Myeloid-derived suppressor cells (MDSC) represent a heterogeneous group of immature myeloid cells with immunoregulatory function in cancer and autoimmune diseases. In humans, two subsets of MDSC were determined based on the characteristic surface markers, monocytic MDSC (M-MDSC) and granulocytic MDSC (G-MDSC). Expansion of MDSC has been reported in some murine models and patients with autoimmune diseases and their immune-suppressive properties were characterized. However, the exact role of MDSC in the pathogenesis of autoimmune diseases is more complex and/or controversial. In type 1 diabetes mellitus (T1D), the increased frequency of MDSC was found in the blood of T1D patients but their suppressor capacity was diminished. In our study, we assessed the role of M-MDSC in the pathogenesis of T1D and showed for the first time the increased frequency of M-MDSC not only in the blood of T1D patients but also in their at-risk relatives compared to healthy donors. T1D patients with inadequate long term metabolic control showed an elevation of M-MDSC compared to patients with better disease control. Furthermore, we described the positive correlation between the percentage of M-MDSC and Th17 cells and IFN-γ producing T cells in T1D patients and their at-risk relatives. Finally, we found that the ability of M-MDSC to suppress autologous T cells is efficient only at the high MDSC: T cells ratio and dependent on cell-cell-contact and TGF-β production. Our data show that the engagement of MDSC in the pathogenesis of T1D is evident, yet not entirely explored and more experiments are required to clarify whether MDSC are beneficial or harmful in T1D.

• MeSH
• buňky Th17 imunologie   MeSH
• diabetes mellitus 1. typu krev   imunologie   MeSH
• dítě MeSH
• interferon gama metabolismus   MeSH
• lidé MeSH
• mladiství MeSH
• myeloidní supresorové buňky imunologie   MeSH
• počet CD4 lymfocytů MeSH
• regulační T-lymfocyty imunologie   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• autoimunita MeSH
• beta-buňky MeSH
• buněčná smrt MeSH
• buňky NK imunologie   MeSH
• diabetes mellitus 1. typu * etiologie   imunologie   prevence a kontrola   MeSH
• lidé MeSH
• NKT buňky imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

• MeSH
• autoimunita MeSH
• beta-buňky MeSH
• buněčná smrt MeSH
• buňky NK imunologie   MeSH
• diabetes mellitus 1. typu * etiologie   imunologie   prevence a kontrola   MeSH
• lidé MeSH
• NKT buňky imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH

Diabetes mellitus is characterized by long standing hyperglycemia leading to numerous life-threatening complications. For type 1 diabetes mellitus, resulting from selective destruction of insulin producing cells by exaggerated immune reaction, the only effective therapy remains exogenous insulin administration. Despite accurate compliance to treatment of certain patients, transient episodes of hyperglycemia cannot be completely eliminated by this symptomatic treatment. Novel immunotherapeutic approaches based on tolerogenic dendritic cells, T regulatory cells and mesenchymal stem cells (MSCs) have been tested in clinical trials, endeavoring to directly modulate the autoimmune destruction process in pancreas. However, hyperglycemia itself affects the immune system and the final efficacy of cell-based immunotherapies could be affected by the different glycemic control of enrolled patients. The present review explores the impact of hyperglycemia on immune cells while providing greater insight into the molecular mechanisms of high glucose action and subsequent metabolic reprogramming of different immune cells. Furthermore, over-production of mitochondrial reactive oxygen species, formation of advanced glycation end products as a consequence of hyperglycemia and their downstream signalization in immune cells are also discussed. Since hyperglycemia in patients with type 1 diabetes mellitus might have an impact on immune-interventional treatment, the maintenance of a tight glucose control seems to be beneficial in patients considered for cell-based therapy.

• MeSH
• dendritické buňky imunologie   metabolismus   transplantace   MeSH
• diabetes mellitus 1. typu imunologie   MeSH
• hyperglykemie imunologie   MeSH
• imunologická tolerance účinky léků   MeSH
• imunoterapie adoptivní metody   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• mezenchymální kmenové buňky imunologie   MeSH
• mitochondrie metabolismus   MeSH
• monitorování fyziologických funkcí MeSH
• přeprogramování buněk MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• regulační T-lymfocyty imunologie   transplantace   MeSH
• transplantace mezenchymálních kmenových buněk MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Tolerogenic dendritic cells (tolDCs) may offer an interesting intervention strategy to re-establish Ag-specific tolerance in autoimmune diseases, including type 1 diabetes (T1D). T1D results from selective destruction of insulin-producing β cells leading to hyperglycemia that, in turn, specifically affects a patient's immune system. In this study, we prepared monocyte-derived tolDCs modulated by dexamethasone and vitamin D2 from 31 T1D patients with optimal glycemic control and 60 T1D patients with suboptimal glycemic control and assessed their tolerogenic properties in correlation with metabolic state of patients. tolDCs differentiated from both groups of patients acquired a regulatory phenotype and an anti-inflammatory profile. Interestingly, tolDCs from well-controlled patients expressed higher levels of inhibitory molecules IL-T3 and PD-L1. Additionally, glutamic acid decarboxylase (GAD)65-loaded tolDCs from well-controlled patients decreased significantly primary Th1/Th17 responses, induced stable GAD65-specific T cell hyporesponsiveness, and suppressed markedly control DC-induced GAD65-specific T cell activation compared with poorly controlled patients. The ability of tolDCs from poorly controlled patients to induce durable GAD65-specific T cell hyporesponsiveness was reversed once the control of glycemia improved. In both groups of patients, tolDCs were able to induce regulatory T cells from autologous naive CD4(+) T cells. However, regulatory T cells from well-controlled patients had better suppressive abilities. The functionality of tolDCs was confirmed in the adoptive transfer model of NOD-SCID mice where tolDCs delayed diabetes onset. These results suggest that metabolic control of T1D affects the functional characteristics of tolDCs and subsequent effector T cell responses. Metabolic control may be relevant for refining inclusion criteria of clinical trials in the settings of T1D.

• MeSH
• aktivace lymfocytů imunologie   MeSH
• dendritické buňky imunologie   MeSH
• diabetes mellitus 1. typu imunologie   MeSH
• imunologická tolerance imunologie   MeSH
• lidé MeSH
• myši inbrední NOD MeSH
• myši SCID MeSH
• myši MeSH
• převzatá imunita MeSH
• průtoková cytometrie MeSH
• regulační T-lymfocyty imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Tolerogenní dendritické buňky představují specifickou skupinu dendritických buněk. Nachází se v různých tkáních a podílí se na udržování centrální i periferní imunologické tolerance širokým spektrem mechanismů. Mezi jejich nejdůležitější vlastnosti patří schopnost tlumit antigen-specifické T-lymfocyty, schopnost indukovat T-regulační a B-regulační buňky a produkce protizánětlivých cytokinů. Díky schopnosti navodit antigenně specifickou toleranci představují tolerogenní dendritické buňky slibný terapeutický nástroj pro léčbu autoimunitních onemocnění a dalších imunopatologických stavů bez nežádoucího efektu celkové imunosuprese. KLÍČOVÁ SLOVA: tolerogenní dendritické buňky, terapie, imunologická tolerance, autoimunitní choroby

Tolerogenic dendritic cells (tDC) are specific group of dendritic cells. At steady-state they are located in diverse tissue and play a pivotal role in maintaining central and peripheral immune tolerance. tDC restore and maintain immune homeostasis by inhibition of antigen-specific T-lymphocytes, induction of T-regulatory cells as well as B-regulatory cells and production of anti-inflammatory cytokines. tDC due to their ability to down-regulate immune response are promising tool to re-establish antigen-specific tolerance in autoimmune diseases without adverse effects of systemic immunosuppression. This interventional strategy also offers an interesting way to treat other immunopathological processes.

• Klíčová slova
• tolerogenní dendritické buňky,
• MeSH
• autoimunita MeSH
• autoimunitní nemoci * MeSH
• biomedicínský výzkum MeSH
• dendritické buňky * cytologie   imunologie   transplantace   MeSH
• diabetes mellitus 1. typu imunologie   terapie   MeSH
• imunologická tolerance * imunologie   účinky léků   MeSH
• imunoterapie MeSH
• lidé MeSH
• transplantace buněk MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

T regulatory cells (Tregs) are essential for maintaining tolerance and preventing autoimmune diseases, such as type 1 diabetes (T1D). In our study, we investigated CD25 + FoxP3 + Tregs and thymic FoxP3 + Helios + Tregs in large cohorts of children with T1D at onset and with long-term T1D, and further in their relatives and healthy controls. We observed significantly decreased numbers of CD25 + FoxP3 + Tregs, but not FoxP3 + Helios + Tregs, in long-term patients compared with the control group and T1D onset. Furthermore, long-term T1D patients exhibited highly significant decrease of CD25 expression on both CD25 + FoxP3 + Tregs and FoxP3 + Helios + Tregs, independently on age or the duration of diabetes. A similar reduction of CD25 expression was also found in T1D relatives, more significant in those with positive autoantibodies. Low CD25 expression was associated with impaired signal transducer and activator of transcription 5 (STAT5) phosphorylation after IL-2 exposure. Our results show that the frequency of Tregs is altered in a large cohort of long-term T1D patients, a profound decrease in CD25 expression and altered IL-2 signaling are typical features of Tregs populations in long-term diabetic patients and their relatives.

• MeSH
• biologické markery MeSH
• buněčná diferenciace MeSH
• diabetes mellitus 1. typu diagnóza   etiologie   metabolismus   MeSH
• dítě MeSH
• forkhead transkripční faktory metabolismus   MeSH
• fosforylace MeSH
• imunofenotypizace MeSH
• interleukin-2 metabolismus   farmakologie   MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• počet lymfocytů MeSH
• předškolní dítě MeSH
• receptor interleukinu-2 - alfa-podjednotka genetika   metabolismus   MeSH
• regulační T-lymfocyty cytologie   imunologie   metabolismus   MeSH
• signální transdukce MeSH
• studie případů a kontrol MeSH
• thymocyty cytologie   imunologie   metabolismus   MeSH
• transkripční faktor STAT5 MeSH
• věkové faktory MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Tolerogenic dendritic cells (tDCs) may offer an intervention therapy in autoimmune diseases or transplantation. Stable immaturity and tolerogenic function of tDCs after encountering inflammatory environment are prerequisite for positive outcome of immunotherapy. However, the signaling pathways regulating their stable tolerogenic properties are largely unknown. In this study, we demonstrated that human monocyte-derived tDCs established by using paricalcitol (analogue of vitamin D2), dexamethasone and monophosphoryl lipid A exposed for 24h to LPS, cytokine cocktail, polyI:C or CD40L preserved reduced expression of co-stimulatory molecules, increased levels of inhibitory molecules ILT-3, PDL-1 and TIM-3, increased TLR-2, increased secretion of IL-10 and TGF-β, reduced IL-12 and TNF-α secretion and reduced T cell stimulatory capacity. tDCs further induced IL-10-producing T regulatory cells that suppressed the proliferation of responder T cells. In the inflammatory environment, tDCs maintained up-regulated indoleamine 2, 3 dioxygenase but abrogated IκB-α phosphorylation and reduced transcriptional activity of p65/RelA, RelB and c-Rel NF-κB subunits except p50. Mechanistically, p38 MAPK, ERK1/2, mTOR, STAT3 and mTOR-dependent glycolysis regulated expression of ILT-3, PDL-1 and CD86, secretion of IL-10 and T cell stimulatory capacity of tDCs in the inflammatory environment. Stability of tDCs in the inflammatory environment is thus regulated by multiple signaling pathways.

• MeSH
• buněčná diferenciace fyziologie   MeSH
• dendritické buňky účinky léků   metabolismus   MeSH
• dexamethason farmakologie   MeSH
• ergokalciferoly farmakologie   MeSH
• glykolýza účinky léků   MeSH
• kultivované buňky MeSH
• lidé MeSH
• mitogenem aktivované proteinkinasy metabolismus   MeSH
• NF-kappa B metabolismus   MeSH
• signální transdukce MeSH
• TOR serin-threoninkinasy metabolismus   MeSH
• transkripční faktor STAT3 metabolismus   MeSH
• zánět metabolismus   patologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Celiac disease (CD) is a gluten-responsive, chronic inflammatory enteropathy. IL-1 cytokine family members IL-1β and IL-18 have been associated with the inflammatory conditions in CD patients. However, the mechanisms of IL-1 molecule activation in CD have not yet been elucidated. We show in this study that peripheral blood mononuclear cells (PBMC) and monocytes from celiac patients responded to pepsin digest of wheat gliadin fraction (PDWGF) by a robust secretion of IL-1β and IL-1α and a slightly elevated production of IL-18. The analysis of the upstream mechanisms underlying PDWGF-induced IL-1β production in celiac PBMC show that PDWGF-induced de novo pro-IL-1β synthesis, followed by a caspase-1 dependent processing and the secretion of mature IL-1β. This was promoted by K+ efflux and oxidative stress, and was independent of P2X7 receptor signaling. The PDWGF-induced IL-1β release was dependent on Nod-like receptor family containing pyrin domain 3 (NLRP3) and apoptosis-associated speck like protein (ASC) as shown by stimulation of bone marrow derived dendritic cells (BMDC) from NLRP3(-/-) and ASC(-/-) knockout mice. Moreover, treatment of human PBMC as well as MyD88(-/-) and Toll-interleukin-1 receptor domain-containing adaptor-inducing interferon-β (TRIF)(-/-) BMDC illustrated that prior to the activation of caspase-1, the PDWGF-triggered signal constitutes the activation of the MyD88/TRIF/MAPK/NF-κB pathway. Moreover, our results indicate that the combined action of TLR2 and TLR4 may be required for optimal induction of IL-1β in response to PDWGF. Thus, innate immune pathways, such as TLR2/4/MyD88/TRIF/MAPK/NF-κB and an NLRP3 inflammasome activation are involved in wheat proteins signaling and may play an important role in the pathogenesis of CD.

• MeSH
• adaptorové proteiny vezikulární transportní genetika   imunologie   MeSH
• celiakie MeSH
• dospělí MeSH
• gliadin chemie   imunologie   MeSH
• inflamasomy účinky léků   genetika   imunologie   MeSH
• interleukin-1beta genetika   imunologie   MeSH
• leukocyty mononukleární účinky léků   imunologie   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mitogenem aktivované proteinkinasy genetika   imunologie   MeSH
• myeloidní diferenciační faktor 88 genetika   imunologie   MeSH
• myši knockoutované MeSH
• myši MeSH
• pepsin A MeSH
• peptidové fragmenty farmakologie   MeSH
• primární buněčná kultura MeSH
• regulace genové exprese účinky léků   imunologie   MeSH
• signální transdukce účinky léků   genetika   imunologie   MeSH
• toll-like receptor 2 genetika   imunologie   MeSH
• toll-like receptor 4 genetika   imunologie   MeSH
• transportní proteiny genetika   imunologie   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Diplomová práce, která se zaměřila na imunologické aspekty rozvoje celiakie.

• MeSH
• buněčná imunita MeSH
• celiakie MeSH
• gliadin MeSH
• imunoanalýza MeSH
• interleukin-1beta MeSH
• kaspasa 1 MeSH
• klinické chemické testy MeSH
• přirozená imunita MeSH
• Publikační typ
• vysokoškolské kvalifikační práce MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• alergologie a imunologie
• gastroenterologie