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S L Pender

Publications and source records attributed to S L Pender.

23 records · Page 2Linked to original sources
PubMed1998

Suppression of T cell-mediated injury in human gut by interleukin 10: role of matrix metalloproteinases.

BACKGROUND & AIMS: Activation of lamina propria T cells with pokeweed mitogen in human fetal gut explant cultures results in severe mucosal injury. In the same system, Staphylococcus aureus enterotoxin B produces villus atrophy and crypt cell hyperplasia. The aim of this study was to examine the ability of interleukin (IL)-10 to modify these changes. METHODS: Mucosal pathology and lamina propria glycosaminoglycans were assessed histologically, and CD3(+), CD25(+) and alpha-actin smooth muscle-positive cells were determined by immunohistochemistry. Reverse plaque assays and quantitative reverse-transcriptase polymerase chain reaction were used to analyze the cytokine response. Matrix metalloproteinase production was analyzed by Western blotting, in situ hybridization, and zymography. RESULTS: Both experimental enteropathies produced mucosal damage, although injury was greater after pokeweed mitogen activation than S. aureus enterotoxin B. In both cases, the increase in cytokine-secreting cells and transcripts observed after T-cell activation was inhibited by IL-10. IL-10 also inhibited the increase in collagenase and stromelysin-1 in the explant culture supernatants and the loss of glycosaminoglycans. IL-10 decreased metalloproteinase production in control explants and increased matrix. In mesenchymal cells, IL-10 had a minor effect on metalloproteinase production. CONCLUSIONS: IL-10 down-regulates mucosal T-cell activation, metalloproteinase production, and loss of extracellular matrix and prevents mucosal damage in the gut.

Antigens, CD↗
PubMed1997

A major role for matrix metalloproteinases in T cell injury in the gut.

Activated lamina propria T cells responding to luminal Ags are thought to be important in celiac disease and Crohn's disease, and T cells responding to foreign MHC products are also important in intestinal graft-vs-host disease and intestinal transplant rejection. However, the mechanism(s) by which T cells mediate damage in the gut is not known. We have previously shown that activation of lamina propria T cells by PWM in explant cultures of second trimester human small intestine produces severe tissue injury, with epithelial cell shedding and loss of villi. In this study, we have investigated the role of matrix metalloproteinases in this system. Organ culture supernatants of explants stimulated with PWM showed a 3-fold increase in the concentration of interstitial collagenase and a 10-fold increase in stromelysin-1 compared with control explant culture supernatants. Tissue inhibitors of metalloproteinase-1 and -2 concentrations were unchanged. Increased metalloproteinase enzymatic activity was detected by gelatin and casein zymography. Western blotting revealed the active forms of interstitial collagenase and stromelysin-1 in PWM-stimulated culture supernatants. Up-regulation of mRNA for interstitial collagenase, stromelysin-1, and gelatinase-B was also seen. Nanomolar amounts of recombinant stromelysin-1 added directly to explants produced rapid severe tissue injury. PWM-induced mucosal injury was inhibited by a synthetic peptidomimetic inhibitor of matrix metalloproteinases. Mesenchymal cells isolated from the mucosa of human fetal small intestine produced increased amounts of interstitial collagenase, gelatinase A, and stromelysin-1 when stimulated with IL-1beta or TNF-alpha. These results suggest that T cell activation in the lamina propria results in increased production of matrix metalloproteinases, which by degrading the lamina propria matrix represent a major pathway by which T cells cause injury in the gut.

Cell Line↗
PubMed1996

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↗
PubMed1996

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↗