantages. Thus, Treg cells were sensitized to cell cycle-specific cytostatic drugs via application of IL-2/anti-IL-2 JES6.1 mAb immunocomplexes that induce vigorous selective proliferation of this cell population. Subsequent application of cell cycle-specific cytostatics showed steep decrease of Treg cell...
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Interaction of mesenchymal stem cells with immune system and their use in cancer therapy
Sivák, Ladislav ; Kovář, Marek (advisor) ; Paňková, Daniela (referee)
Mesenchymal stem cells (MSC) are multipotent progenitor cells with the ability to differentiate into ectodermal, mesodermal and endodermal cell line. They interact with innate and adaptive immunity and modulate their effector functions. Immunoregulatory effect of MSC results in suppression of inflammatory immune response and induces anti-inflammatory immune response. In addition, MSC have the ability to migrate into tumor site trough soluble factors produced by tumor cells and contribute to tumor growth and metastasis. Preferential homing to site of cancer growth and regulation of immune system make the MSC a promising tool for cancer therapy. Key words: mesenchymal stem cells, immunoregulation, tumors, cancer gene therapy
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