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
• Názvy látek
• interferon gama MeSH

Dendritic cells (DCs) are key regulators of immune responses that operate at the interface between innate and adaptive immunity, and defects in DC functions contribute to the pathogenesis of a variety of disorders. For instance, cancer evolves in the context of limited DC activity, and some autoimmune diseases are initiated by DC-dependent antigen presentation. Thus, correcting aberrant DC functions stands out as a promising therapeutic paradigm for a variety of diseases, as demonstrated by an abundant preclinical and clinical literature accumulating over the past two decades. However, the therapeutic potential of DC-targeting approaches remains to be fully exploited in the clinic. Here, we discuss the unique features of DCs that underlie the high therapeutic potential of DC-targeting strategies and critically analyze the obstacles that have prevented the full realization of this promising paradigm.

• Klíčová slova
• autoimmune disorders, cancer, dendritic cells, immunotherapy, vaccine preparation,
• MeSH
• antigen prezentující buňky imunologie   metabolismus   MeSH
• autoimunita MeSH
• autoimunitní nemoci etiologie   metabolismus   terapie   MeSH
• buněčná diferenciace genetika   imunologie   MeSH
• dendritické buňky imunologie   metabolismus   MeSH
• imunita * MeSH
• imunologická tolerance * MeSH
• imunoterapie MeSH
• lidé MeSH
• mezibuněčná komunikace MeSH
• náchylnost k nemoci MeSH
• nádory etiologie   metabolismus   patologie   terapie   MeSH
• plasticita buňky genetika   imunologie   MeSH
• prezentace antigenu imunologie   MeSH
• protinádorové vakcíny aplikace a dávkování   imunologie   MeSH
• T-lymfocyty imunologie   metabolismus   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• protinádorové vakcíny MeSH

Tolerogenic dendritic cells (tolDCs) are explored as a promising standalone or combination therapy in type 1 diabetes (T1D). The therapeutic application of tolDCs, including in human trials, has been tested also in other autoimmune diseases, however, T1D displays some unique features. In addition, unlike in several disease-induced animal models of autoimmune diseases, the prevalent animal model for T1D, the NOD mouse, develops diabetes spontaneously. This review compares evidence of various tolDCs approaches obtained from animal (mainly NOD) models of T1D with a focus on parameters of this cell-based therapy such as protocols of tolDC preparation, antigen-specific vs. unspecific approaches, doses of tolDCs and/or autoantigens, application schemes, application routes, the migration of tolDCs as well as their preventive, early pre-onset intervention or curative effects. This review also discusses perspectives of tolDC therapy and areas of preclinical research that are in need of better clarification in animal models in a quest for effective and optimal tolDC therapies of T1D in humans.

• Klíčová slova
• NOD mouse, animal models, cell therapy, protocol optimization, tolerogenic dendritic cells, type 1 diabetes,
• MeSH
• dendritické buňky imunologie   transplantace   MeSH
• diabetes mellitus 1. typu imunologie   MeSH
• imunologická tolerance imunologie   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední NOD MeSH
• myši MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy 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.

• Klíčová slova
• cell-based therapy, dendritic cells, diabetes mellitus, hyperglycemia, immune tolerance,
• 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
• Názvy látek
• reaktivní formy kyslíku MeSH

UNLABELLED: Tolerogenic DCs (tolDCs) are being researched as a promising intervention strategy also in autoimmune diseases including type 1 diabetes (T1D). T1D is a T-cell-mediated, organ-specific disease with several well-defined and rather specific autoantigens, i.e., proinsulin, insulin, glutamic acid decarboxylase 65 (GAD65), that have been used in animal as well as human intervention trials in attempts to achieve a more efficient, specific immunotherapy. In this study, we have tested tolerogenic DCs for their effectiveness to prevent adoptive transfer of diabetes by diabetogenic splenocytes into non-obese diabetes (NOD)-severe combined immunodeficiency (NOD-SCID) recipients. While i.p. application of tolDCs prepared from bone marrow of prediabetic NOD mice by vitamin D2 and dexamethasone significantly reduced diabetes transfer into the NOD-SCID females, this effect was completely abolished when tolDCs were loaded with the mouse recombinant GAD65, but also with a control protein-ovalbumin (OVA). The effect was not dependent on the presence of serum in the tolDC culture. Similar results were observed in NOD mice. Removal of possible bystander antigen-presenting cells within the diabetogenic splenocytes by negative magnetic sorting of T cells did not alter this surprising effect. Tolerogenic DCs loaded with an immunodominant mouse GAD65 peptide also displayed diminished diabetes-preventive effect. Tolerogenic DCs were characterized by surface maturation markers (CD40, CD80, CD86, MHC II) and the lipopolysaccharide stability test. Data from alloreactive T cell proliferation and cytokine induction assays (IFN-γ) did not reveal the differences observed in the diabetes incidence. Migration of tolDCs, tolDCs-GAD65 and tolDCs-OVA to spleen, mesenteric- and pancreatic lymph nodes displayed similar, mucosal pattern with highest accumulation in pancreatic lymph nodes present up to 9 days after the i.p. APPLICATION: These data document that mechanisms by which tolDCs operate in vivo require much better understanding for improving efficacy of this promising cell therapy, especially in the presence of an antigen, e.g., GAD65.

• Klíčová slova
• autoantigen, cell therapy, dendritic cells, glutamic acid decarboxylase 65, non-obese diabetes mice, non-obese diabetes-severe combined immunodeficiency mouse, tolerogenic, type 1 diabetes,
• MeSH
• autoantigeny imunologie   MeSH
• dendritické buňky imunologie   MeSH
• diabetes mellitus 1. typu imunologie   MeSH
• glutamát dekarboxyláza imunologie   MeSH
• imunologická tolerance imunologie   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši inbrední NOD MeSH
• myši SCID MeSH
• myši MeSH
• převzatá imunita MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• autoantigeny MeSH
• glutamát dekarboxyláza MeSH
• glutamate decarboxylase 2 MeSH Prohlížeč