Oxpentifylline, tumour necrosis factor-alpha and Crohn's disease.
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Crohn Disease↗
Biomedical subjects
T T MacDonald
Publications and source records attributed to T T MacDonald.
Analysis of TH1 and TH2 cytokine production in low grade B cell gastric MALT-type lymphomas stimulated in vitro with Helicobacter pylori.
Previous studies have suggested that the dependence of low grade B cell gastric lymphoma on infection of the gastric mucosa with Helicobacter pylori results from help provided by H pylori specific tumour infiltrating T cells. ELISPOT analysis was used to characterise functional subpopulations of tumour infiltrating T cells. The production of the TH1 cytokine interferon gamma and TH2 cytokines interleukin (IL)-4, IL-5, and IL-10 were measured in tumour cell suspensions from two cases of low grade B cell gastric lymphoma, one case of thyroid gland lymphoma, and one case of salivary gland lymphoma. Cells were assayed on day 0 and following 24 hours incubation either in culture medium or with a range of strains of H pylori. There was a dominant TH1-type (pro-inflammatory) response consistent with the TH1 response observed in H pylori gastritis.
Antigens, Bacterial↗
Intestinal immune cells in Strongyloides stercoralis infection.
BACKGROUND: Strongyloides stercoralis can cause a wide spectrum of disease in man, ranging from a chronic asymptomatic infection to a hyperinfective, often fatal syndrome. In rodents, spontaneous expulsion of Strongyloides spp occurs after experimental infection. Mast cells, goblet cells, and eosinophils have been identified as possible effectors of this expulsion. AIMS: To investigate intestinal histopathology and mucosal immunity in immunocompetent patients with chronic S stercoralis infection. METHODS: Jejunal biopsies were performed in 19 immunocompetent patients with a positive stool examination for S stercoralis and few or no symptoms, and in seven healthy controls. Specimens were processed for histopathological analysis and stained by the immunoperoxidase technique, using the following monoclonal antibodies: CD2, CD3, CD4, CD8, anti-T cell receptor (TcR) gamma/delta, RFD1 and RFD7 (two different macrophage markers), Ki67+ (proliferating) cells, antihuman leucocyte antigen (HLA)-DR, and anticollagen IV. In addition, CD25+ cells, mast cells, IgE expressing cells, calprotectin containing cells, and neutrophil elastase positive cells were stained by the alkaline phosphatase method. RESULTS: Jejunal morphology and the numbers of different T cell subsets, mast cells, IgE expressing cells, eosinophils, and goblet cells were unaffected by S stercoralis infection. Conversely, the numbers of mature macrophages and dividing enterocytes in the crypts were reduced significantly. Crypt enterocytes did not express HLA-DR in both groups. The expression of HLA-DR by villus enterocytes was also comparable in patients and controls. There were no activated (CD25+) cells in the mucosa of either patients or controls. CONCLUSIONS: Compared with seven healthy uninfected volunteers, a group of 19 Brazilians with clinically mild strongyloides infection showed no abnormality of mucosal structure and no increase in non-specific inflammatory cells. Likewise, there was no increase in mucosal T cells or macrophages.
Adult↗
The frequency of cells secreting interferon-gamma and interleukin-4, -5, and -10 in the blood and duodenal mucosa of children with cow's milk hypersensitivity.
Enzyme-linked immunoabsorbant spots (ELISPOTs) have been used to analyze the frequency of cells spontaneously secreting interferon-gamma (INF-gamma), IL-4, IL-5, or IL-10 in mononuclear cells isolated from the blood of children with cow's milk-sensitive enteropathy (CMSE), cow's milk allergy (CMA), and age-matched controls. In addition, cytokine profiles of duodenal lamina propria lymphocytes were compared in patients with CMSE and control subjects. In blood, spontaneous cytokine-secreting cells were uncommon, but there was significantly increased IFN-gamma, IL-4, IL-5, and IL-10 ELISPOTs in children with CMSE and CMA compared with control subjects. IL-4 ELISPOTs were significantly greater in the blood of children with CMA compared with those with CMSE. In the lamina propria the frequencies of spontaneous cytokine-secreting cells were high compared with that in blood. Significantly increased ELISPOTs for IFN-gamma and IL-4 were found in CMSE compared with controls. IL-5 ELISPOTs were unchanged, and IL-10 ELISPOTs were reduced in CMSE compared with controls. These results show a general enhancement of Th1 and Th2-type cytokine-secreting cells in the blood of children with cow's milk hypersensitivity, although the increased IL-4-secreting cells in blood in CMA may be of relevance in view of the fact that this disease is IgE-mediated. In the lamina propria, there is also enhancement of IFN-gamma- and IL-4-secreting cells in CMSE compared with control subjects; however, cells secreting IFN-gamma are 10 times more numerous than cells secreting IL-4, showing a dominance of Th1-type responses in both controls and CMSE patients.
Animals↗
Keratinocyte growth factor in inflammatory bowel disease. Increased mRNA transcripts in ulcerative colitis compared with Crohn's disease in biopsies and isolated mucosal myofibroblasts.
Inflammation in the gastrointestinal tract is associated with increased epithelial cell proliferation. Keratinocyte growth factor (KGF) is an epithelial cell mitogen widely expressed by mesenchymal cells subjacent to the epithelial cells. In this study, we have investigated the expression and distribution of KGF in normal and diseased (Crohn's disease and ulcerative colitis(UC)) intestine by quantitative competitive reverse-transcriptase polymerase chain reaction in whole biopsies and purified lamina propria myofibroblasts and by in situ hybridization. Analysis of whole mucosal biopsies reveals significantly higher numbers of KGF mRNA transcripts in UC compared with Crohn's colitis and control colon (P < 0.001). KGF transcripts were also elevated in Crohn's ileitis compared with normal ileum. In situ hybridization showed a marked increase in cells expressing KGF mRNA throughout the lamina propria in both UC and Crohn's tissue. In Crohn's disease, positively hybridizing cells were only rarely seen in the submucosa but were abundant around the bases of the crypts and were not associated with lymphoid aggregates. In purified mucosal myofibroblasts, increased (15- to 20-fold) KGF mRNA expression was seen in UC compared with control and Crohn's tissue. These results confirm and extend earlier studies showing that KGF transcripts are elevated in inflammatory bowel disease, but they show for the first time that transcripts are higher in UC than Crohn's disease because of increased production by mucosal mesenchymal cells.
Adolescent↗
Demonstration of local clonality of mucosal T cells in human colon using DNA obtained by microdissection of immunohistochemically stained tissue sections.
Intraepithelial lymphocytes have been shown to be oligoclonal and to be disseminated widely along the human intestine. However, studies using monoclonal antibodies have suggested that superimposed on the widespread clones, there is local variability in the mucosal T cell population. We have investigated the possibility that local dominant clones of T cells are present in the colonic mucosa by polymerase chain reaction (PCR) amplification of T cell receptor beta chain junctional regions using DNA extracted from microdissected fragments of tissue sections. Colon from two right hemicolectomy specimens was sampled at 7-cm intervals. Adjacent areas of mucosa were microdissected from sections from each colon sample. When the PCR products were separated according to size on polyacrylamide gels, bands of identical size were often observed when DNA extracted from adjacent fragments of mucosa had been used. Different bands were present when the different samples of colon had been studied. Sequencing of the PCR products confirmed that clonally related T cells were present in adjacent areas of mucosa, whereas different clones dominated at distant sites. DNA extracted from cells microdissected from the T cell zone of Peyer's patch was treated identically. The sequences obtained from the Peyer's patch, as expected, were diverse. However, one of the sequences identified was identical to that of one of the clones in the colon, implying that this clone was either trafficking through the Peyer's patch or possibly originated from the Peyer's patch. In this study, we also identified the Peyer's patches as a site of proliferation of CD4+ T cells. No T cell division was observed in the lamina propria. The molecular and immunohistochemical observations together support the hypothesis that the Peyer's patches are a source of mucosal T cells.
Adenocarcinoma↗
The distribution of dividing T cells throughout the intestinal wall in inflammatory bowel disease (IBD).
T cell hypersensitivity has been implicated in the tissue damage in Crohn's disease (CD). All studies to date have examined mucosal T cells, although much of the tissue damage occurs in the submucosa and muscle layers. The aim of this work was to study T cell proliferation throughout the intestinal wall in children with IBD. Surgical resection material from 19 children with CD (10 ileal, 10 colonic), seven with ulcerative colitis (UC), and 12 normal controls was studied. The distribution of dividing T cells was investigated by double-immunohistochemistry using Ki67 to identify proliferating cells, and CD3 to identify T cells. In ileal and colonic lamina propria virtually no Ki67+, CD3+ cells were seen in control, UC or CD tissue. In contrast, there were significantly more Ki67+, CD3+ cells within the lymphoid follicles of ileal and colonic CD than in the follicles in UC and controls. Increased numbers of Ki67+, CD3+ cells were present in the submucosa, muscle layers (M) and serosa in Crohn's ileitis and colitis compared with the lamina propria (LP), although only in the muscle of the colon was the difference statistically significant (LP, 0.4% (0-1%); M, 1.6% (0-5.2%); P = 0.03). Pooling data from ileal and colonic CD, however, did show significantly increased Ki67+, CD3+ cells in both serosa and muscle layers compared with the LP. Dividing T cells have been identified in the deeper layers of the gut wall in CD. These may contribute to the fibrosis and muscle hyperplasia characteristic of the condition.
Adolescent↗
Accessory cells in the human gastrointestinal tract.
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Antigen-Presenting Cells↗
Increased division of alpha beta TCR+ and gamma delta TCR+ intestinal intraepithelial lymphocytes after oral administration of cholera toxin.
Cholera toxin (CT) or its subunits were given orally to mice and division of intestinal intraepithelial lymphocytes (IEL) in vivo measured by double immunofluorescence using 5-bromo-2'-deoxyuridine (BRdU) and membrane alpha beta T-cell receptors (TCR) or gamma delta TCR staining in frozen sections. Cholera toxin (10 micrograms) produced a two- to eightfold-increase in the uptake of BRdU in alpha beta TCR+ IEL in the duodenum and a two-to fivefold increase in gamma delta TCR IEL in the ileum. Increased uptake of BRdU was also seen after a dose of 100 micrograms of CT but this dose was also associated with the loss of alpha beta TCR+ IEL and gamma delta TCR+ IEL in the duodenum. CT-A and CT-B subunit produced increased BRdU incorporation by alpha beta TCR in the duodenum and by gamma delta TCR IEL in the ileum. Cholera toxin therefore appears to be mitogenic for IEL probably due to an indirect mechanism.
Animals↗
T cell receptor V beta expression in human intestine: regional variation in postnatal intestine and biased usage in fetal gut.
A panel of T cell receptor V beta specific monoclonal antibodies was used to analyse V beta gene usage at different sites in human postnatal and fetal intestine. In normal small intestine, at a single site, different patients showed expansion of T cells expressing individual V beta s. Lamina propria and epithelial T cells from the same patient showed overlapping but not identical V beta dominance. V beta dominance was also shown in the T cells of the colonic lamina propria. Analysis of two separate regions of intestine from the same patient (5-100 cm apart) showed that T cells expressing a dominant V beta region were often present at both sites. In most patients, however, major biases in T cell V beta usage (two to 12-fold variation) were also apparent between the two sites. Analysis of V beta expression in human fetal intestine also showed considerable skewing, although the most common dominant V beta in postnatal intestine (V beta 22) was never predominant in fetal intestine. Patchy local variation in the expression of individual V beta s therefore occurs against a background of V beta dominance over large regions of the human gut. Furthermore the results from fetal gut show that factors other than luminal antigen control V beta expression in the gut.
Adolescent↗
Proteolytic degradation of intestinal mucosal extracellular matrix after lamina propria T cell activation.
BACKGROUND: Proteoglycans, consisting of glycosaminoglycan (GAG) side chains covalently linked to a protein core, are a major component of the extracellular matrix of the intestinal lamina propria. AIMS: This study investigated the effects of lamina propria T cell activation on the proteoglycan component of the matrix. METHODS: The high degree of sulphation of GAGs means that they are polyanionic and thus can be visualised in tissue sections by means of colloidal-gold labelled cationic probes. RESULTS: In human fetal small intestine there is a dense meshwork of anionic residues in the lamina propria and basement membrane. When explants of human fetal small intestine are cultured ex vivo, and resident lamina propria T cells are activated with pokeweed mitogen, mucosal destruction occurs within three days. This is associated with the rapid loss of anionic sites from the lamina propria. Dermatan sulphate proteoglycan is lost from the tissue and is present at increased concentrations in the organ culture supernatants, indicating that T cell activation has led to solubilisation of lamina propria proteoglycans. Tissue destruction and loss of anionic residues are inhibited in a dose dependent fashion by dexamethasone, and by the protease inhibitor, alpha 2 macroglobulin. CONCLUSIONS: Proteolytic degradation of the lamina propria may therefore be a mechanism by which T cell hypersensitivity injures the intestinal mucosa.
Culture Techniques↗
Mucosal tumor necrosis factor-alpha production and extensive disruption of sulfated glycosaminoglycans begin within hours of birth in neonatal respiratory distress syndrome.
Many of the clinicopathologic features of neonatal respiratory distress syndrome (RDS) may be related to the inflammatory response mounted by the affected infant, although little is known about the interstitial component of this response. We have thus studied the local inflammatory response in this condition by immunohistochemical analysis of whole lung lobes, obtained at postmortem from 40 infants who died from acute RDS in the first week of life. All had demonstrated classical clinical history and histologic features. An archival subgroup from the early 1970s had never received ventilatory support. Immunohistochemical analysis demonstrated rapid temporal increase from birth in the mucosal density of CD68+ macrophages, MAC-387+ monocytes/macrophages, polymorphonuclear neutrophils, and tumor necrosis factor-alpha-immunoreactive cells, maximal in those dying at or after 72 h. Using a cationic probe specific for sulfated glycosaminoglycans (GAGs), the inflammatory infiltration was seen to be associated with striking loss of endothelial, basement membrane, and interstitial GAGs, which was almost complete by 48-72 h. GAG degradation products were found within hyaline membranes in all infants dying after 48 h. This study confirms that neonatal RDS is characterized by intense interstitial inflammation, significantly underestimated on routine staining. This begins within hours of birth and is maximal by 72 h of age. Breakdown of sulfated GAGs within the extracellular matrix follows the same time course and may explain much of the physiologic derangement characteristic of this condition.
Age of Onset↗
Early production of macrophage inflammatory protein-1 alpha occurs in respiratory distress syndrome and is associated with poor outcome.
Although progression to pulmonary fibrosis in preterm infants with respiratory distress syndrome (RDS) is related to the inflammatory response, the nature of this response remains controversial. We have therefore performed sequential bronchoalveolar lavages in 30 infants with RDS (13 of whom developed bronchopulmonary dysplasia) and 7 ventilated control infants, characterizing the cells obtained by immunohistochemical analysis of lineage-specific markers and assaying macrophage-associated chemokines and cytokines in supernatant fluid. At all ages from birth, lavage supernatants demonstrated highly significant increase over controls of the beta-chemokine macrophage inflammatory protein (MIP)-1 alpha, although not of regulated upon activation, normal T cell expressed and secreted (RANTES), of the cytokines tumor necrosis factor (TNF)-alpha and IL-1 beta, and of elastase/alpha-1 antitrypsin. Significantly higher concentrations of MIP-1 alpha in particular were associated with the later development of fibrosis. Increased numbers of macrophages expressing the activation marker RM/3-1 were found at all ages in bronchopulmonary dysplasic infants, whereas neutrophil numbers were increased from d 3. Dexamethasone administered to 10 infants induced rapid decrease in inflammatory cell numbers and concentrations of MIP-1 alpha, tumor necrosis factor-alpha, IL-1 beta, and elastase/alpha-1 antitrypsin. The inflammatory response in neonatal RDS begins within the first day of life. Long-term outcome is associated with the magnitude of this early response, in particular production of MIP-1 alpha. The early introduction of specific therapy is thus likely to be beneficial.
Biomarkers↗
The immunologic basis for celiac disease and related disorders.
Celiac disease is the classical food-sensitive enteropathy and is caused by an antigen-specific immunologic hypersensitivity response to gluten within the small intestinal mucosa. Antibody and T-cell hypersensitivity may play a role in vivo, but it is more likely that the primary problem is an inappropriate T-cell response to gluten. The deleterious effects of gluten in celiac patients can be completely explained by the immune-mediated alterations in upper small-intestinal mucosal shape; these alterations include the replacement of long villi and short crypts with short or absent villi and hyperplastic crypts. It is an extremely unusual disease in that it is highly linked to human leukocyte antigen (HLA)-DQ2, and CD4+ T-cell clones that recognize gluten in the context of DQ2 have been isolated from celiac mucosa lamina propria. HLA-DQ2 is commonly used in Whites, but the incidence of celiac disease varies greatly between different countries and with time, without any obvious explanation. Celiac disease is also unusual in that it has features of autoimmune disease. Patients with active disease have immunoglobulin (Ig)A antibodies in endomysium, an uncharacterized extracellular matrix protein, and the presence of these antibodies is very specific for this condition. However, because celiac disease is more common in IgA-deficient patients, the IgA antiendomysial antibodies are unlikely to be pathogenic.
CD4 Antigens↗
Measles vaccination as a risk factor for inflammatory bowel disease.
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Colitis, Ulcerative↗
Mucosal adaptation and destruction in response to lamina propria T cell activation in explants of human fetal intestine.
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Adaptation, Physiological↗
Expression of cell adhesion molecules in the fetal gut.
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E-Selectin↗
Lipocortin-1 autoantibody concentration in children with inflammatory bowel disease.
BACKGROUND: Corticosteroids are widely used to treat children with inflammatory bowel disease although the response is variable, side-effects are common, and many patients develop a partial or complete steroid resistance. The mechanism underlying these phenomena are unclear. Corticosteroids mediate some of their actions through lipocortin-1, and the induction of autoantibodies to lipocortin has been proposed as a possible mechanism by which steroid efficacy is suboptimal in vivo. PATIENTS AND METHODS: We have measured serum lipocortin-1 antibody concentration by ELISA in 38 children with Crohn's disease, 12 with ulcerative colitis and in 15 controls. RESULTS: IgG and IgA anti-lipocortin-1 antibody levels were higher in the Crohn's group than in the ulcerative colitis or control groups. Elevated concentrations did not relate to disease activity, history of steroid therapy or steroid-responsiveness. Lipocortin IgM antibody status was similar in all three groups. CONCLUSION: It is therefore unlikely that serum antibodies to lipocortin-1 have a role in the development of steroid-resistance in children with inflammatory bowel disease.
Adolescent↗