The presence of myenteric plexitis in the proximal resection margins is a predictive factor of early postoperative recurrence in Crohn's disease. To decipher the mechanisms leading to their formation, T-cell interactions with enteric neural cells were studied in vitro and in vivo.
T cells close to myenteric neural cells were retrospectively quantified in ileocolonic resections from 9 control subjects with cancer and 20 patients with Crohn's disease. The mechanisms involved in T-cell adhesion were then investigated in co-cultures of T lymphocytes with enteric glial cells (glia). Finally, the implication of adhesion molecules in the development of plexitis and colitis was studied in vitro but also in vivo in Winnie mice.
The mean number of T cells close to glia, but not neurons, was significantly higher in the myenteric ganglia of relapsing patients with Crohn's disease (2.42 ± 0.5) as compared with controls (0.36 ± 0.08, P = .0007). Co-culture experiments showed that exposure to proinflammatory cytokines enhanced T-cell adhesion to glia and increased intercellular adhesion molecule-1 (ICAM-1) expression in glia. We next demonstrated that T-cell adhesion to glia was inhibited by an anti-ICAM-1 antibody. Finally, using the Winnie mouse model of colitis, we showed that the blockage of ICAM-1/lymphocyte function-associated antigen-1 (LFA-1) with lifitegrast reduced colitis severity and decreased T-cell infiltration in the myenteric plexus.
Our present work argues for a role of glia-T-cell interaction in the development of myenteric plexitis through the adhesion molecules ICAM-1/LFA-1 and suggests that deciphering the functional consequences of glia-T-cell interaction is important to understand the mechanisms implicated in the development and recurrence of Crohn's disease.
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

Novel therapeutics have sought to stimulate the endogenous repair mechanisms in the mammalian myocardium as the native regenerative potential of the adult cardiac tissue is limited. In particular, a myocardial matrix derived injectable hydrogel has shown efficacy and safety in various animal myocardial infarction (MI) including evidence of increased myocardium. In this study, investigation on the properties of this myocardial matrix material demonstrated its native capability as an effective reactive oxygen species (ROS) scavenger that can protect against oxidative stress and maintain cardiomyocyte proliferation in vitro. In vivo assessment of of myocardial matrix hydrogel treatment post-MI demonstrated increased thymidine analog uptake in cardiomyocytes compared to saline controls along with co-staining with cell cycle progression marker, phospho-histone H3. Overall, this study provides further evidence that properties of the myocardial matrix hydrogel promote an environment supportive of cardiomyocytes undergoing cell cycle progression.

Our research in the past few years has identified B cell-specific biomarkers able to predict optimal Ab responses in both young and elderly individuals. These biomarkers are activation-induced cytidine deaminase (AID), the enzyme of class switch recombination and somatic hypermutation; the transcription factor E47, crucial for AID expression; and the ability to generate optimal memory B cells. Moreover, we have found that the increased proinflammatory status of the elderly, both in sera and intrinsic to B cells, negatively impacts B cell function. We have now investigated whether particular inflammatory microRNAs (miRs) contribute to decreased E47 and AID in aged B cells. Our data indicate that E47 and AID mRNA stability is lower in stimulated B cells from elderly individuals. We measured the expression of two miRs crucial for class switch recombination, miR-155 and miR-16, in human unstimulated B cells from young and elderly individuals with the rationale that increases in these before stimulation would decrease E47/AID upon cell activation. We found these miRs and B cell-intrinsic inflammation upregulated in aged unstimulated B cells and negatively associated with AID in the same B cells after stimulation with CpG. We propose that the downregulation of AID in aged human B cells may occur through binding of miR-155 to the 3'-untranslated regions of AID mRNA and/or binding of miR-16 to the 3'-untranslated regions of E47 mRNA, as well as at the transcriptional level of less E47 for AID. Our results indicate novel molecular pathways leading to reduced B cell function with aging.
Copyright © 2015 by The American Association of Immunologists, Inc.

We aimed to investigate the osteogenic properties of bone marrow stromal cell (BMSC)-loaded biomimetic constructs composed of hydroxyapatite (HA), with or without in vitro cell-derived extracellular matrix (HA-ECM), and to assess the cellular components of the elicited foreign body reaction. HA-ECM constructs were produced by adult rat dermal fibroblasts cultured on top of synthetic HA microparticles. Rat calvarial critical-sized defects (8 mm) were created and treated with the generated HA-ECM constructs or HA microparticles, alone or combined with green fluorescent protein (GFP)-expressing BMSCs. The new bone formation and the local cellular inflammatory response (macrophages, neutrophils, lymphocytes, eosinophils and PCNA-index) were assessed by histomorphometry and immunohistochemistry at 2 and 12 weeks postoperatively. In addition, the BMSCs' survival and engraftment were checked. The largest volume of the newly formed bone was found in defects treated with HA-ECM constructs combined with BMSCs (p < 0.05). Moreover, the implanted BMSCs modulated the local inflammatory response, demonstrated by either a significant increase (HA vs HA + BMSCs) or decrease (HA-ECM vs HA-ECM + BMSCs) of the inflammatory cell number. No donor BMSCs were detected at the site of implantation or in the host bone marrow at 2 or 12 weeks postoperatively. In conclusion, the treatment of critical-sized calvarial defects with the BMSC-loaded biomimetic constructs has significantly enhanced bone repair by modulating the foreign body reaction. Our findings highlight the implications of BMSCs in the regulation of the foreign body reaction triggered by tissue-engineered constructs, proving a higher efficiency for the BMSC combination therapy.
Copyright © 2012 John Wiley & Sons, Ltd.

Aging significantly decreases the influenza vaccine-specific response as we and others have previously shown. Based on our previous data in aged mice, we hypothesize that the inflammatory status of the individual and of B cells themselves would impact B cell function. We here show that the ability to generate a vaccine-specific antibody response is negatively correlated with levels of serum TNF-α. Moreover, human unstimulated B cells from elderly make higher levels of TNF-α than those from young individuals, and these positively correlate with serum TNF-α levels. These all negatively correlate with B cell function, measured by activation-induced cytidine deaminase, the enzyme of class switch recombination and somatic hypermutation. Only memory B cells (either IgM or switched), but not naïve B cells, make appreciable levels of TNF-α and more in elderly as compared to young individuals. Finally, an anti-TNF-α antibody can increase the response in cultured B cells from the elderly, suggesting that TNF-α secreted by memory B cells affects IgM memory B cells and naïve B cells in an autocrine and/or paracrine manner. Our results show an additional mechanism for reduced B cell function in the elderly and propose B cell-derived TNF-α as another predictive biomarker of in vivo and in vitro B cell responses.
Copyright © 2014 Elsevier Inc. All rights reserved.