From immune activation to gut tissue injury: The pieces of the puzzle are coming together

doi:10.1016/S0016-5085(99)70411-7

Gastroenterology

Volume 117, Issue 5, November 1999, Pages 1238-1241

https://doi.org/10.1016/S0016-5085(99)70411-7 Get rights and content

Abstract

GASTROENTEROLOGY 1999;117:1238-1241

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C Fiocchi
Inflammatory bowel disease: etiology and pathogenesis
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Enhancing lamina propria Th1 cell responses with interleukin 12 produces severe tissue injury
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Anti–interleukin 12 treatment regulates apoptosis of Th1 T cells in experimental colitis in mice
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Antibodies to interleukin 12 abrogate established experimental colitis in mice

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Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease

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Cytokines, chemokines, growth factors, eicosanoids and other bioactive molecules in IBD

Cited by (23)

Solid lipid nanoparticles as anti-inflammatory drug delivery system in a human inflammatory bowel disease whole-blood model
2010, European Journal of Pharmaceutical Sciences
Standard treatment for inflammatory bowel diseases (IBD) necessitates frequent intake of anti-inflammatory and/or immunosuppressive drugs, leading to significant adverse events.
To evaluate the role solid lipid nanoparticles (SLN) play as drug delivery system in enhancing anti-inflammatory activity for drugs such as dexamethasone and butyrate in a human inflammatory bowel diseases whole-blood model. ELISA assay and the peripheral blood mononuclear cell (PBMC) cytokine mRNA expression levels were evaluated by quantitative SYBR Green real-time RT-PCR to determine the IL-1β, TNF-α, IFN-γ and IL-10 secretion in inflammatory bowel diseases patients’ PBMC culture supernatants. There was a significant decrease in IL-1β (p < 0.01) and TNF-α (p < 0.001) secretion, whilst IL-10 (p < 0.05) secretion significantly increased after cholesteryl butyrate administration, compared to that of butyrate alone at the highest concentration tested (100 μM), at 24 h exposure. There was a significant decrease in IL-1β (p < 0.01), TNF-α (p < 0.001) and IL-10 (p < 0.001) secretion after dexamethasone loaded SLN administration, compared to dexamethasone alone at the highest concentration tested (250 nM) at 24 h exposure. No IFN-γ was detected under any conditions and no cytotoxic effects observed even at the highest concentration tested.
The incorporation of butyrate and dexamethasone into SLN has a significant positive anti-inflammatory effect in the human inflammatory bowel disease whole-blood model.
Nonimmune cells in inflammatory bowel disease: from victim to villain
2008, Trends in Immunology
Citation Excerpt :
Only recently has more emphasis been given to genetics, environmental factors, intestinal microbial flora and the tissue response. An increasing number of reports have called attention to the significant contribution of epithelial, mesenchymal, nerve and vascular cells, platelets and the ECM to the pathogenesis of IBD [1–3]. Indeed, many of the functions traditionally attributed to classical immune cells can also be exerted by nonlymphoid cells, blurring the definition of ‘immune’ and ‘nonimmune’ [4].
Nonimmune cells have traditionally been viewed as target cells of the aberrant inflammatory process present in chronic immune-mediated conditions such as inflammatory bowel disease (IBD). However, the discovery that many of the functions traditionally attributed to immune cells are also performed by nonimmune cells has caused a shift to a multidirectional hypothesis in which nonimmune cells and acellular elements play active roles. Many types of interactions occur within this multidirectional system, and the difficulties associated with modeling these complex interactions currently limit our understanding of the cellular network that occurs in IBD. I describe the current knowledge of the roles played by nonimmune cells in the pathogenesis of IBD, as they emerge as crucial alternative targets for therapeutic intervention.
VEGF in inflammatory bowel disease: A master regulator of mucosal immune-driven angiogenesis
2008, Digestive and Liver Disease
Crohn's disease: Step up or top down therapy
2003, Bailliere's Best Practice and Research in Clinical Gastroenterology
The concept of a ‘step-up’ or ‘top-down’ approach to the treatment of Crohn's disease has evolved from the impact of novel anti-TNF (anti-tumour necrosis factor) therapies that have been effective for patients who are refractory to other medical treatments. In addition, the potential to produce mucosal healing with anti-TNF treatments without the well-recognized systemic complications of glucocorticoid therapy has created debate as to whether earlier, more aggressive, therapies should be advocated. This controversy arises at a time when the concept of sequential therapy to induce and maintain remissions for Crohn's disease has begun to be accepted and precedes our ability to define the concept of disease modification or predict the natural history of Crohn's disease based upon clinical, pathological, molecular orgenetic criteria. Evidence for therapeutic efficacy in Crohn's disease is presented as a prologue to considerations necessary to determine the benefits and risks of early aggressive treatment versus sequential approaches based upon disease severity.
Prevention of colitis by interleukin 10-transduced T lymphocytes in the SCID mice transfer model
2002, Gastroenterology
Background & Aims: Regulatory CD4⁺ cells secreting the anti-inflammatory cytokine interleukin (IL)-10 play a key role in maintaining the immune balance in the intestinal mucosa. In this study we engineered primary CD4⁺ cells to express IL-10 and investigated the efficacy of this approach in offering protection against experimental colitis. Methods: Spleen-derived CD4⁺ cells were transduced by using a retroviral vector to simultaneously express IL-10 and green fluorescent protein (GFP). The therapeutic benefit of CD4⁺ cells transduced with IL-10 GFP was studied in experimental colitis, induced by transfer of CD45RB^high CD4⁺ cells to severe combined immunodeficient mice, and in acute trinitrobenzene sulfonic acid (TNBS)–induced colitis. Results: Transferred engineered GFP fluorescent cells were detected for at least 15 weeks in peripheral blood, spleens, colon, and lymph nodes draining the intestine of recipient SCID mice. IL-10–GFP CD4⁺ cells prevented CD45RB^high-induced transfer colitis effectively, whereas no effect was observed after transfer of nontransduced CD4⁺ cells. IL-10–GFP CD45RB^high CD4⁺ cells lost the capacity to induce colitis. By contrast, no therapeutic benefit was observed in TNBS-induced colitis. Conclusions: Primary murine CD4⁺ cells that were engineered to express IL-10 by retroviral transduction act as regulatory cells in CD45RB^high-induced transfer colitis. This approach may induce long-term maintenance of mucosal immune homeostasis in Crohn's disease.
GASTROENTEROLOGY 2002;123:1865-1876
Epithelial barrier defects in ulcerative colitis: Characterization and quantification by electrophysiological imaging
2001, Gastroenterology
Citation Excerpt :
Apoptotic regulation of the stem cell population is unlikely in the colon (in contrast to the small intestine).28 Thus, epithelial apoptosis may be up-regulated by inflammatory mediators, e.g., members of the tumor necrosis factor receptor family,11,13 which arise from an autoimmune process29-31 or in response to bacterial antigens of enteric origin.32,33 Recently, we induced apoptosis in a suitable experimental setting, using a colonic model epithelium (HT-29/B6), and measured the correlated leak of about 1 μS.17
Background & Aims: In ulcerative colitis (UC), the epithelial barrier is impaired by erosion/ulcer-type lesions and epithelial apoptosis causing local leaks, and generalized tight junction alterations increasing the basal permeability. We quantified the contribution of these mechanisms to the increased colonic ion permeability. Methods: Sigmoid colon was stripped, and the spatial distribution of current clamped across the viable epithelium was recorded by a microelectrode probe, using the conductance scanning method. Local leaks (circumscribed conductive peaks) were marked, and structural changes were studied in H&E-stained series sections. Results: Overall conductivity increased from 8.4 ± 0.7 mS/cm² (mean ± SEM) in controls to 11.7 ± 0.6 in specimens with mild inflammation (i.e., with intact epithelium) and 34.4 ± 6.2 mS/cm² in moderate-to-severe inflammation (i.e., with visible epithelial lesions). Only in part this was caused by a generalized increase in basal conductivity (12.2 ± 1.5 mS/cm² in moderate-to-severe UC vs. 8.3 ± 0.7 in controls). More importantly, the spatial distribution of conductivity, which was even in controls, showed dramatic leaks in UC. Leaks found in mild inflammation without epithelial lesion turned out to be foci of epithelial apoptosis. In moderate-to-severe inflammation, leaks correlated with epithelial erosion/ulcer-type lesions or crypt abscesses. Conclusions: In early UC, but not in controls, seemingly intact epithelium comprises leaks at apoptotic foci. With more intensive inflammation, erosion/ulcer-type lesions are highly conductive, even if covered with fibrin. Local leaks contribute 19% to the overall epithelial conductivity in mild and 65% in moderate-to-severe inflammation.
GASTROENTEROLOGY 2001;121:1320-1328

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^☆: Address requests for reprints to: Claudio Fiocchi, M.D., Division of Gastroenterology, University Hospitals of Cleveland, Case Western Reserve University School of Medicine (BRB 425), 10900 Euclid Avenue, Cleveland, Ohio 44106-4952. Fax: (216) 368-1674.

^☆☆: Supported by grants DK30399 and DK50984 from the National Institutes of Health and by the Crohn's & Colitis Foundation of America, Inc.

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EditorialsFrom immune activation to gut tissue injury: The pieces of the puzzle are coming together☆,☆☆

Abstract

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Immunol Today

Clin Immunol Immunopathol

Gastroenterology

Gastroenterology

J Allergy Clin Immunol

Gastroenterology

Antibodies to interleukin 12 abrogate established experimental colitis in mice

J Exp Med

Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease

Nat Med

Cytokines, chemokines, growth factors, eicosanoids and other bioactive molecules in IBD

Editorials
From immune activation to gut tissue injury: The pieces of the puzzle are coming together☆,☆☆