Objectives: The activation of immune responses in mucosal tissues is a key factor for the development and sustainment of several pathologies including infectious diseases and autoimmune diseases. However, translational research and personalised medicine struggle to advance because of the lack of suitable preclinical models that successfully mimic the complexity of human tissues without relying on in vivo mouse models. Here, we propose two in vitro human 3D tissue models, deprived of any resident leucocytes, to model mucosal tissue inflammatory processes. Methods: We developed human 3D lung and intestinal organoids differentiated from induced pluripotent stem cells to model mucosal tissues. We then compared their response to a panel of microbial ligands and investigated their ability to attract and host human primary monocytes. Results: Mature lung and intestinal organoids comprised epithelial (EpCAM+) and mesenchymal (CD73+) cells which responded to Toll-like receptor stimulation by releasing pro-inflammatory cytokines and expressing tissue inflammatory markers including MMP9, COX2 and CRP. When added to the organoid culture, primary human monocytes migrated towards the organoids and began to differentiate to an 'intermediate-like' phenotype characterised by increased levels of CD14 and CD16. Conclusion: We show that human mucosal organoids exhibit proper immune functions and successfully mimic an immunocompetent tissue microenvironment able to host patient-derived immune cells. Our experimental set-up provides a novel tool to tackle the complexity of immune responses in mucosal tissues which can be tailored to different human pathologies.
- Publication type
- Journal Article MeSH
V dnešnej dobe existuje niekoľko druhov liečby nešpecifických zápalov čreva alebo ich kombinácií, medzi ktorými sa často neľahko rozhodujeme. Príchod nových biologík umožňuje optimalizovať liečbu a podstatne zlepšiť priebeh ochorenia. Vedolizumab je monoklonálna protilátka proti α4β7 integrínu selektívna pre črevo, ktorá inhibuje vaskulárnu adhéziu leukocytov a ich migráciu do mukózy čreva interakciou s mukóznymi adresínmi črevných ciev. Je indikovaný u pacientov so stredne ťažkou a ťažkou formou ulceróznej kolitídy (UC - ulcerative colitis) a Crohnovej choroby. Nedávne štúdie potvrdzujú vyššiu efektivitu a bezpečnosť liečby vedolizumabom, či už u bionaivných pacientov v porovnaní s exponovanými anti-tumor nektorizujícímu faktoru (EVOLVE), alebo v priamom (head-to-head) porovnaní s adalimumabom (VARSITY), kde sa potvrdila vyššia klinická a endoskopická remisia u pacientov s UC.
Currently, there are several types of treatment for inflammatory bowel disease, but it is often difficult to decide on the best treatment. The arrival of new biologics helps us to optimize treatment and improve significantly the course of the disease. Vedolizumab is a monoclonal antibody against integrin α4β7. It is gut selective and inhibits vascular adhesion of leucocytes and their migration to the mucosa of the gut, as well as their interactions with mucosal addresins of the gut wall. It is approved for the treatment of moderate to severe form of ulcerative colitis (UC) and Crohn's disease. Recent studies confirm higher effectivityhave confirmed it to be more effective and safer than adalimumab (VARSITY clinical trial) in both bionaive and anti-tumor necrosis factor exposed (EVOLVE) patients, with higher clinical and endoscopic remission in patients with UC.
The age-related deterioration of the function of immune cells, or immunosenescence, is based on oxidative stress (an imbalance between the levels of oxidants and antioxidant defences with an increase of the former). Accordingly, the ingestion of a diet supplemented with thiolic antioxidants such as N-acetylcysteine (NAC), a glutathione precursor, by aged subjects improved their leucocyte functions. The aim of the present study was to show if NAC improves in vitro several functions of leucocytes from chronologically old mice and if this antioxidant is able to bring the values of these functions to the levels of those of adult animals. Six concentrations of NAC (in a range from 0.001 mM to 2.5 mM) were investigated on several functions of peritoneal leucocytes from old (78±2 weeks of age) BALB/c mice. These functions were those of the phagocytic process in macrophages, namely: adherence to substrate, directed migration or chemotaxis, phagocytosis of inert particles and superoxide anion levels as a measure of digestion capacity, as well as of the adherence and chemotaxis of lymphocytes. These functions were also studied in peritoneal leucocytes from adult (18±2 weeks of age) mice. The results showed that NAC in vitro improves all the functions studied, especially at the highest concentrations, which had shown impaired values in old mice, approaching those of adult animals. Since the immune functions studied are markers of health and predictors of longevity, the administration to aged subjects of NAC, which shows a direct action in leucocytes, seems to be a good strategy to improve their immune system and, therefore, to reach a healthy longevity.
- MeSH
- Acetylcysteine analogs & derivatives chemistry MeSH
- Antioxidants therapeutic use MeSH
- Animal Experimentation MeSH
- Financing, Organized MeSH
- Immune System Phenomena physiology drug effects MeSH
- Leukocytes drug effects MeSH
- Lymphocytes drug effects MeSH
- Macrophages drug effects MeSH
- Meta-Analysis as Topic MeSH
- Mice, Inbred BALB C MeSH
- Oxidative Stress physiology immunology drug effects MeSH
- Peritoneal Cavity cytology MeSH
- Aging physiology immunology pathology MeSH
- Statistics as Topic MeSH
- Animals MeSH
- Check Tag
- Female MeSH
- Animals MeSH
- MeSH
- Aniline Compounds administration & dosage toxicity MeSH
- Biodegradation, Environmental MeSH
- Cell Migration Inhibition MeSH
- Leukocytes physiology immunology drug effects MeSH
- Linuron analogs & derivatives pharmacokinetics toxicity MeSH
- Mitogens pharmacology MeSH
- In Vitro Techniques MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Female MeSH
- Animals MeSH
... CELL MIGRATION AND INFLAMMATION -- Dr David Male -- Cell Migration and Localization 13.2 -- Intercellular ... ... Anaemias 20.7 -- 18.5 Drug-induced Reactions to Blood -- 18.5 Components 20.8 -- 18.7 Reactions to Leucocytes ...
3rd ed. přeruš. str. : barev. fot., obr., tab., grafy, přeruš. lit., rejstř. ; 28 cm
- MeSH
- Allergy and Immunology MeSH
- Immune System MeSH
- Communicable Diseases immunology MeSH
- Neoplasms immunology MeSH
- Conspectus
- Patologie. Klinická medicína
- NML Fields
- alergologie a imunologie
- infekční lékařství
- NML Publication type
- učebnice vysokých škol
- MeSH
- Allergens MeSH
- Chromium adverse effects MeSH
- Diagnostic Techniques and Procedures MeSH
- Diagnosis MeSH
- Adult MeSH
- Cell Migration Inhibition MeSH
- Dermatitis, Contact diagnosis etiology MeSH
- Leukocytes MeSH
- Humans MeSH
- Nickel adverse effects MeSH
- In Vitro Techniques MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Comparative Study MeSH
- MeSH
- Antigens, Neoplasm MeSH
- Immunity, Cellular MeSH
- Cell Migration Inhibition MeSH
- Carcinoma MeSH
- Leukocytes MeSH
- Humans MeSH
- Ovarian Neoplasms MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Comparative Study MeSH
