Warren Strober, MD; Bjorn R. Ludviksson, MD; Ivan J. Fuss, MD
Strober W, Ludviksson BR, Fuss IJ. The Pathogenesis of Mucosal Inflammation in Murine Models of Inflammatory Bowel Disease and Crohn Disease. Ann Intern Med. 1998;128:848-856. doi: 10.7326/0003-4819-128-10-199805150-00009
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Published: Ann Intern Med. 1998;128(10):848-856.
In recent years, it has become apparent that overproduction of the Th1 cytokines interleukin-12 and interferon-γ is the probable driving force behind murine models of intestinal inflammation resembling Crohn disease and intestinal inflammation in humans with Crohn disease. In addition, studies of murine models strongly suggest that this overproduction is associated with inadequate secretion of the counter-regulatory and anti-inflammatory cytokine transforming growth factor-β. Thus, mucosal inflammation in models (and possibly in humans) may result from an imbalance between normally occurring positive (immunogenic or inflammatory) responses and negative (tolerogenic or anti-inflammatory) mucosal immune responses. These new findings and the hypotheses that arise from them are being used to construct new approaches to the treatment of Crohn disease that are based on the administration of anti-inflammatory cytokines and anti-cytokine antibodies.
Secretion of interferon-γ and interleukin-5 by purified CD4+ T cells. Cells were obtained from the lamina propria of six controls (black bars), eight patients with Crohn disease (striped bars), and six patients with ulcerative colitis (white bars). These cells were stimulated by anti-CD3 and anti-CD2 (alone or in combination with anti-CD28) and were enumerated by enzyme-linked immunospot assay (ELISPOT) analysis as described elsewhere . Error bars represent the mean ± SE from six experiments. Unstim = unstimulated cells.
Interleukin-2 deficiency leads to an excessive Th1 T-cell response in the lamina propria because of a defect in the ability to generate a Th2 T-cell response and T cells producing transforming growth factor-β (TGF-β). This problem is compounded by the formation of autoreactive Th1 T cells in the thymus that migrate to the colon. APC = antigen-presenting cell; MAC = macrophage; TNF-α = tumor necrosis factor-α. The minus sign indicates a negative suppressor effect.
Intrarectal administration of TNBS and formation of trinitrophenyl-haptenated colonic protein lead to induction of a polarized Th1 T-cell response in the lamina propria that is not counter-regulated by transforming growth factor-β (TGF-β)-producing T cells; the resultant unfettered interferon-γ production leads to activation of macrophages, production of inflammatory cytokines, and development of colitis. Oral administration of trinitrophenyl-haptenated colonic protein leads to induction of T cells producing TGF-β, which shuts down the excessive Th1 T-cell response of TNBS colitis. APC = antigen-presenting cell; TNF-α = tumor necrosis factor-α; PP = Peyer patch; T = T cell.
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