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IL-25: Novel target to treat allergic diseases
Lišková, Kateřina ; Hrdý, Jiří (advisor) ; Boháčová, Pavla (referee)
Interleukin (IL) 25 is a proinflammatory cytokine that promotes a Th2-type cell response. Its alternate name is IL-17E, and along with 5 other members, IL-25 belongs to to the family of cytokine IL-17. The family is based on the similarity of their amino acid sequences. The source and target cells of IL-25 include many different cell types. IL-25 is not only produced by many types of immune cells, but epithelial and Paneth cells are involved in its production as well. Its receptors form heterodimers composed of 2 subunits - IL-17RA and IL-17RB. Both receptor proteins are required for IL-25 mediated activities and occur in other IL-17 family members. IL-25 also plays an important role in allergies - one of the most common diseases in developed countries. Cytokine IL-25 has been studied primarily in asthma. However, other very common types of allergies, such as food allergies, atopic dermatitis and allergic rhinitis, can not be overlooked. Even in these cases, the role of IL-25 is not negligible and is studied. Based on the knowledge of IL-25 biology and its role in allergies, this cytokine may be an important therapeutic target in the treatment of allergic diseases. One possibility is, for example, the use of neutralizing antibody and subsequent blocking of IL-25 activity. Key words: interleukin-25,...
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Regulatory B lymphocytes and mechanisms of their action
Boháčová, Pavla ; Holáň, Vladimír (advisor) ; Krulová, Magdaléna (referee)
Regulatory B lymphocytes (Bregs) represent a small population of B cells which participate in immunomodulations and in suppression of immune responses. These cells can regulate the immune system by different mechanisms, but the main mechanism of their action is a production of anti-inflammatory cytokine interleukin 10. The regulatory effects of Bregs were described in various models of inflammation, autoimmune diseases, transplantation reactions and in anti-tumor immunity. During autoimmune diseases Bregs function as important regulatory elements which can support remission or repression of the disease. Bregs have also important therapeutic potential in transplantation immunity where they can suppress rejection reactions. However, Bregs can disturb immune surveillance due to their immunosuppressive influence and thus they can attenuate anti-tumor immunity. Therefore, the aim of this thesis is to summarize the recent knowledge about Bregs. The thesis is focused on the mechanisms of Breg action in regulation of immune responses. The imunoregulatory effects of Bregs are described in various models of autoimmune diseases, transplantation immunity and anti-tumor immunity. The recognition of mechanisms of Breg action may have a great impact for their potential use in a clinical setting.
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Cellular and molecular mechanisms of immunoregulatory action of stem cells and their effect on adaptive immune cells
Boháčová, Pavla ; Holáň, Vladimír (advisor) ; Hrdý, Jiří (referee) ; Kalina, Tomáš (referee)
Regulation of immune reactions represents an entire system of maintenance of homeostasis, self-tolerance, and host defense. Regardless of intensive research, the cellular and molecular insights into immunomodulation remain incomplete. Therefore, we aimed to study different approaches to modulate the immune system, primarily focused on the induction, expansion, and activation of immunoregulatory cells. We analyzed the therapeutic effect of the combined action of mesenchymal stem/stromal cells (MSCs) and immunosuppressive drugs on the balance among T cell populations. We found that MSCs ameliorated unfavorable effects of immunosuppressants on T cell activation. As a result of this approach, T cell development was altered from the T helper (Th) 1, Th2, and Th17 cell polarization to anti-inflammatory regulatory T cell-mediated response. Additionally, we studied the effect of the immunoregulatory action of MSCs on B cells. We evaluated the impact of cytokine-primed MSCs on the induction of interleukin (IL)-10-producing B cells. Results revealed that interferon (IFN)-γ- and IL-4-primed MSCs suppressed the production of IL-10 by activated B cells. This suppression was dependent on cell-to-cell contact. In the case of IFN-γ-primed MSCs, the inhibition of IL-10 secretion involved the cyclooxygenase-2...
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Use of the nanofiber scaffold for transfer of stem cells onto the injured ocular surface in mouse experimental model
Kössl, Jan ; Zajícová, Alena ; Heřmánková, Barbora ; Javorková, Eliška ; Boháčová, Pavla ; Holáň, Vladimír
Corneal damage is one of the most common causes of impaired vision or even blindness. When the injury is more extensive and the limbal region is involved, the natural regeneration of the cornea is not sufficient. Such damage can lead to the limbal stem cell deficiency (LSCD). The only option for LSCD treatment is transplantation of the limbal tissue or a transfer of limbal stem cells (LSCs) cultured from the healthy eye. The allogenic transplantation of the limbus or cultivated LSCs with a systemic administration of immunosuppressive drugs is needed in the case of bilateral LSCD. Nevertheless, the cell therapy is very promising approach for LSCD treatment. Transplantation of mesenchymal stem cells (MSCs) seeded on an appropriate scaffold turned out to be a suitable therapy of the LSCD. In our experimental model of LSCD we use nanofiber scaffold for MSC and LSC cultivation and for transplantation of these cells onto the chemically injured mouse eye. MSCs have immunosuppressive and immunomodulatory properties. We showed that MSCs have the ability to inhibit production of molecules associated with the inflammation and support epithelial regeneration in the damaged cornea. These inhibitory properties were confirmed in both in vitro and in vivo mouse model. Results thus showed beneficial effects of stem cell transplantation for murine corneal healing and for suppression of a local immune reaction which can impede the healing process. Such similarity of in vivo and in vitro results allows us further experiments to clarify mechanisms of MSC regenerative and healing properties after the transplantation onto the injured cornea.
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Nanofiber scaffolds for local delivery of stem cells and immunosuppressive drugs for therapeutic purposes
Zajícová, Alena ; Kössl, Jan ; Heřmánková, Barbora ; Boháčová, Pavla ; Holáň, Vladimír
Cell-based therapy of local tissue injuries or damages requires application of stem cells and inhibition of harmful inflammatory reaction which could impede the healing process. To increase the effectiveness of this therapy, a local administration of drugs can avoid their side effects associated with a systemic treatment. A local therapy requires suitable carriers, which can transfer the cells and drugs to the site of injury. As a promising carriers turned out nanofiber scaffolds prepared by electrospinning technology from various types of polymers. The main advantage of this technology is a possibility to define properties of nanofiber scaffolds, optimal for the growth and transfer of stem cells, and which could incorporate various types of immunosuppressive drugs. Here we describe the formation and use of nanofiber scaffolds prepared by needleless electrospinning technology from poly (L-lactic acid) (PLA) which are loaded with immunosuppressive drug Cyclosporine A (CsA). We show that CsA-loaded nanofibers effectively and selectively inhibit proliferation of activated T cells and suppress the production of T cell cytokines in vitro. Simultaneously, these nanofiber scaffolds enable growth of mesenchymal stem cells (MSCs) and thus can serve as stem cell carriers. Moreover, using an experimental mouse model of skin transplantation, we showed that covering skin allografts with MSC-seeded and CsA-loaded nanofibers significantly inhibited the local production of pro-inflammatory cytokines IL-2, IL-17 and IFN-gamma, and supported healing. Thus, nanofiber scaffolds seeded with stem cells and loaded with CsA can serve as carriers of cells and drugs for a local cell therapy and for simultaneous effective immunosuppression.
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Mesenchymal stem cells and their effects on regulatory B cells
Smolová, Helena ; Boháčová, Pavla (advisor) ; Stříž, Ilja (referee)
Mesenchymal stem cells (MSC) are multipotent cells with the ability to regulate reactivity of cells of immune system. Regulatory B cells (Bregs) are also capable of modulating immune responses. Both these cell types are able of creating anti-inflammatory and tolerogenic environments and represent potential of cell-mediated therapy for autoimmune diseases and transplantation reactions. The effect of MSC on Bregs activation and function has been only studied in recent years, and mechanisms of their effects are not yet well characterized. However, studies have demonstrated a decrease in effector B lymphocytes and antibody production, and a support of activation of Bregs subpopulation and increased production of anti-inflammatory interleukin 10. Various molecules produced by MSC are involved in Bregs induction. Unfortunately, their effects have not yet been sufficiently described, and different models yields diverse results. In addition to the current studies in experimental models, the first clinical trials on Bregs have been initiated. The positive results suggesting the potential for future use of Bregs for the treatment of autoimmune diseases and transplantation reactions have been obtained in both cases. Key words: regulatory B cells, mesenchymal stem cells, immunomodulation, autoimmune diseases,...
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The effect of melatonin on the immune system
Hrubcová, Leona ; Moravcová, Simona (advisor) ; Boháčová, Pavla (referee)
Melatonin is an important hormone which is known to have very diverse functions. It was originally discovered as a product of the pineal gland synthesized in a 24 hour rhythm, but in later studies was found to be synthesized in many different tissue types. Melatonin is an important part of the circadian system and its effects on sleep rhythm are well known. The effects of melatonin on the circadian system are briefly covered in the opening chapters of this thesis. Furthermore, the basic mechanism of inflammation and the diverse effects of melatonin on the immune system are described in this thesis. Melatonin acts in an anti-inflammatory as well as pro-inflammatory manner and is part of many research projects focusing on curing for example diseases associated with chronic inflammation. This thesis presents studies regarding the effects of melatonin on pathological conditions like neurodegenerative diseases, rheumatoid arthritis and sepsis. This thesis also describes how changes in immune system activity can change the expression of melatonin, as it is not a one way effect. However, this interaction is not well known yet. Key words: melatonin, circadian system, immune system, inflammation
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IL-25: Novel target to treat allergic diseases
Lišková, Kateřina ; Hrdý, Jiří (advisor) ; Boháčová, Pavla (referee)
Interleukin (IL) 25 is a proinflammatory cytokine that promotes a Th2-type cell response. Its alternate name is IL-17E, and along with 5 other members, IL-25 belongs to to the family of cytokine IL-17. The family is based on the similarity of their amino acid sequences. The source and target cells of IL-25 include many different cell types. IL-25 is not only produced by many types of immune cells, but epithelial and Paneth cells are involved in its production as well. Its receptors form heterodimers composed of 2 subunits - IL-17RA and IL-17RB. Both receptor proteins are required for IL-25 mediated activities and occur in other IL-17 family members. IL-25 also plays an important role in allergies - one of the most common diseases in developed countries. Cytokine IL-25 has been studied primarily in asthma. However, other very common types of allergies, such as food allergies, atopic dermatitis and allergic rhinitis, can not be overlooked. Even in these cases, the role of IL-25 is not negligible and is studied. Based on the knowledge of IL-25 biology and its role in allergies, this cytokine may be an important therapeutic target in the treatment of allergic diseases. One possibility is, for example, the use of neutralizing antibody and subsequent blocking of IL-25 activity. Key words: interleukin-25,...
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Mechanisms of immunoregulatory action of IL-10-producing B lymphocytes in dependence on the cytokine environment
Boháčová, Pavla ; Holáň, Vladimír (advisor) ; Stříž, Ilja (referee)
Regulatory B lymphocytes (Bregs) represent a small heterogeneous subpopulation of B cells which participate in a regulation of immune responses by the antibody-independent mechanisms. The main mechanisms of Breg action is a production of anti-inflammatory cytokines or a direct cell contact through their surface molecules. This study deals with an induction of suppressive Bregs from mouse spleen B cells in vitro. We were aiming for a description of an influence of the selected cytokines to the induction of Bregs from lipopolysaccharide (LPS)-stimulated B cells and a determination of the mechanism of Breg action. We also analyzed the ability of inducted Bregs to produce interleukin-10 (IL) and to express genes for Fas ligand (FasL) and programmed death ligand 1 (PD-L1) molecules. We found that only two cytokines, IL-12 and IFN-γ, supported development of Bregs in a population of LPS-stimulated B cells. IFN-γ enhanced production of IL-10 and gene expression of FasL and PD-L1. Furthermore, we analyzed effects of Bregs on macrophages and their following action on T cells. Expression of costimulatory molecules CD80 and CD86, gene expression of IL-1α and the production of IL-6 were tested to determine the effects of macrophages on T cells. Macrophages influenced by Bregs had decreased ability to stimulate...
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Regulatory B lymphocytes and mechanisms of their action
Boháčová, Pavla ; Holáň, Vladimír (advisor) ; Krulová, Magdaléna (referee)
Regulatory B lymphocytes (Bregs) represent a small population of B cells which participate in immunomodulations and in suppression of immune responses. These cells can regulate the immune system by different mechanisms, but the main mechanism of their action is a production of anti-inflammatory cytokine interleukin 10. The regulatory effects of Bregs were described in various models of inflammation, autoimmune diseases, transplantation reactions and in anti-tumor immunity. During autoimmune diseases Bregs function as important regulatory elements which can support remission or repression of the disease. Bregs have also important therapeutic potential in transplantation immunity where they can suppress rejection reactions. However, Bregs can disturb immune surveillance due to their immunosuppressive influence and thus they can attenuate anti-tumor immunity. Therefore, the aim of this thesis is to summarize the recent knowledge about Bregs. The thesis is focused on the mechanisms of Breg action in regulation of immune responses. The imunoregulatory effects of Bregs are described in various models of autoimmune diseases, transplantation immunity and anti-tumor immunity. The recognition of mechanisms of Breg action may have a great impact for their potential use in a clinical setting.
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