Ontogeny of the mucosal immune response.
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Animals↗
Biomedical subjects
T T MacDonald
Publications and source records attributed to T T MacDonald.
Changes in the rate of crypt epithelial cell proliferation and mucosal morphology induced by a T-cell-mediated response in human small intestine.
The rate of crypt epithelial cell proliferation and mucosal morphology have been studied in vitro in explants of fetal human small intestine in organ culture in which a cell-mediated immune response has been elicited by stimulating lamina propria T cells with pokeweed mitogen or monoclonal anti-CD3 antibodies. Twelve hours after the addition of anti-CD3 or pokeweed mitogen, most lamina propria T cells expressed CD25. By 18 and 24 h after the addition of anti-CD3, there were significantly more crypt cells in the cell cycle than in controls, although villus height and crypt depth are the same in both groups. After 3 days, by dissecting microscopy, the villi appeared shorter in cultures in which the T cells were stimulated than in control cultures, and the mucosal surface was obscured by a layer of extruded enterocytes. Villus atrophy was confirmed by direct measurement of Feulgen-stained, microdissected villi. Crypts were longer in T-cell-stimulated cultures, and the rate of crypt epithelial cell proliferation measured by metaphase arrest was increased 10-fold. By electron microscopy, the microvilli and cellular morphology of the surface enterocytes were normal in T-cell-stimulated cultures. These experiments clearly show that a profound immune-mediated crypt epithelial cell hyperplasia can occur in the absence of damage to surface enterocytes.
Antibodies, Monoclonal↗
Gut immunology.
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Acquired Immunodeficiency Syndrome↗
The role of activated T lymphocytes in gastrointestinal disease.
Activated T cells can be visualized in the intestinal lamina propria in a number of gastrointestinal diseases including food-sensitive enteropathy (coeliac disease), inflammatory bowel disease and intractable diarrhoea of infancy. Experimental studies have shown that T-cell activation in human intestinal lamina propria in vitro produces an increase in crypt cell proliferation, villous atrophy, increased HLA-DR expression on enterocytes, increased intra-epithelial lymphocyte numbers, and phenotypically, macrophage activation. All of these features are seen in human gastrointestinal disorders and it is proposed that T-cell activation to wheat (in coeliac disease), milk (cows' milk-sensitive enteropathy), and unidentified luminal antigens (Crohn's disease) plays a primary role in the pathogenesis of these disorders.
Animals↗
Tumour necrosis factor-alpha and interferon-gamma production measured at the single cell level in normal and inflamed human intestine.
The spot-ELISA technique has been used to enumerate the frequency of cells secreting tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), isolated from biopsies of normal intestine and from biopsies of children with inflammatory bowel disease. TNF-alpha production was undetectable in six out of 12 biopsies from normal intestine and in the other six biopsies it ranged from 60 to 580 TNF-alpha-secreting cells/10(6) isolated intestinal cells. In contrast, cells isolated from biopsies of children with Crohn's disease (n = 9) all showed elevated frequencies of TNF-alpha-secreting cells (500-12,000 secreting cells/10(6) cells). In ulcerative colitis, four out of eight children had increased production of TNF-alpha and in children with indeterminate colitis two out of three had elevated levels. There was no correlation between plasma TNF-alpha levels and the number of intestinal cells secreting TNF-alpha. In controls and all groups of patients IFN-gamma-secreting cells were uncommon. These results suggest that TNF-alpha is an important mediator of inflammation in the human gut, and, furthermore, may play a role in the growth failure frequently seen in children with inflammatory bowel disease.
Adolescent↗
Differential expression of CD25 (interleukin-2 receptor) on lamina propria T cells and macrophages in the intestinal lesions in Crohn's disease and ulcerative colitis.
Many interleukin-2 receptor (CD25) bearing cells can be identified by alkaline phosphatase immunohistochemistry in the diseased intestinal lamina propria of children with Crohn's disease or ulcerative colitis, but rarely in normal intestine. In both diseases, the CD25+ cells are present as aggregates in the lamina propria below the epithelium, and constitute a large proportion of the lamina propria mononuclear cells. In Crohn's disease, but not ulcerative colitis, CD25+ cells are abundant in the submucosa. The CD25+ cells in Crohn's disease are 58-88% CD3+, CD4+, CD8-, indicating that they are T cells, whereas in ulcerative colitis the CD25+ cells are greater than 80% CD3-, CD4+, HLA-DR+, indicating that they are macrophages. Thus, differential expression of CD25 on T cells and macrophages serves to distinguish the immunologic lesions in ulcerative colitis and Crohn's disease.
Adolescent↗
Gamma/delta T cells in the gut epithelium.
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Animals↗
Increased expression of laminin/collagen receptor (VLA-1) on epithelium of inflamed human intestine.
Immunohistochemical techniques were used to investigate the epithelial expression of VLA-1 in inflammatory bowel disease in six patients with Crohn's disease, in four patients with ulcerative colitis, and in one patient with indeterminate colitis, and compared with that in the small intestine and colons of 10 normal controls. In normal small bowel VLA-1 was expressed on crypt epithelial cells and only weakly or not at all on surface epithelium. VLA-1 was again expressed weakly in normal colon, except in one case, a 1 year old child with diarrhoea but no histological abnormalities. In small and large intestine affected with Crohn's disease, ulcerative colitis, or indeterminate colitis, there was increased expression of VLA-1 on the basolateral aspects of crypt cells and de novo expression on surface epithelium. It is suggested that this is an adaptive response to prevent epithelial cell loss as a result of inflammation in the underlying lamina propria.
Child, Preschool↗
The role of activated T cells in transformed intestinal mucosa.
Activated T cells can be identified immunohistochemically in the intestinal lamina propria in a number of gastrointestinal diseases including food sensitive enteropathy (coeliac disease) and intractable diarrhoea of infancy. Experimental studies have shown that T cell activation in human intestinal lamina propria in vitro produces an increase in crypt cell proliferation, villous atrophy, increased HLA-DR expression on enterocytes, increased intraepithelial lymphocyte numbers, and, phenotypically, macrophage activation. All of these features are seen in food sensitive enteropathy and it is proposed that lamina propria T cell activation to food antigens plays the primary role in the pathogenesis of these disorders by altering mucosal morphology and the rate of epithelial cell proliferation.
Food Hypersensitivity↗
Growth suppression in the Trichuris dysentery syndrome.
The Trichuris Dysentery Syndrome (Ramsey, 1962) is an insidious, chronic condition which has clinical features similar to Crohn's ileocolitis and ulcerative colitis, diseases similarly associated with growth retardation. The attained heights and weights of 19 children at the time of diagnosis of intens, -2.4 Standard Deviation (Z) scores from the Tanner-Whitehouse median with weight, adjusted for height-age, -1.3 Z. We present data on the growth velocities of 11 of the children in the half-year following worm expulsion by mebendazole. These children returned to their home environments without food supplementation or close follow-up, but showed an average height velocity of +5.5 Z and weight velocity (for height-age) of +2.4 Z. Of 8 children with unequivocal height spurts only 3 had any weight spurt. We suggest that the pattern of catch-up growth points to the existence of some specific link between allergy or inflammation in the lower intestinal tract and suppression of linear growth, rather than to stunting due to general deprivation and undernutrition.
Animals↗
Expression of disulfide-linked and non-disulfide-linked forms of the T cell receptor gamma/delta heterodimer in human intestinal intraepithelial lymphocytes.
Immunohistochemistry has been used to investigate disulfide- and non-disulfide-linked forms of the T cell receptor gamma/delta heterodimer (TcR gamma/delta) in blood and intestinal epithelium of normal human small intestine, intestine of patients with untreated coeliac disease (in whom T cells expressing TcR gamma/delta are disproportionately raised), intestine of patients with tropical malabsorption, and in the human fetus. In blood from adult volunteers, 90% of T cells expressing TcR gamma/delta use the disulfide-linked form. In contrast in the epithelium in normal small intestine, coeliac disease and tropical malabsorption, most of the T cells expressing TcR gamma/delta use the non-disulfide-linked form. This is especially prominent in untreated coeliac disease where the increase in TcR gamma/delta T cells is mainly restricted to those using the non-disulfide-linked form. In human fetal small intestinal epithelium, however, only cells using the disulfide-linked form are present. These variations in expression of different forms of TcR gamma/delta in the gut epithelium in different conditions suggests that antigen, or some as yet undefined factor may determine the frequency of each subpopulation.
Antibodies, Monoclonal↗
Alpha beta T cell receptor expression in rat intestinal epithelium.
Intra-epithelial lymphocytes (IEL) in normal rat small intestine have been analysed for alpha beta T cell receptor (TcR) expression by immunoperoxidase histochemistry on frozen sections of gut, and by immunofluorescence on isolated cells. In frozen sections, a mean value of 61% of IEL were stained by the monoclonal antibody R73, which is specific for an invariant determinant of the alpha beta TcR. Analysis of isolated IEL by flow cytometry gave similar results and showed that 40-62% of IEL were stained by R73. Of the IEL population as a whole, 98% of cells were LCA+, 90% CD8+ and 10% CD4+. These results for alpha beta TcR expression in rat intestinal IEL closely parallel our recent data for mice, and are at variance with the view that this lymphoid compartment is dominated by gamma delta T cells.
Animals↗
Heterogeneity in intraepithelial lymphocyte subpopulations in fetal and postnatal human small intestine.
Intraepithelial lymphocytes (IEL) are present in fetal human small intestine from 14 weeks' gestation independent of exogenous dietary or microbial antigens. We have now studied the heterogeneity of IEL in 18-22-week-old human fetal intestine and in postnatal small intestine by single and sequential immunoenzyme histochemistry. In normal children and adults, there were 6-27 CD3+ IEL per 100 epithelial cells, whereas in fetal gut there were 3-5 CD3+ IEL per 100 epithelial cells. Postnatal intestine contained a population of CD3-,7+, non-T cell IEL (7-25% of total CD7+). These cells were absent from fetal IEL but were occasionally seen in the fetal lamina propria. About 6% of CD3+ postnatal IEL were CD4-,8-. In contrast in the fetus, 35-70% of CD3+ IEL were subset negative. Since CD3 and CD7 are always co-expressed on fetal IEL, 28-58% of fetal IEL were also CD7+,4-,8-. Only about 20% of the CD3+ IEL expressed the gamma delta chains of the T cell antigen receptor. We conclude from these studies that CD3+,4-,8- T cells migrate to the epithelium in the absence of exogenous antigen and that there is a population of CD3-,7+ non-T cells in postnatal gut which is absent in fetal gut.
Biopsy↗
Changes in intraepithelial lymphocyte subpopulations in coeliac disease and enteropathy associated T cell lymphoma (malignant histiocytosis of the intestine).
Studies of the morphologic and phenotypic diversity of intraepithelial T cells in human small intestine have shown them to be heterogeneous, yet distinct from most extra intestinal T cells. In this study sequential immunoenzymatic staining was used to define new intraepithelial lymphocyte subpopulations in man. In normal human jejunum approximately 6% of the intraepithelial T cells expressing CD3 (an antigen associated with the T cell receptor) do not express the T cell subset antigens CD4 or CD8. Approximately 20% of CD7+ cells (T cells and null cells) do not express CD4 or CD8 and 14% of the CD7+ cells do not express CD3 and are therefore not T cells. The CD7+, CD3+/-, CD4-, CD8- population is concentrated in the tips of the villi. In coeliac disease, the ratios of the subsets change significantly. The percentage of CD3+, 4-, 8- cells increases to 28%, the proportion of CD7+, 4-, 8- cells remains unchanged and the CD7+, CD3- (non-T cell) population is reduced to 1.4% of the CD7+ cells. In contrast, in patients with villous atrophy of uncertain aetiology, all CD4-, CD8- lymphocyte subsets are decreased compared with normal biopsies. Finally, in enteropathy associated T cell lymphoma (malignant histiocytosis of the intestine) in which the 'uninvolved mucosa' is histologically similar to untreated coeliac disease, the changes in the intraepithelial T cell sub-sets are indistinguishable from those in coeliac disease, suggesting that the lymphoma is a complication of coeliac disease.
Adult↗
T-cell receptor expression in intestinal intra-epithelial lymphocyte subpopulations of normal and athymic mice.
Intra-epithelial lymphocytes (IEL) in murine small intestine were analysed for the presence of cell-surface antigens and T-cell receptor allotype in normal and athymic BALB/c mice by immunoperoxidase histochemistry on frozen sections and immunofluorescence on isolated IEL. In frozen sections, IEL of normal mice were 97.7% CD45+, 93.5% CD3+, 46.2% Thy-1+, 91.1% CD8+, 10.7% CD4+ and 21.1% KJ16+ (V beta 8.1 and 8.2). FACS analysis of isolated IEL confirmed the level of KJ16 expression and also demonstrated that 25% of IEL were F23.1+ (V beta 8.1-8.3). Immunofluorescent double-staining revealed a skewed distribution of T-cell receptor (TcR) expression on Thy-1+ and Thy-1- IEL. KJ16 and F23.1 were expressed on 25.9% and 32.7% of Thy-1+ IEL, respectively; however, the frequency of V beta 8 expression was diminished on Thy-1- IEL (4.1% KJ16+ and 12.1% F23.1+). IEL are present in athymic mice, but at reduced levels. In frozen sections these cells were 91.9% CD45+, 69.5% CD3+, less than 1% Thy-1+, 83.6% CD8+, less than 1% CD4+ and less than 1% KJ16+. Thus it appears that in normal mice there may be two distinct lineages of IEL, a thymus-dependent Thy-1+ population which utilizes the alpha beta T-cell receptor and a thymus-independent Thy-1- population (represented in athymic mice), which may possibly utilize the alternative gamma delta TcR.
Animals↗
Evidence that activated mucosal T cells play a role in the pathogenesis of enteropathy in human small intestine.
T cells in explants of human fetal small intestine in organ culture were stimulated in situ with PWM or anti-CD3 antibody to test the hypothesis that activated T cells produce enteropathy in human small intestine. T cell activation was measured by the appearance of CD25+ cells in the lamina propria of the explants and IL-2 production into the organ culture supernatant. We have previously shown that the number of T cells in human fetal gut increased between 14 and 22 wk gestation. Accordingly, after the addition of PWM to cultured explants of fetal intestine the number of CD25+ cells in the lamina propria and the amounts of IL-2 secreted into the organ culture supernatant increased with the age of the explanted tissue. The addition of PWM also produced an age-related enteropathy, most noticeably crypt epithelial cell hyperplasia and villous atrophy, with relatively minor changes in 14-17-wk-old intestine but severe tissue damage in 18-22-wk-old fetal intestine. These enteropathic effects were also produced when mucosal T cells were activated with anti-CD3 mAb. Cyclosporin A completely inhibited the PWM-induced development of CD25+ cells and related tissue damage. These experiments show that activated T cells in human small intestine produce enteropathy. The model provides a new system with which to dissect the mechanisms of T cell-mediated intestinal damage.
Antibodies, Monoclonal↗
Multigenic control of resistance to Yersinia enterocolitica in inbred strains of mice.
By using recombinant inbred mice derived from strains genetically resistant or susceptible to Yersinia enterocolitica, we demonstrated a tentative linkage of resistance with the Es-1 locus on murine chromosome 8. No correlation with resistance and genes associated with immune regulation was evident. In addition, resistance appeared to be multigenic.
Animals↗
Passive protection of chickens against Eimeria tenella infection by monoclonal antibody.
Monoclonal antibodies reactive with the surface of Eimeria tenella sporozoites were produced in mice. This paper concerns one of these monoclonal antibodies, designated 1073.10, which agglutinated sporozoites in vitro and lysed the parasite in the presence of complement. This treatment neutralized sporozoite infections when the treated parasites were injected into the ceca of normal chickens. Passive transfer of ammonium sulfate-precipitated 1073.10 ascites fluid into 2- to 3-day-old or 3-week-old chickens conferred protection against challenge infection with E. tenella. These studies show that serum antibody may play a role in immunity to coccidiosis and that the sporozoite surface epitope recognized by 1073.10 is a possible vaccine candidate antigen.
Agglutination↗