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Background:
Inflammatory bowel disease (IBD) represents a dysregulation of the mucosal immune system. The pathogenesis of Crohn’s disease (CD) and ulcerative colitis (UC) is linked to the loss of intestinal tolerance and barrier function. The healthy mucosal immune system has previously been shown to be inert against food antigens. Since the small intestine is the main contact surface for antigens and therefore the immunological response, the present study served to analyse food-antigen-specific T cells in the peripheral blood of IBD patients.
Methods:
Peripheral blood mononuclear cells of CD, with an affected small intestine, and UC (colitis) patients, either active or in remission, were stimulated with the following food antigens: gluten, soybean, peanut and ovalbumin. Healthy controls and celiac disease patients were included as controls. Antigen-activated CD4+ T cells in the peripheral blood were analysed by a magnetic enrichment of CD154+ effector T cells and a cytometric antigen-reactive T-cell analysis (‘ARTE’ technology) followed by characterisation of the ef- fector response.
Results:
The effector T-cell response of antigen-specific T cells were compared between CD with small intestinal inflammation and UC where inflammation was restricted to the colon. Among all tested food antigens, the highest frequency of antigen-specific T cells (CD4+CD154+) was found for gluten. Celiac disease patients were included as control, since gluten has been identified as the disease- causing antigen. The highest frequency of gluten antigen-specific T cells was revealed in active CD when compared with UC, celiac disease on a gluten-free diet (GFD) and healthy controls. Ovalbuminspecific T cells were almost undetectable, whereas the reaction to soybean and peanut was slightly higher. But again, the strong- est reaction was observed in CD with small intestinal involvement compared with UC. Remarkably, in celiac disease on a GFD only
antigen-specific cells for gluten were detected. These gluten-specific T cells were characterised by up-regulation of the pro-inflammatory cytokines IFN-γ, IL-17A and TNF-α. IFN-g was exclusively elevated in CD patients with active disease. Gluten-specific T-cells expressing IL-17A were increased in all IBD patients. Furthermore, T cells of CD patients, independent of disease activity, revealed a high expression of the pro-inflammatory cytokine TNF-α.
Conclusion:
The ‘ARTE’-technique allows to analyse and quantify food antigen specific T cells in the peripheral blood of IBD patients indicating a potential therapeutic insight. These data provide evidence that small intestinal inflammation in CD is key for the development of a systemic pro-inflammatory effector T-cell response driven by food antigens.
New data from the LEADER trial show that the glucagon-like peptide 1 receptor agonist liraglutide protects against diabetic nephropathy in patients with type 2 diabetes mellitus. The renoprotective efficacy of liraglutide is not, however, as great as that reported for the sodium-glucose cotransporter 2 inhibitor emplagiflozin in the EMPA-REG OUTCOME trial.
Oxidative posttranslationale Modifikationen endogener Proteine werden v. a. durch reaktive Sauerstoff- und Stickstoffspezies (engl:. Reactive Oxygen Species, ROS, reactive nitrogen species, RNS) hervorgerufen und können sowohl reversibel (z. B. Disulfidbindungen) als auch irreversibel (z. B. Proteincarbonyle) erfolgen [1–3]. Lange wurde angenommen, dass oxidative posttranslationale Proteinmodifikationen (oxPTPM) nur von untergeordneter Bedeutung für den Metabolismus sind. Tatsächlich handelt es sich jedoch um einen physiologischen Prozess, der über die Modulation der Proteinstruktur auch die Proteinfunktion (z. B. Enzymaktivität, Stabilität) und somit zahlreiche Stoffwechselwege wie den Energiestoffwechsel, die Immunfunktion, die vaskuläre Funktion sowie Apoptose und Genexpression beeinflussen kann. Die Bildung von oxPTPM ist dabei hochreguliert und hängt u. a. von der Proteinstruktur, der Verfügbarkeit von ROS und RNS sowie dem lokalen Mikromilieu der Zelle ab [2, 4].
Preclinical assessment of penetration not only in intact, but also in barrier‐disrupted skin is important to explore the surplus value of novel drug delivery systems, which can be specifically designed for diseased skin. Here, we characterized physical and chemical barrier disruption protocols for short‐term ex vivo skin cultures with regard to structural integrity, physiological and biological parameters. Further, we compared the penetration of dexamethasone (Dex) in different nanoparticle‐based formulations in stratum corneum, epidermis and dermis extracts of intact vs. barrier‐disrupted skin as well as by dermal microdialysis at 6, 12 and 24 hours after topical application. Dex was quantified by liquid‐chromatography ‐ tandem‐mass spectrometry (LC‐MS/MS). Simultaneously, we investigated the Dex efficacy by interleukin (IL) analysis. Tape‐stripping (TS) and 4 hours sodium lauryl sulfate 5 % (SLS) exposure were identified as highly effective barrier disruption methods assessed by reproducible transepidermal water loss (TEWL) changes and IL‐6/8 increase which was more pronounced in SLS‐treated skin. The barrier state has also a significant impact on the Dex penetration kinetics: for all formulations, TS highly increased dermal Dex concentration despite the fact that nanocrystals quickly and effectively penetrated both, intact and barrier‐disrupted skin reaching significantly higher dermal Dex concentration after 6 hours compared to Dex cream. The surplus value of encapsulation in ethyl cellulose nanocarriers could mostly be observed when applied on intact skin, in general showing a delayed Dex penetration. Estimation of cytokines was limited due to the trauma caused by probe insertion. In summary, ex vivo human skin is a highly interesting short‐term preclinical model for the analysis of penetration and efficacy of novel drug delivery systems.