scholarly journals Pro-Resolving Factors Released by Macrophages After Efferocytosis Promote Mucosal Wound Healing in Inflammatory Bowel Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Omayra Martin-Rodriguez ◽  
Thierry Gauthier ◽  
Francis Bonnefoy ◽  
Mélanie Couturier ◽  
Anna Daoui ◽  
...  
Keyword(s):  
Wound Healing ◽  
T Cell ◽  
Intestinal Cell ◽  
Apoptotic Cells ◽  
Cell Transfer ◽  
Inflammatory Bowel ◽  
T Cell Transfer ◽  
Naïve T Cell ◽  
Naive T Cell

Nonresolving inflammation is a critical driver of several chronic inflammatory diseases, including inflammatory bowel diseases (IBD). This unresolved inflammation may result from the persistence of an initiating stimulus or from the alteration of the resolution phase of inflammation. Elimination of apoptotic cells by macrophages (a process called efferocytosis) is a critical step in the resolution phase of inflammation. Efferocytosis participates in macrophage reprogramming and favors the release of numerous pro-resolving factors. These pro-resolving factors exert therapeutic effects in experimental autoimmune arthritis. Here, we propose to evaluate the efficacy of pro-resolving factors produced by macrophages after efferocytosis, a secretome called SuperMApo, in two IBD models, namely dextran sodium sulfate (DSS)-induced and T cell transfer-induced colitis. Reintroducing these pro-resolving factors was sufficient to decrease clinical, endoscopic and histological colitis scores in ongoing naive T cell-transfer-induced colitis and in DSS-induced colitis. Mouse primary fibroblasts isolated from the colon demonstrated enhanced healing properties in the presence of SuperMApo, as attested by their increased migratory, proliferative and contractive properties. This was confirmed by the use of human fibroblasts isolated from patients with IBD. Exposure of an intestinal epithelial cell (IEC) line to these pro-resolving factors increased their proliferative properties and IEC acquired the capacity to capture apoptotic cells. The improvement of wound healing properties induced by SuperMApo was confirmed in vivo in a biopsy forceps-wound colonic mucosa model. Further in vivo analysis in naive T cell transfer-induced colitis model demonstrated an improvement of intestinal barrier permeability after administration of SuperMApo, an intestinal cell proliferation and an increase of α-SMA expression by fibroblasts, as well as a reduction of the transcript coding for fibronectin (Fn1). Finally, we identified TGF-β, IGF-I and VEGF among SuperMApo as necessary to favor mucosal healing and confirmed their role both in vitro (using neutralizing antibodies) and in vivo by depleting these factors from efferocytic macrophage secretome using antibody-coated microbeads. These growth factors only explained some of the beneficial effects induced by factors released by efferocytic macrophages. Overall, the administration of pro-resolving factors released by efferocytic macrophages limits intestinal inflammation and enhance tissue repair, which represents an innovative treatment of IBD.

scholarly journals A7 AN INULIN-TYPE FRUCTAN ENRICHED EXCLUSIVE ENTERAL NUTRITION FORMULA MODULATES THE GUT MICROBIOME AND PROMOTES EXPANSION OF ANTI-INFLAMMATORY T CELL SUBSETS TO SUPPRESS COLITIS

2021 ◽  
Vol 4 (Supplement_1) ◽  
pp. 7-9
Author(s):  
G R Healey ◽  
K Tsai ◽  
D Lisko ◽  
B Vallance ◽  
K Jacobson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Gut Microbiome ◽  
T Cell Subsets ◽  
Cell Transfer ◽  
Exclusive Enteral Nutrition ◽  
Normal Chow ◽  
T Cell Transfer ◽  
Naïve T Cell ◽  
Naive T Cell

Abstract Background Exclusive enteral nutrition (EEN), a nutritionally complete fiber-free enteral formula, is the gold standard therapy for newly diagnosed children with Crohn’s disease (CD) but this therapy is not routinely used in pediatric ulcerative colitis patients due to lower efficacy in this subgroup. EEN therapy leads to high remission rates, however it also leads to a dysbiotic gut microbiota profile and disease relapse occurs in 60–80% of CD patients within 12 months of EEN discontinuation. Little is known about the mechanisms underlying the actions of EEN. Notably, previous studies have demonstrated that prebiotics, such as inulin-type fructans (IN), can beneficially modulate the gut microbiome, increase butyrate production and reduce inflammation by leading to anti-inflammatory T cell (i.e. FOXP3+IL10+ CD4+) expansion. To date, the effects of an IN enriched EEN (EEN IN) have not been studied. Aims To examine the effects of EEN vs EEN IN on colitis development, the gut microbiome and CD4+ T cell subsets using an adoptive T cell transfer model of colitis. Methods Mice were split into four groups: 1) Control – normal chow + PBS (n=13; negative control), 2) Chow – normal chow + naive T cell transfer (n=13; positive control), 3) EEN – Ensure Plus® + naive T cell transfer (n=13) and 4) EEN IN – Ensure Plus® with 3% IN + naive T cell transfer (n=13). Naïve T cells (or PBS) were transferred into TCR-b deficient mice and each group was started on their subsequent diets. The naïve T cells will expand into anti- or pro-inflammatory T cells subsets to either cause or suppress colitis in a gut microbiome dependent manner. Body weight and disease activity were monitored for 5-weeks. At the end of the experiment, spleen weights and colon lengths were recorded. Spleen and mesenteric/colonic lymph nodes (MLN) were collected for T cell subset analysis using flow cytometry. Gut microbiota differences were assessed using ddPCR. Short-chain fatty acid levels were analyzed using gas chromatography. The histopathology of the distal colon was scored. Results Mice fed EEN IN showed a reduction in colonic shortening (p<0.001) and histology scores (p=0.0088) compared to EEN mice, and reduced disease activity (p=0.0046) compared to Chow mice. Moreover, EEN IN mice showed a higher expansion of FOXP3+IL10+ CD4+ T cells in the MLN (p=0.0424) and spleen (p=0.0088). EEN IN also led to higher butyrate, Bifidobacterium and Bacteroides concentrations compared to EEN (p=0.0113, p=0.0063, p=0.0224; respectively) and Chow (p=0.0252, p=0.0042, p=0.0416; respectively). Conclusions EEN IN lead to superior outcomes compared to EEN and Chow. These results provide evidence to support undertaking a clinical trial utilizing EEN IN in pediatric inflammatory bowel disease patients. Funding Agencies Michael Smith Foundation for Health Research

CMVpp65-Specific T cells generated from naïve T cell populations recognize atypical but not canonical epitopes and may be protective in Vivo

Cytotherapy ◽  
2015 ◽  
Vol 17 (6) ◽  
pp. S9-S10
Author(s):  
Patrick Hanley ◽  
Joseph Melenhorst ◽  
Russell Cruz ◽  
Caridad Martinez ◽  
Helen Heslop ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Populations ◽  
Naïve T Cell ◽  
Naive T Cell

P098 Receptor-interacting protein 1 kinase inhibition therapeutically ameliorates experimental T-cell-dependent colitis in mice

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S184-S184
Author(s):  
T Gobbetti ◽  
F Kathryn ◽  
A Beal ◽  
A Rowles ◽  
G Pearse ◽  
...  
Keyword(s):  
T Cell ◽  
Kinase Activity ◽  
Mucosal Damage ◽  
Transfer Model ◽  
Cell Transfer ◽  
Chronic Colitis ◽  
Kinase Inhibition ◽  
Interacting Protein ◽  
Inflammatory Bowel ◽  
T Cell Transfer

Abstract Background Inflammatory bowel disease (IBD) is a multifactorial disorder characterised by chronic and relapsing intestinal inflammation. Receptor-interacting protein 1 (RIP1) kinase activity is emerging as a driver of pro-inflammatory cytokine production and cell death and has been implicated in multiple inflammatory diseases including IBD. To this end, recent work has shown that RIP1 kinase inhibition reduces the spontaneous production of cytokines from human ulcerative colitis (UC) and Crohn’s disease explants. Methods The aim of this study was to investigate the anti-inflammatory effect of a highly selective inhibitor of RIP1 kinase activity (GSK547A) in the mouse T-cell transfer model of colitis; a model that shares many features with human IBD. All animal studies were ethically reviewed and carried out in accordance with Animals (Scientific Procedures) Act 1986 and the GSK Policy on the Care, Welfare and Treatment of Animals. Chronic colitis was achieved by transferring CD4+CD45RBhigh T cells into immunodeficient female SCID mice (6/8 weeks old). After confirming the development of pathology using endoscopy and MRI, animals were treated therapeutically with the RIP1 inhibitor GSK547A (50 mg/kg twice a day PO) or vehicle (0.5% hydroxypropyl methylcellulose in water). The severity of colitis was measured 5 weeks after cell transfer both macro- and microscopically. Mucosal damage by endoscopy was also assessed. RT-PCR and MSD analysis were performed to detect colon cytokine/chemokine and calprotectin levels. SAA in the plasma was measured using ELISA. Results We found that treatment with GSK547 significantly ameliorated experimental T-cell-dependent colitis in mice. GSK547A-treated mice displayed decreased weight loss, colon density (ratio weight/length), macroscopic disease activity index, colon thickness compared with vehicle-treated animals. Mucosal damage, assessed by endoscopy and histopathology, was also reduced following treatment with RIP1 kinase inhibitor. In addition, GSK547A reduced the expression of cytokines in the colon (TNF-α, IL-17A, INF-γ, IL-6 and MCP-1), both at a protein and RNA level. Relevant translational biomarkers such as SAA in plasma and RNA calprotectin in the colon were also decreased in the GSK547A treated group when compared with vehicle. Conclusion Our results suggest that RIP1K inhibition is a strong protective factor with anti-inflammatory potential in the progression of chronic colitis, when applied to the translationally relevant T-cell transfer model of colitis. These findings suggest the potential application in the management of inflammatory bowel disease and support the ongoing clinical program evaluating the effect of RIP1 kinase inhibition in UC patients.

Adoptive Transfer of Adenovirus Specific T-Cells in Children with Systemic Adenovirus Infection after Allogeneic Stem Cell Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 80-80
Author(s):  
Tobias F. Feuchtinger ◽  
Susanne Matthes-Martin ◽  
Celine Richard ◽  
Thomas Lion ◽  
Klaus Hamprecht ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Adoptive Transfer ◽  
Cell Transfer ◽  
New Treatment ◽  
T Cell Transfer

Abstract Allogeneic stem cell transplantation (SCT) has become an increasing treatment option for a variety of malignant and non-malignant disease. During immune reconstitution the host is at significant risk for viral infections. Human adenovirus (HAdV) infection is especially in children an important and serious complication. Virus-specific T-cells are essential for the clearance of HAdV, since antiviral chemotherapy has been insufficient to date. We present a new treatment option using virus-specific donor T-cells for adoptive transfer of immunity to patients with systemic HAdV-infection. We isolated in 6 patients with systemic HAdV-infection after SCT virus-specific T-cells of the donor, according to INF-γ secretion after short in vitro stimulation with viral antigen, resulting in a combination of CD4+ and CD8+ T-cells. Between 5-50x103/kg T-cells were infused for adoptive transfer. For follow-up, the infection and the in-vivo expansion of infused T-cells were evaluated. Isolated cells showed high specificity and markedly reduced but residual alloreactivity in-vitro. In three of four evaluable patients the infused T-cells underwent an in-vivo expansion and in these three patients the viral load decreased in peripheral blood after adoptive T-cell transfer. In-vivo expansion of specific T-cells was dose-independent. T-cell infusion was well tolerated. One patient experienced GvHD°II of the skin after T-cell transfer. In conclusion specific T-cell immunotherapy as a new treatment approach for children was performed in 6 cases of systemic HAdV-infection after allogeneic SCT. Induction of a specific T-cell response through adoptive transfer has been shown feasible and effective to protect from HAdV-related complications.

scholarly journals Carboxylesterase-1 assisted targeting of HDAC inhibitors to mononuclear myeloid cells in Inflammatory Bowel Disease

2021 ◽  
Author(s):  
Ahmed M I Elfiky ◽  
Mohammed Ghiboub ◽  
Andrew Y F Li Yim ◽  
Ishtu L Hageman ◽  
Jan Verhoeff ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Dendritic Cells ◽  
T Cell ◽  
Human Blood ◽  
Bowel Disease ◽  
Cell Transfer ◽  
Inflammatory Bowel ◽  
Carboxylesterase 1 ◽  
T Cell Transfer

Abstract Background and Aims Histone deacetylase inhibitors (HDACi) exert potent anti-inflammatory effects. Because of the ubiquitous expression of HDACs, clinical utility of HDACi is limited by off-target effects. Esterase-sensitive motif (ESM) technology aims to deliver ESM-conjugated compounds to human mononuclear myeloid cells, based on their expression of carboxylesterase 1 (CES1). This study aims to investigate utility of an ESM-tagged HDACi in inflammatory bowel disease (IBD). Methods CES1 expression was assessed in human blood, in vitro differentiated macrophage and dendritic cells and Crohn's disease (CD) colon mucosa by mass cytometry, quantitative PCR and immunofluorescence staining respectively. ESM-HDAC528 intracellular retention was evaluated by mass spectrometry. Clinical efficacy of ESM-HDAC528 was tested in DSS-induced colitis and T cell transfer colitis models using transgenic mice expressing human CES1 under the CD68 promotor. Results CES1 mRNA was highly expressed in human blood CD14 + monocytes, in vitro differentiated and LPS stimulated macrophages and dendritic cells. Specific hydrolysis and intracellular retention of ESM-HDAC528 in CES1 + cells was demonstrated. ESM-HDAC528 inhibited LPS-stimulated IL-6 and TNF-α production 1000 times more potently than its control, HDAC800, in CES1 high monocytes. In healthy donors peripheral blood, CES1 expression was significantly higher in CD14 ++CD16 - monocytes compared to CD14 +CD16 ++ monocytes. In CD inflamed colon, a higher number of mucosal CD68 + macrophages expressed CES1 compared to non-inflamed mucosa. In vivo, ESM-HDAC528 reduced monocyte differentiation in the colon and significantly improved colitis in a T cell transfer model, whilst having limited potential in ameliorating DSS-induced colitis. Conclusions We demonstrate that monocytes and inflammatory macrophages specifically express CES1, and can be preferentially targeted by ESM-HDAC528 to achieve therapeutic benefit in IBD.

Balance of NLRP3-Mediated IL-1β and IL-18 Signaling Regulates Colitis Induction in a T Cell Transfer Model of Inflammatory Bowel Disease

2017 ◽  
Vol 152 (5) ◽  
pp. S615
Author(s):  
Rachel Mak'Anyengo ◽  
Peter Duewell ◽  
Hans Anton Lehr ◽  
Sandra Fischer ◽  
Thomas Clavel ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
T Cell ◽  
Bowel Disease ◽  
Transfer Model ◽  
Cell Transfer ◽  
Inflammatory Bowel ◽  
T Cell Transfer

scholarly journals IMMU-07. CELLULAR IMMUNOTHERAPY TO OVERCOME TEMOZOLOMIDE INDUCED T CELL EXHAUSTION IN GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi120-vi120
Author(s):  
Aida Karachi ◽  
Farhad Dastmalchi ◽  
Ashley O’Malley ◽  
Megan Saia ◽  
Duane Mitchell ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Transfer ◽  
T Cell Exhaustion ◽  
Ifn Gamma ◽  
Cell Exhaustion ◽  
Tumor Bearing ◽  
Dc Vaccines ◽  
T Cell Transfer ◽  
Naive T Cell

Abstract INTRODUCTION We have previously demonstrated that standard dose (SD) temozolomide results in T cell exhaustion in glioblastoma. In this study, we hypothesized that cellular immunotherapies will prevent T cell exhaustion. We tested temozolomide treatment with adoptive T cell transfer alone, dendritic cell (DC) vaccines alone and T cell transfer in combination with DC vaccines. METHOD GL-261-gp100 tumor-bearing mice were treated with SD (50 mg/kg for 5 days) or metronomic dose (MD) (25 mg/kg for 10 days) temozolomide. CD3+ T cells were isolated from Pmel mice and infused intravenously. Antigen-specific DC vaccines (gp-100) were given intradermally at the concentration of 50×104. Peripheral blood T cell populations were evaluated by flow cytometry. IFN-gamma secretion was measured for evaluation of T cells function. Survival was compared between groups. RESULTS Survival analysis demonstrated that naïve T cell transfer alone and DC vaccine alone add no survival benefit to temozolomide treatment for tumor-bearing animals. There were no significant differences in the expression of exhaustion markers of Tim-3 and Lag-3 on T cells of animals that received a combination of activated T cells and DC vaccines in the context of temozolomide therapy compared to the animals that just received temozolomide. Combination of activated T cell transfer and DC vaccines did not increase IFN-gamma secretion from T cells compared to temozolomide treated animals. Combination of naïve T cell transfer and two DC vaccines increased IFN-gamma secretion from T cells of GL-261 gp100 tumor-bearing animals. However, naïve T cell transfer and two DC vaccines in the context of temozolomide was not potent enough to extend the survival of these tumor-bearing animals. CONCLUSION Combinatorial treatment with naïve antigen-specific T cells and three dendritic cell vaccine boosters in the context of temozolomide is a promising approach to preserve T cell function and avoid T cell exhaustion.

scholarly journals Autophagy-independent functions of UVRAG are essential for peripheral naive T-cell homeostasis

2015 ◽  
Vol 112 (4) ◽  
pp. 1119-1124 ◽  
Author(s):  
Samia Afzal ◽  
Zhenyue Hao ◽  
Momoe Itsumi ◽  
Yasser Abouelkheer ◽  
Dirk Brenner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Gene Knockout ◽  
Homozygous Deletion ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
Independent Functions ◽  
Naïve T Cell ◽  
Naive T Cell

UV radiation resistance-associated gene (UVRAG) encodes a tumor suppressor with putative roles in autophagy, endocytic trafficking, and DNA damage repair but its in vivo role in T cells is unknown. Because conditional homozygous deletion of Uvrag in mice results in early embryonic lethality, we generated T-cell–specific UVRAG-deficient mice that lacked UVRAG expression specifically in T cells. This loss of UVRAG led to defects in peripheral homeostasis that could not be explained by the increased sensitivity to cell death and impaired proliferation observed for other autophagy-related gene knockout mice. Instead, UVRAG-deficient T-cells exhibited normal mitochondrial clearance and activation-induced autophagy, suggesting that UVRAG has an autophagy-independent role that is critical for peripheral naive T-cell homeostatic proliferation. In vivo, T-cell–specific loss of UVRAG dampened CD8+ T-cell responses to LCMV infection in mice, delayed viral clearance, and impaired memory T-cell generation. Our data provide novel insights into the control of autophagy in T cells and identify UVRAG as a new regulator of naïve peripheral T-cell homeostasis.

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