scholarly journals Fluorescence-labeled liposome accumulation in injured colon of a mouse model of T-cell transfer-mediated inflammatory bowel disease

2017 ◽  
Vol 494 (1-2) ◽  
pp. 188-193 ◽  
Author(s):  
Midori Yamasaki ◽  
Yo Muraki ◽  
Yutaka Nishimoto ◽  
Yusuke Murakawa ◽  
Takanori Matsuo
Author(s):  
Ahmed M I Elfiky ◽  
Mohammed Ghiboub ◽  
Andrew Y F Li Yim ◽  
Ishtu L Hageman ◽  
Jan Verhoeff ◽  
...  

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.


2017 ◽  
Vol 152 (5) ◽  
pp. S615
Author(s):  
Rachel Mak'Anyengo ◽  
Peter Duewell ◽  
Hans Anton Lehr ◽  
Sandra Fischer ◽  
Thomas Clavel ◽  
...  

Apmis ◽  
1997 ◽  
Vol 105 (7-12) ◽  
pp. 655-662 ◽  
Author(s):  
SØOREN BREGENHOLT ◽  
DICK DELBRO ◽  
MOGENS H. CLAESSON

2010 ◽  
Vol 16 (5) ◽  
pp. 776-782 ◽  
Author(s):  
Norman R. Harris ◽  
Patsy R. Carter ◽  
Seungjun Lee ◽  
Megan N. Watts ◽  
Songlin Zhang ◽  
...  

2002 ◽  
Vol 282 (4) ◽  
pp. G690-G701 ◽  
Author(s):  
Fergus R. Byrne ◽  
Catherine L. Farrell ◽  
Richard Aranda ◽  
Karen L. Rex ◽  
Sheila Scully ◽  
...  

There is an acute need for effective therapy for inflammatory bowel disease (IBD), particularly at the level of repair of the damaged epithelium. We evaluated the efficacy of recombinant human keratinocyte growth factor (rHuKGF) in both the dextran sodium sulfate (DSS) and the CD4+CD45RBHi T cell transfer models of IBD. Disease was induced either by the ad libitum administration to normal mice of 4% DSS in the drinking water or by the injection of 4 × 105 CD4+CD45RBHi T cells into immunodeficient scid/scid mice. rHuKGF was administered by subcutaneous injection at doses of 1.0 or 3.0 mg/kg in both preventative and therapeutic regimens during both studies. rHuKGF significantly improved survival and body weight loss in the DSS model in both preventative and therapeutic dosing regimens. It also improved diarrhea, hematochezia, and hematological parameters, as well as large intestine histopathology. In the T cell transfer model, rHuKGF improved body weight loss, diarrhea, and levels of serum amyloid A, as well as large intestine histopathology. In both models of IBD, the colonic levels of intestinal trefoil factor (ITF) were elevated by the disease state and further elevated by treatment with rHuKGF. These data suggest that rHuKGF may prove useful in the clinical management of IBD and its effects are likely mediated by its ability to locally increase the levels of ITF.


2020 ◽  
Vol 70 (1) ◽  
pp. 16-24
Author(s):  
Charlie C Hsu ◽  
Karuna Patil ◽  
Audrey Seamons ◽  
Thea L Brabb ◽  
Piper M Treuting ◽  
...  

Murine norovirus (MNV) infection is highly prevalent in laboratory mice. Although MNV infection does not typically induce clinical disease in most laboratory mice, infection may nonetheless affect mouse models of disease by altering immune responses. We previously reported that MNV altered the bacterial-induced mouse model of inflammatory bowel disease (IBD) using Helicobacter-infected Mdr1a–/– mice. Therefore, we hypothesized that MNV infection would exacerbate another mouse model of IBD, the T-cell adoptive transfer (AT) model. In this model, Helicobacter infection is used to accelerate the progression of IBD induced by AT of naïve CD4+CD45RBhigh T cells into B6.129S7- Rag1tm1Mom/J (Rag1–/–) mice. We evaluated the effects of MNV infection in both Helicobacter-accelerated as well as Helicobacter-free AT models. In our studies, Helicobacter-infected Rag1–/– mice that received CD4+CD45RBhigh T cells through AT rapidly developed weight loss and typhlocolitis; MNV infection had no effect on disease severity or rate of progression. In the absence of Helicobacter infection, progression of IBD caused by AT of CD4+CD45RBhigh T cells was slower and typhlocolitis was less severe; this inflammation likewise was unaltered by MNV infection. These results indicate that MNV infection does not alter IBD progression and severity in the CD4+CD45RBhigh T-cell AT model in Rag1–/– mice.


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