Transmembrane TNF-α, induction of apoptosis, and the efficacy of TNF-targeting therapies in Crohn's disease

Deventer, S. J. H. Van

doi:10.1053/gast.2001.29035

Cited by 112 publications

(69 citation statements)

References 25 publications

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“…7A) and the failure to induce VCAM-1 expression when activated PBT were separated from HIMEC in a Transwell system (data not shown). Infliximab has also been reported to induce apoptosis of activated T cells, an effect believed to be of central importance in reducing mucosal inflammation in CD (29,34,41,42). We confirmed this observation by assessing apoptosis of PBT in unstimulated and anti-CD3/CD28-activated cells.…”

Section: Figuresupporting

confidence: 76%

“…The first is the decrease in CD40L expression by activated T cells exposed to infliximab as we discussed above. The second is the recognized ability of infliximab to induce T cell apoptosis (29,34,41,42), an effect we reproduced in our experimental system and that would result in a diminished availability of activated T cells for binding to the inflamed mucosal microvasculature.…”

Section: Discussionmentioning

confidence: 89%

“…During inflammation CD40 and TNF-␣ influence each other's biological activity: CD40 ligation leads to production of TNF-␣ in various cell types (24 -26), while TNF-␣ up-regulates expression of CD40 and promotes CD40 downstream signaling pathways (27,28). Because of its potent proinflammatory activity, several highly specific neutralizing Abs have been developed against this molecule for therapeutic purposes (29). Among these, infliximab is a chimeric mAb highly effective in neutralizing the biological activity of TNF-␣ and is currently used for severe, steroid-refractory, or fistulizing CD (30).…”

mentioning

confidence: 99%

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TNF-α Blockade Down-Regulates the CD40/CD40L Pathway in the Mucosal Microcirculation: A Novel Anti-Inflammatory Mechanism of Infliximab in Crohn’s Disease

Danese¹,

Sans

Scaldaferri³

et al. 2006

The Journal of Immunology

153

102

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The CD40/CD40 ligand (CD40L) pathway is involved in Crohn’s disease (CD) pathogenesis. In the patients’ circulation, soluble CD40L (sCD40L) levels are elevated and surface CD40L is increased in platelets and T cells, whereas in the intestine CD40 is overexpressed in the microvasculature and CD40L in platelets and T cells. The therapeutic effects of infliximab in CD are attributed to its systemic anti-TNF-α action, but because TNF-α modulates both CD40 and CD40L, we investigated whether infliximab affects the CD40/CD40L pathway in the intestine. Eighteen CD patients were evaluated before and after infliximab therapy. Plasma sCD40L was measured by ELISA and platelet and peripheral blood T cell (PBT) CD40L expression by flow cytometry. Microvascular CD40 and VCAM-1 expression were assessed in mucosal biopsies by immunohistochemistry and by flow cytometry in human intestinal microvascular endothelial cells (HIMEC). Cell cultures were performed in the presence and absence of infliximab. Infliximab treatment significantly reduced plasma sCD40L levels and eliminated CD40 and VCAM-1 from mucosal microvessels. In vitro infliximab prevented TNF-α-induced CD40 and VCAM-1 expression by HIMEC, and reduced PBT, but not platelet, surface CD40L expression and sCD40L release. In addition, infliximab decreased T cell-induced VCAM-1 expression in HIMEC by down-regulating CD40L in T cells and promoting T cells apoptosis. These findings point to a novel mechanism of action of infliximab, i.e., the disruption of CD40/CD40L-dependent cognate interactions between intestinal microvessels and T cells. Thus, in addition to neutralizing TNF-α and inducing T cell death, the therapeutic effects of infliximab in CD appear to be also mediated by inhibition of vascular inflammation in the gut.

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Section: Figuresupporting

confidence: 76%

Section: Discussionmentioning

confidence: 89%

mentioning

confidence: 99%

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TNF-α Blockade Down-Regulates the CD40/CD40L Pathway in the Mucosal Microcirculation: A Novel Anti-Inflammatory Mechanism of Infliximab in Crohn’s Disease

Danese¹,

Sans

Scaldaferri³

et al. 2006

The Journal of Immunology

153

102

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“…The striking effects of this TNF-targeted therapy may in IBD also be attributed to the cell-depleting effect of some of these therapies, including the removal of TNFexpressing monocytes/macrophages [99]. TNF produced by nonlymphoid cells (mostly macrophages) is essential for colitis in an adoptive T cell model of colitis induction in lymphopenic recipients.…”

Section: Inflammatory Bowel Diseasesmentioning

confidence: 99%

Intestinal macrophages: differentiation and involvement in intestinal immunopathologies

2009

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Intestinal macrophages, preferentially located in the subepithelial lamina propria, represent the largest pool of tissue macrophages in humans. As an adaptation to the local antigen-and bacteria-rich environment, intestinal macrophages exhibit several distinct phenotypic and functional characteristics. Notably, microbe-associated molecular pattern receptors, including the lipopolysaccharide (LPS) receptors CD14 and TLR4, and also the Fc receptors for IgA and IgG are absent on most intestinal macrophages under homeostatic conditions. Moreover, while macrophages in the intestinal mucosa are refractory to the induction of proinflammatory cytokine secretion, they still display potent phagocytic activity. These adaptations allow intestinal macrophages to comply with their main task, i.e., the efficient removal of microbes while maintaining local tissue homeostasis. In this paper, we review recent findings on the functional differentiation of monocyte subsets into distinct macrophage populations and on the phenotypic and functional adaptations that have evolved in intestinal macrophages in response to their antigen-rich environment. Furthermore, the involvement of intestinal macrophages in the pathogenesis of celiac disease and inflammatory bowel diseases is discussed.

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“…Adalimumab and Infliximab target transmembrane TNF alpha, which is highly expressed by the lamina propria T-lymphocytes, therefore blocking the transmembrane signaling pathway and inducing apoptosis of the activated T-lymphocytes [26]. Etanercept is a soluble TNF receptor with a different mechanism of action and also a different pharmacokinetic than the above mentioned anti TNF alpha antibodies [27,28].…”

Section: Discussionmentioning

confidence: 99%

Different effects of anti-TNF-alpha biologic drugs on the small bowel macroscopic inflammation in patients with ankylosing spondylitis

Chitul

Voiosu

et al. 2017

Romanian Journal of Internal Medicine

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Background & Aims. Considering the ability of anti-TNF alpha drugs to lower the burden intestinal inflammation in patients with inflammatory bowel disease (IBD), and the similarity between IBD and ankylosing spondylitis (AS) regarding inflammatory intestinal involvement, we aimed to investigate the impact of anti-TNF alpha biologic therapy on subclinical intestinal inflammation in AS patients.Methods. Between January 2008 and December 2013, 38 AS patients and 23 controls were enrolled in the study and investigated with small bowel videocapsule endoscopy examination and ileocolonoscopy. Each tertile of the small bowel (proximal, mid and distal) was assessed by calculating the Lewis score based on the image stream.Results. The Lewis scores were significantly higher in the AS group compared to controls (580.9 ± 818 vs. 81 ± 121, p<0.001). 16 patients (42.1%) were on anti-TNF alpha therapy (Adalimumab (n = 5), Infliximab (n = 5) or Etanercept (n = 6)).31.3% of them used NSAIDs simultaneously, compared with 77.3% of the other patients (p<0.01). Their Lewis scores were lower compared to the other patients for the entire small bowel (306 ± 164 vs. 790 ± 1038, p = 0.015), its proximal and distal tertiles (238 ± 154 vs. 560 ± 543, p = 0.021, and 140 ± 189 vs. 300 ± 220, p = 0.027, respectively). The Lewis score was also lower in patients receiving Adalimumab/ Infliximab compared to those on Etanercept for the entire bowel and its distal tertile (262 ± 165 vs. 380 ± 148, p = 0.069 and 62 ± 101 vs. 273 ± 236, p = 0.060, respectively).Conclusion. Anti-TNF alpha therapy in patients with AS reduces the subclinical intestinal inflammation, but the magnitude seems to depend upon the class anti-TNF alpha agent used (Clinical Trials. gov NCT00768950).

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Transmembrane TNF-α, induction of apoptosis, and the efficacy of TNF-targeting therapies in Crohn's disease

Cited by 112 publications

References 25 publications

TNF-α Blockade Down-Regulates the CD40/CD40L Pathway in the Mucosal Microcirculation: A Novel Anti-Inflammatory Mechanism of Infliximab in Crohn’s Disease

TNF-α Blockade Down-Regulates the CD40/CD40L Pathway in the Mucosal Microcirculation: A Novel Anti-Inflammatory Mechanism of Infliximab in Crohn’s Disease

Intestinal macrophages: differentiation and involvement in intestinal immunopathologies

Different effects of anti-TNF-alpha biologic drugs on the small bowel macroscopic inflammation in patients with ankylosing spondylitis

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