Evidence that activated mucosal T cells play a role in the pathogenesis of enteropathy in human small intestine.

Abstract

Intestinal damage as a result of allergy and infection is a major cause of morbidity in man and animals (1-3). In intestinal allergy the most commonly seen lesions are small intestinal villous atrophy and crypt cell hyperplasia resulting in malabsorption due to a decreased intestinal absorptive surface and decreased digestive enzyme levels in the epithelial cells. The mechanisms involved in these changes in man are not known, but there is evidence from experimental animal studies that T cells may play an important role in the pathogenesis of the intestinal lesion (4). The enteropathy observed in intestinal graft-versus-host disease and rejection of transplanted intestinal allografts is characterized by a lymphocytic infiltrate, shortening of the villi, lengthening of the crypts and an increased rate of epithelial cell proliferation (5, 6). However, these in vivo models, although useful, do not allow a dissection of the mechanisms involved in the development of enteropathy in human small intestine.We have recently shown (7) that fetal human small intestine becomes increasingly populated with T cells from^-14 wk of gestation. By 19-22 wk the fetal gut epithelium and lamina propria contain many isolated T cells and the lamina propria contains aggregates of T and B cells that are probably early Peyer's patches (8). Small explants of human fetal small intestine can be maintained in organ culture for several weeks with retention of gut structure and normal epithelial cell function (9) . We have thus attempted to directly stimulate mucosal T cells in situ in cultures of human small intestine. Materials and MethodsOrgan Culture of Fetal Human Small Intestine. Small intestine from therapeutically aborted fetuses was placed in a petri dish in serum-free CMRL-1066 medium (Flow Laboratories, Inc ., McLean, VA) modified as described by Autrup et al (10) . The intestine was cut into segments 2-3 mm in length which were then bisected longitudinally to expose the lumen . The explants were then trimmed into pieces 2-3 mm square . Five pieces of tissue were cultured in 7 ml modified CMRL-1066 medium in 5-cm diameter tissue culture dishes (Sterilin ; Scientific Supplies Co . Ltd ., Vine Hill, London) . The cultures were incubated for 72 h at 37°C in a 95% oxygen, 5% CO atmosphere . At the end of the culture period the five explants in each dish were carefully removed from the

Increased proinflammatory cytokine gene expression in the colonic mucosa of coeliac disease patients in the early period after gluten challenge

“…Several studies have reported that mucosal injury, pathologically similar to that seen in coeliac disease, can be induced experimentally in the intestinal mucosa by T cell activation [17][18][19] or by cytokines that are produced by T cells and monocytes/ macrophages (e.g. tumour necrosis factor-alpha (TNF-), interferon-gamma (IFN-), IL-1, IL-4) [20][21][22][23][24].…”

IL-4 enhances IEC-6 intestinal epithelial cell proliferation yet has no effect on IL-6 secretion

“…However, several gastrointestinal diseases show pathologic changes in the epithelial cell layer such as villous atrophy and crypt cell hyperplasia. Studies using intestinal explants have shown that activation of T cells by specific antibody or mitogens resulted in crypt hyperplasia [9,10] and villous atrophy [9], suggesting a role for T cells or their secreted cytokines in these effects. Further, it has been suggested that the manifestations of villous atrophy are probably due to the T cell-derived cytokines interferon-gamma (IFN-) and tumour necrosis factor (TNF) [11], but the mechanisms involved in the induction of crypt cell hyperplasia are unknown.…”

Estimating the importance of infection in IBS

“…Here, there is a clear genetic predisposition associated with human lymphocyte antigen DRQ2 shared by one-third of the population, which only leads to disease in a few. In some, onset of symptoms follows an acute infection (26,27). Experimentally, nonspecifically activating mucosal lymphocytes can result in villus atrophy (26) and may thus precipitate symptomatic disease, which may resolve once the superimposed infection has subsided (26).…”