scholarly journals Ameliorating effect of anti-Fas ligand MAb on wasting disease in murine model of chronic colitis

2003 ◽  
Vol 285 (4) ◽  
pp. G754-G760 ◽  
Author(s):  
N. Dan ◽  
T. Kanai ◽  
T. Totsuka ◽  
R. Iiyama ◽  
M. Yamazaki ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lamina Propria ◽  
Fas Ligand ◽  
Intestinal Inflammation ◽  
Therapeutic Effects ◽  
Cell Transfer ◽  
Chronic Colitis ◽  
Wasting Disease ◽  
T Cell Transfer

Fas/Fas ligand (FasL) interaction has been implicated in the pathogenesis of various diseases. To clarify the involvement of Fas/FasL in the pathogenesis of intestinal inflammation, we investigated the preventive and therapeutic effects of neutralizing anti-FasL monoclonal antibody (MAb) on the development of chronic colitis induced by adaptive transfer of CD4+CD45RBhigh T cells to SCID mice. Administration of anti-FasL MAb from 1 day after T cell transfer (prevention study) resulted in a significant improvement of clinical manifestations such as wasting and diarrhea. However, histological examination showed that mucosal inflammation in the colon, such as infiltration of T cells and macrophages, was not improved by the anti-FasL MAb treatment. In vitro studies showed that anti-FasL MAb did not inhibit IFN-γ production by anti-CD3/CD28-stimulated lamina propria CD4+ T cells but suppressed TNF-α and IL-1β production by lamina propria mononuclear cells. Therapeutic administration of anti-FasL MAb from 3 wk after T cell transfer also improved ongoing wasting disease but not intestinal inflammation. These results suggest that the Fas/FasL interaction plays a critical role in regulating systemic wasting disease but not local intestinal inflammation.

scholarly journals Commensal epitopes drive differentiation of colonic Tregs

2020 ◽  
Vol 6 (16) ◽  
pp. eaaz3186 ◽  
Author(s):  
Michal P. Kuczma ◽  
Edyta A. Szurek ◽  
Anna Cebula ◽  
Benoit Chassaing ◽  
Yu-Jin Jung ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptors ◽  
Intestinal Inflammation ◽  
Transfer Model ◽  
Cell Transfer ◽  
Wasting Disease ◽  
New Approach ◽  
Lymphocyte Responses ◽  
T Cell Transfer

The gut microbiome is the largest source of intrinsic non–self-antigens that are continuously sensed by the immune system but typically do not elicit lymphocyte responses. CD4+ T cells are critical to sustain uninterrupted tolerance to microbial antigens and to prevent intestinal inflammation. However, clinical interventions targeting commensal bacteria–specific CD4+ T cells are rare, because only a very limited number of commensal-derived epitopes have been identified. Here, we used a new approach to study epitopes and identify T cell receptors expressed by CD4+Foxp3+ (Treg) cells specific for commensal-derived antigens. Using this approach, we found that antigens from Akkermansia muciniphila reprogram naïve CD4+ T cells to the Treg lineage, expand preexisting microbe specific Tregs, and limit wasting disease in the CD4+ T cell transfer model of colitis. These data suggest that the administration of specific commensal epitopes may help to widen the repertoire of specific Tregs that control intestinal inflammation.

Therapeutic effect of anti-OX40L and anti-TNF-α MAbs in a murine model of chronic colitis

2003 ◽  
Vol 284 (4) ◽  
pp. G595-G603 ◽  
Author(s):  
T. Totsuka ◽  
T. Kanai ◽  
K. Uraushihara ◽  
R. Iiyama ◽  
M. Yamazaki ◽  
...  
Keyword(s):  
T Cells ◽  
Crohn’S Disease ◽  
T Cell ◽  
Crohn's Disease ◽  
Lamina Propria ◽  
Therapeutic Effect ◽  
Therapeutic Effects ◽  
Chronic Colitis ◽  
Tnf Α ◽  
Ifn Γ

Interaction of OX40 (CD134) on T cells with its ligand (OX40L) on antigen-presenting cells has been implicated in pathogenic T cell activation. This study was performed to explore the involvement of OX40/OX40L in the development of T cell-mediated chronic colitis. We evaluated both the preventive and therapeutic effects of neutralizing anti-OX40L MAb on the development of chronic colitis in SCID mice induced by adoptive transfer of CD4+CD45RBhighT cells as an animal model of Crohn's disease. We also assessed the combination of anti-OX40L and anti-TNF-α MAbs to improve the therapeutic effect. Administration of anti-OX40L MAb markedly ameliorated the clinical and histopathological disease in preventive and therapeutic protocols. In vivo treatment with anti-OX40L MAb decreased CD4+T cell infiltration in the colon and suppressed IFN-γ, IL-2, and TNF-α production by lamina propria CD4+T cells. The combination with anti-TNF-α MAb further improved the therapeutic effect by abolishing IFN-γ, IL-2, and TNF-α production by lamina propria CD4+T cells. Our present results suggested a pivotal role of OX40/OX40L in the pathogenesis of T cell-mediated chronic colitis. The OX40L blockade, especially in combination with the TNF-α blockade, may be a promising strategy for therapeutic intervention of Crohn's disease.

T cell-induced inflammation of the small and large intestine in immunodeficient mice

2006 ◽  
Vol 290 (1) ◽  
pp. G109-G119 ◽  
Author(s):  
Dmitry V. Ostanin ◽  
Kevin P. Pavlick ◽  
Sulaiman Bharwani ◽  
Dwain D′Souza ◽  
Kathryn L. Furr ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Small Bowel ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Cell Transfer ◽  
Chronic Colitis ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
T Cell Transfer

It is well known that transfer of CD4+CD45RBhigh (naïve) T cells into syngeneic lymphocyte-deficient mice induces chronic colitis. However, no studies have reported the presence of small bowel inflammation in this T cell-dependent model. Therefore, the objective of this study was to evaluate and compare small and large bowel inflammation induced by transfer of naïve T cells into two different immunodeficient recipient mice. T and B cell-deficient recombinase activating gene 1-deficient [RAG knockout (KO)] and T cell-deficient T cell receptor-β × T cell receptor-δ double-deficient (TCR KO) mice were reconstituted with wild-type naïve T cells and observed for signs of disease. We found that reconstituted RAG KO mice developed moderate to severe colitis and inflammation of the entire small intestine at 6–8 wk after T cell transfer. Adoptive transfer of naïve T cells into TCR KO mice induced a milder form of chronic colitis and small bowel inflammation that was confined primarily to the duodenum at 10–12 wk after T cell transfer. T helper cell 1 and macrophage-derived proinflammatory cytokine mRNA levels correlated well with the localization and severity of the chronic large and small bowel inflammation. In addition, we observed comparable homing and expansion of donor lymphocytes in the gut and secondary lymphoid tissues of both recipients. Taken together, our data demonstrate that transfer of naïve T cells into immunodeficient recipient mice induces both chronic small and large bowel inflammation and that the presence of B cells in the TCR KO recipients may play a role in regulating chronic intestinal inflammation.

scholarly journals P032 MiR-511 deficiency aggravates T cell transfer colitis in mice

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S147-S147
Author(s):  
S Rahman ◽  
A Elfiky ◽  
P H P van Hamersveld ◽  
C Verseijden ◽  
O Welting ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Intestinal Inflammation ◽  
Activity Index ◽  
Disease Activity Index ◽  
Cell Populations ◽  
Spleen Weight ◽  
Cell Transfer ◽  
Rag 1 ◽  
T Cell Transfer

Abstract Background MiR-511 is embedded in intron region 5 of the CD206/MRC1 gene, expressed by macrophage and dendritic cell populations. In this study, we aimed to investigate the effect of MiR-511 deficiency on intestinal inflammation in a murine T cell transfer colitis model. Methods A double MiR-511- and Rag-1 (knockout) KO mouse was generated and a T cell transfer colitis was induced by intraperitoneal injection of naïve T cells from donor WT mice. Since these mice lack mature T and B cells, first signs of inflammation appeared at week 3 after T cell injection. An endoscopy score was obtained to determine inflammation at week 3 and 5, respectively. The experiment was terminated at week 5 and severity of inflammation was assessed on the basis of weight loss, colon weight/length ratio, histology score, spleen weight and disease activity index. In addition, flow cytometry was performed for analysing immune cell populations (monocyte, macrophages, dendritic cells, neutrophils) in the colons of both control and colitis groups and T cells in the spleens of colitis group, respectively. Results Following the induction of T cell transfer colitis, colon weight/length ratio, spleen weight and endoscopic score were significantly increased in the double KO mice compared to Rag-1 KO control mice. A higher histology score and disease activity index in the double KO with no change in weight loss compared to Rag-1 KO control mice was observed. A significant increase in monocyte population in the colons of double KO was seen and increased numbers of monocytes was also observed in the double KO control group with no inflammation. Also, a higher influx of T cells in the double KO mice with a significant increase in Foxp3 and IL4 population was observed in the group with colitis. Conclusion MiR-511 deficiency aggravates intestinal inflammation compared to Rag-1 KO control mice. Also, a higher presence of monocyte as well as T cell populations were observed in these mice. Together these data show that MiR-511 is involved in the regulation of intestinal health. Future research will focus on underlying mechanisms.

scholarly journals Nematode Asparaginyl-tRNA Synthetase Resolves Intestinal Inflammation in Mice with T-Cell Transfer Colitis

2012 ◽  
Vol 20 (2) ◽  
pp. 276-281 ◽  
Author(s):  
Michael A. Kron ◽  
Ahmed Metwali ◽  
Sanja Vodanovic-Jankovic ◽  
David Elliott
Keyword(s):  
T Cell ◽  
Cellular Response ◽  
Intestinal Inflammation ◽  
Trna Synthetase ◽  
Therapeutic Effects ◽  
Cell Transfer ◽  
Content Type ◽  
Anti Inflammatory ◽  
T Cell Transfer

ABSTRACTThe therapeutic effects of a controlled parasitic nematode infection on the course of inflammatory bowel disease (IBD) have been demonstrated in both animal and human models. However, the inability of individual well-characterized nematode proteins to recreate these beneficial effects has limited the application of component immunotherapy to human disease. The nematodes that cause chronic human lymphatic filariasis,Brugia malayiandWuchereria bancrofti, are among the parasites that induce immune suppression. Filarial lymphatic pathology has been shown to involve NF-κB pathway-dependent production of vascular endothelial growth factor (VEGF), and stimulation of VEGF expression has also been reported by interleukin 8 (IL-8) via NF-κB pathways. Previously, we have shown that the filarial asparaginyl-tRNA synthetase (rBmAsnRS) interacts with IL-8 receptors using a combination of extracellular loops that differ from those bound by IL-8. To test the hypothesis that rBmAsnRS might induce an anti-inflammatory effectin vivo, we studied the effects of rBmAsnRS in an established murine colitis model using T-cell transfer mice. T-cell transfer colitis mice treated intraperitoneally with 100 μg of rBmAsnRS four times over 2 weeks showed resolution of cellular infiltration in the colonic mucosa, along with induction of a CD8+cellular response. In addition, rBmAsnRS induced a rise in IL-10 production from CD3+and lipopolysaccharide (LPS)- and cytosine phosphate guanosine (CPG)-stimulated splenic cells. In summary, this work demonstrates a novel anti-inflammatory nematode protein, supports the hygiene hypothesis, and supports continued refinement of alternative immunotherapies for treatment of IBD.

scholarly journals T cell transfer model of chronic colitis: concepts, considerations, and tricks of the trade

2009 ◽  
Vol 296 (2) ◽  
pp. G135-G146 ◽  
Author(s):  
Dmitry V. Ostanin ◽  
Jianxiong Bao ◽  
Iurii Koboziev ◽  
Laura Gray ◽  
Sherry A. Robinson-Jackson ◽  
...  
Keyword(s):  
T Cell ◽  
Intestinal Inflammation ◽  
Transfer Model ◽  
Cell Transfer ◽  
Chronic Colitis ◽  
Immunological Mechanisms ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
T Cell Transfer ◽  
Detailed Protocol

The inflammatory bowel diseases (Crohn's disease; ulcerative colitis) are idiopathic chronic inflammatory disorders of the intestine and/or colon. A major advancement in our understanding of the pathogenesis of these diseases has been the development of mouse models of chronic gut inflammation. One model that has been instrumental in delineating the immunological mechanisms responsible for the induction as well as regulation of intestinal inflammation is the T cell transfer model of chronic colitis. This paper presents a detailed protocol describing the methods used to induce chronic colitis in mice. Special attention is given to the immunological concepts that explain disease pathogenesis in this model, considerations and potential pitfalls in using this model, and finally different “tricks” that we have learned over the past 12 years that have allowed us to develop a more simplified version of this model of experimental IBD.

scholarly journals Cell membrane-anchored and tumor-targeted IL-12 (attIL12)-T cell therapy for eliminating large and heterogeneous solid tumors

2022 ◽  
Vol 10 (1) ◽  
pp. e003633
Author(s):  
Jiemiao Hu ◽  
Qing Yang ◽  
Wendong Zhang ◽  
Hongwei Du ◽  
Yuhui Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Membrane ◽  
Cell Therapy ◽  
Solid Tumors ◽  
Cell Transfer ◽  
T Cell Therapy ◽  
A Cell ◽  
T Cell Transfer ◽  
Heterogeneous Solid

BackgroundAdoptive T-cell transfer has become an attractive therapeutic approach for hematological malignancies but shows poor activity against large and heterogeneous solid tumors. Interleukin-12 (IL-12) exhibits potent antitumor efficacy against solid tumors, but its clinical application has been stalled because of toxicity. Here, we aimed to develop a safe approach to IL-12 T-cell therapy for eliminating large solid tumors.MethodsWe generated a cell membrane-anchored IL-12 (aIL12), a tumor-targeted IL-12 (ttIL12), and a cell membrane-anchored and ttIL-12 (attIL12) and a cell membrane-anchored and tumor-targeted ttIL-12 (attIL12) armed T cells, chimeric antigen receptor-T cells, and T cell receptor-T (TCR-T) cells with each. We compared the safety and efficacy of these armed T cells in treating osteosarcoma patient-derived xenograft tumors and mouse melanoma tumors after intravenous infusions of the armed T cells.ResultsattIL12-T cell infusion showed remarkable antitumor efficacy in human and mouse large solid tumor models. Mechanistically, attIL12-T cells targeted tumor cells expressing cell-surface vimentin, enriching effector T cell and interferon γ production in tumors, which in turn stimulates dendritic cell maturation for activating secondary T-cell responses and tumor antigen spreading. Both attIL12- and aIL12-T-cell transfer eliminated peripheral cytokine release and the associated toxic effects.ConclusionsThis novel approach sheds light on the safe application of IL-12-based T-cell therapy for large and heterogeneous solid tumors.

Abstract 2310: With a little help from CD4 T cells in adoptive T-cell transfer

2016 ◽  
Author(s):  
Else M. Inderberg ◽  
Sébastien Wälchli ◽  
Marit R. Myhre ◽  
Kari Lislerud ◽  
Gunnar Kvalheim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cell Transfer ◽  
Adoptive T Cell Transfer ◽  
T Cell Transfer
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