TNF-αneutralization ameliorates the severity of murine Crohn's-like ileitis by abrogation of intestinal epithelial cell apoptosis

Abstract

Tumor necrosis factor ␣ (TNF-␣) is an important mediator of programmed cell death, and TNF-␣ blockade significantly improves disease severity in several inflammatory conditions, including Crohn's disease (CD), one of the idiopathic inflammatory bowel diseases. However, the precise mechanism(s) of action of anti-TNF-␣ therapy in CD remains poorly understood. SAMP1͞YitFc mice develop a spontaneous ileitis with similarities to human CD in regard to histological features as well as response to conventional treatments. In this report, we tested the novel hypothesis that the beneficial effects of anti-TNF-␣ therapy in CD are mediated by a mechanism that involves down-regulation of intestinal epithelial cell (IEC) apoptosis. Similar to the efficacy of monoclonal anti-TNF-␣ antibodies in human CD, a single injection of a chimeric anti-murine TNF-␣ antibody into SAMP1͞YitFc mice resulted in a marked suppression of intestinal inflammation and epithelial cell damage compared with mice injected with an isotype control antibody. These effects were associated with a significant reduction in apoptosis of freshly isolated IEC as assessed by propidium iodide staining and DNA laddering. In contrast, an increase in lamina propria mononuclear cell apoptosis was observed in anti-TNF-␣-treated mice compared with control. These results were confirmed in vivo by using the terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling-assay. In addition, neutralization of TNF-␣ reduced membrane bound FAS͞CD95 expression in IEC from SAMP1͞YitFc mice compared with control antibody. These data demonstrate a novel mechanism of action of anti-TNF-␣ therapy that involves homeostatic regulation of mucosal cell apoptosis, which results in the net decrease of chronic inflammation typically found in CD.

Absence of bacterially induced RELMβ reduces injury in the dextran sodium sulfate model of colitis

“…The pattern of inflammation in these mice is remarkably similar to that of Crohn disease in humans, with the spontaneous development of disease located primarily in the terminal ileum, and is characterized by discontinuous transmural inflammation with the formation of granulomas, the development of perirectal fistulas, and the amelioration of disease by the administration of TNF-α-neutralizing monoclonal antibodies (25,38). As occurs in DSS-induced colitis, and particularly relevant to patterns of RELMβ expression, the inflammatory response in these SAMP1/Fc mice is accelerated by gut bacteria (39).…”

Lack of TNFR2 expression by CD4+ T cells exacerbates experimental colitis

“…This has been most convincingly demonstrated by the improvement of clinical signs and remission of disease in most patients with steroid-refractory CD who have received systemic administrations of a TNF specific chimeric monoclonal Ab (Infliximabs) [28,29]. TNF exerts its pleiotropic functions, including effects on apoptosis and inflammatory responses, by binding to its two receptors, TNFR1 or TNFR2.…”

TNFα blockade in human diseases: Mechanisms and future directions

“…These mouse models have been utilized for testing the efficacy of potential therapies such as anti-TNF blockades. For example, in the SAMP1/ YitFc model [64], a single injection of a chimeric antimurine TNF Ab suppressed intestinal inflammation and epithelial cell damage [65], which was associated with reduced apoptosis of intestinal epithelial cells, while the lamina propria mononuclear cells showed increased cell apoptosis. These data demonstrate that one of the mechanisms of action of anti-TNF therapy involves homeostatic regulation of apoptosis in mucosal and lamina propria mononuclear cells, resulting in a net decrease of chronic inflammation.…”