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Biomedical subjects

T T MacDonald

Publications and source records attributed to T T MacDonald.

At least 127 records · Page 7Linked to original sources
PubMed1992

Intestinal nematode infections in children: the pathophysiological price paid.

The mechanism by which small animals such as rodents resist or eliminate nematode parasites requires mucosal inflammation as the final effector of the immune response. The resulting freedom from chronic infection may be worth the price of short-term illness. Putative vaccines which attempt to enhance the natural effect will have to take into account the inflammatory cost to the host. Human helminthiases involve a more stable equilibrium between host and parasite. The medical literature on hookworm disease and clinical ascariasis describes, for the former, some chronic inflammatory effects correlated with worm burden, but for the latter a less quantified or predictable set of detrimental effects. We describe a current, systematic study of the inflammatory response to whipworm infection, in which anaemia, growth retardation and intestinal leakiness are viewed as predictable consequences related to infection intensity. There is evidence for the absence of cell-mediated immunopathology. However, a specific, IgE-mediated local anaphylaxis may, at least partly, mediate the deleterious effects. Increased numbers of mucosal macrophages may also contribute to the chronic, systemic effects through their output of cytokines. Similar attempts to show the mechanisms of pathogenesis and quantify the effects of hookworm disease should be undertaken.

Animals↗
PubMed1992

Direct in vitro infection of human intestine with HIV-1.

OBJECTIVE: To directly infect human fetal intestine with HIV in vitro. DESIGN: Human fetal intestinal explant cultures were exposed to HIV-1 and monitored for evidence of infection by biochemical assay, immunohistochemistry and in situ hybridization. METHODS: Human fetal intestinal explants (14-21 weeks) were established in culture and exposed to HIV-1. Tissue culture fluid was assayed for p24 antigen and reverse transcriptase activity over a 14-day period. Explants were removed from culture on days 4, 7, 10 and 14 postinoculation and subjected (1) to immunohistochemistry to detect p24 and gp160/41 antigens, and (2) to in situ hybridization to detect HIV-1 RNA. Explant tissue culture fluid was cocultured with Jurkat T-cells to detect infectious viral particles. RESULTS: Reverse transcriptase activity and p24 antigen levels in fetal explant culture fluid rose between 7 and 14 days after viral inoculation. Jurkat T-cell cocultures confirmed the presence of infectious virus. Cells in the lamina propria resembling lymphocytes and macrophages of both small intestine and colon stained positively for the viral proteins p24 and gp41. The same type of cells also stained positively for HIV-1 RNA using in situ hybridization. Dual-label immunohistochemistry, combined immunohistochemistry and in situ hybridization confirmed the presence of viral protein and RNA in cells bearing the CD3, CD4 (lymphocyte) or CD68 (macrophage) surface markers. There was no evidence at any time of HIV-1 infection of epithelial cells. CONCLUSIONS: Cells of the lamina propria of the small intestine and colon, bearing lymphocyte or macrophage markers, can be directly infected by and support the replication of HIV-1. Such infection may be implicated in the pathogenesis of HIV enteropathy.

Connective Tissue↗
PubMed1992

Epithelial proliferation in response to gastrointestinal inflammation.

Intestinal inflammation seems invariably to be associated with increased epithelial proliferation. In the small bowel the pathological consequences of this area an increase in the crypt proliferative compartment and a decrease in the absorptive villus compartment, which can lead to malabsorption. In the colon, it is more difficult to examine changes in cell proliferation, but using Ki67, epithelial proliferation has been shown to be increased in ulcerative colitis and parasitic infection. The teleological advantage of increasing epithelial proliferation during intestinal inflammation is presumably in an effort to get rid of parasitized or infected epithelial cells, or to rapidly replace cells which have been lost. Rejection of helminth parasites from rodent small bowel is associated with partial villous atrophy and crypt hypertrophy, which is probably part of the host response making the mucosa inhospitable to the parasites. The short-term nutritional disadvantage of malabsorption is outweighed by the long-term advantage of being parasite-free. However, when the intestinal inflammation is elicited by a dietary constituent, the consequences are only pathological. At the moment there is no information as to the mechanisms by which inflammatory cells alter mucosal morphology and epithelial renewal. The restructuring of mucosal morphology in the flat-mucosa involves considerable adaptation of the connective tissue elements of the lamina propria. Whether this occurs in response to changes in epithelial renewal is not known. Finally, it is clear that activated T cells in the lamina propria can produce a flat-mucosa. In diseases such as Trichuris dysentery and ulcerative colitis there is no or very little T cell activation, even though epithelial proliferation is increased. Increased epithelial proliferation therefore may occur in response to different inflammatory stimuli.

Animals↗
PubMed1992

Activation of lamina propria T cells induces crypt epithelial proliferation and goblet cell depletion in cultured human fetal colon.

An organ culture model has been used to study the effects of T cell activation in the human colon. Lamina propria T cells in explant cultures of human fetal colon (11 to 23 weeks gestation) were activated in situ using pokeweed mitogen or an anti-CD3 monoclonal antibody, and compared with unstimulated controls. After three days of culture, there was a two to four-fold increase in crypt epithelial cell proliferation in T cell stimulated explants of more than 15 weeks gestation, associated with a fall in crypt goblet cell numbers of up to 20-fold. By three days, the surface epithelium of stimulated explants appeared thin with loss of goblet cells, and by day 7, severe and extensive mucosal damage was observed by light and electron microscopy. These changes did not occur in control cultures and explants deficient in T cells (less than 16 weeks gestation), and were inhibited by cyclosporin A. These experiments indicate that the increase in epithelial cell proliferation and accompanying goblet cell depletion observed in colorectal crypts in chronic inflammatory bowel disease may be mediated by activated T cells.

Cell Division↗
PubMed1992

Tumour necrosis factor in the bronchoalveolar secretions of infants with the respiratory distress syndrome and the effect of dexamethasone treatment.

BACKGROUND: Tumour necrosis factor alpha may contribute to the lung damage that occurs in the adult respiratory distress syndrome. Whether it occurs in the lungs of preterm infants with respiratory distress syndrome is unknown. METHODS: Tumour necrosis factor alpha concentrations in the bronchopulmonary secretions of 28 ventilated preterm infants were determined by the enzyme linked immunosorbent assay. RESULTS: Concentrations were low in the first three days of life, being undetectable in nine of the 20 infants whose bronchopulmonary secretions were sampled. From day 4 concentrations were increased and detectable in all but two of 14 infants. Similar concentrations were found in samples taken on days 8-20 and 21-40. Greater mean concentrations occurred in those infants requiring oxygen for a long time. In six infants who received dexamethasone treatment for prolonged ventilator dependency treatment was associated with a reduction in tumour necrosis factor alpha concentrations. CONCLUSIONS: Tumour necrosis factor may contribute to the neonatal respiratory distress syndrome, as suggested for the adult respiratory distress syndrome. The therapeutic effects of dexamethasone treatment in neonatal respiratory distress syndrome may be mediated, at least in part, by reduced production of pulmonary tumour necrosis factor.

Bronchoalveolar Lavage Fluid↗
PubMed1992

Cell-mediated immune injury in the intestine.

Epithelial adaptation clearly occurs during the course of intestinal cell-mediated immune responses to alloantigens. The adaptive response is similar to that seen in a number of enteropathies, namely villus atrophy, crypt hypertrophy, and crypt cell hyperplasia. In human fetal gut, polyclonal activation of lamina propria CD4+ T cells produces the same epithelial adaptive responses. Although these data provide overwhelming evidence that cell-mediated immune responses can cause enteropathy, the demonstration of antigen-specific T cells in the lamina propria of patients with enteropathy is still lacking, even in a disease as well-characterized as celiac disease. Epithelial adaptation in experimental and clinical situations, however, must involve a change in the mechanisms and mediators involved in normal intestinal homeostasis, such as epidermal growth factor and transforming growth factor-alpha and -beta, and in the interactions between epithelial cells and the underlying stromal cells.

Animals↗
PubMed1992

Lymphokine secretion and proliferation of intraepithelial lymphocytes from murine small intestine.

Compared to other peripheral lymphocytes, intestinal intraepithelial lymphocytes (IEL) have previously been shown to have low proliferative capabilities. However, there are two main populations of IEL in the small intestine of mice. First, there is the thymus-dependent CD3+,Thy-1+ population, most of which expresses the alpha beta T-cell receptor (TcR), and second there is the thymus-independent CD3+,Thy-1- population, most of which expresses the gamma delta TcR. In this study Thy-1-enriched and Thy-1-depleted lymphocytes from murine intestinal epithelium were studied separately for their ability to proliferate and secrete lymphokines in vitro after mitogenic stimulation, after stimulation via the TcR-CD3 complex and after stimulation with the superantigen Staphylococcus aureus B (SEB). Here we show that Thy-1-enriched IEL are not an immunocompromised population of cells but are functionally competent T cells that are capable of proliferation and lymphokine secretion after stimulation with concanavalin A (Con A), phorbol myristate acetate (PMA) and anti-CD3 monoclonal antibody (mAb). Furthermore, Thy-1-enriched IEL proliferate and secrete lymphokines after 'superantigenic' stimulation with SEB. In contrast, the majority of Thy-1-depleted IEL do not proliferate, and secrete only minimal levels of lymphokine to any of the stimuli tested in this study.

Animals↗
PubMed1992

Ontogenetic aspects of the intestinal immune system in man.

The development of the mucosal immune system in the human fetus has been studied in some detail. Aggregates of T and B cells form early Peyer's patches by 16 weeks gestation and by 19 weeks organised Peyer's patches with T and B cell zones are seen. T cells populate the mucosal lamina propria and epithelium from 11 weeks gestation and increase in number thereafter. As in the adult, most intraepithelial lymphocytes are CD8+ and most lamina propria T cells are CD4+. By 20 weeks, villus epithelial cells are HLA-DR+ and secretory component is also expressed. In the absence of lumenal stimulation in the fetus there is no intestinal secretory IgA antibody response. A few IgA plasma cells are present in fetal salivary glands but the number does not dramatically increase until after birth.

Embryonic and Fetal Development↗
PubMed1991

Immediate hypersensitivity in colon of children with chronic Trichuris trichiura dysentery.

There are few data on mucosal immune responses to intestinal helminths in human beings, especially those involving the IgE system, which is thought to be important in parasite expulsion. We sought evidence of an immediate hypersensitivity reaction in the colon of children with chronic dysentery due to Trichuris trichiura. 28 children with Trichuris dysentery syndrome (TDS) were compared with 16 control children (with no TDS or worms visible on colonoscopy). All children were aged 1-11 years. Rectal biopsy samples were taken before and after expulsion of the worms by means of mebendazole treatment. Children with TDS had significantly greater numbers than controls of mast cells (mean [SD] 10.9 [1.3] vs 3.9 [0.6]% of all cells; p less than 0.0003) and of cells with surface IgE (median [range] 11.1 [7.5-11.6] vs 1.0 [0-1.5]%; p less than 0.001) in the subepithelial region of the mucosa. On electronmicroscopy, degranulating mast cells were prominent in parasitised children. In culture, rectal biopsy samples from parasitised children showed high rates of spontaneous histamine release, but only low rates of antigen-specific release. After treatment, spontaneous histamine release was significantly reduced and antigen-specific histamine release could be provoked. Thus, an IgE-mediated immune mucosal response to a helminth infection does occur in human beings but is not sufficient to cause appreciable parasite expulsion.

Anaphylaxis↗
PubMed1991

Gamma/delta T cells and the diagnosis of coeliac disease.

Gamma/delta T cells are increased in the gut epithelium of patients with coeliac disease compared with normal controls. The aim of this study was to determine whether the increase in gamma delta intraepithelial lymphocytes (IEL) is specific for coeliac disease, in which case it could be of diagnostic importance. Biopsies were obtained from children with no intestinal disease, coeliac disease, cow-milk-sensitive enteropathy/post-enteritis syndrome (CMSE PES) and miscellaneous other enteropathies (n = 67). Intraepithelial CD3+ and gamma delta T cells were identified in frozen sections using peroxidase immunohistochemistry. In normal biopsies there were 0-7 gamma delta IEL/100 cells in the epithelium. In untreated coeliac patients this increased to 9-22 gamma delta IEL/100 cells in the epithelium (P = 0.000004). Of 27 patients with morphologic intestinal damage which was not due to coeliac disease, four with CMSE/PES had gamma delta IEL/100 cells in the epithelium in the same range as the patients with coeliac disease. Of these, two had high densities of CD3+ IEL in the epithelium and were indistinguishable from patients with untreated coeliac disease. The other two could be excluded as possible coeliacs because their CD3+ IEL/100 epithelial cells were in the normal range. Thus an increase in gamma delta IEL is not specific for coeliac disease. However, enumeration of both of gamma delta IEL and CD3+ IEL densities will be useful in the exclusion of coeliac disease as a diagnosis in some children.

Adolescent↗
PubMed1991

Serum concentrations of tumour necrosis factor alpha in childhood chronic inflammatory bowel disease.

Serum tumour necrosis factor alpha (TNF alpha) concentrations were measured by enzyme linked immunoadsorbent assay in 31 normal children and during 65 episodes of clinical remission and 54 episodes of relapse in 92 children with chronic inflammatory bowel disease. An appreciable rise in TNF alpha was found only in children in relapse of ulcerative colitis and colonic Crohn's disease. The group of children with small bowel Crohn's disease in relapse did not show increases of TNF alpha above control concentrations, despite an equivalent rise in disease indices. Height velocity was depressed in children with relapse of large bowel Crohn's disease and ulcerative colitis compared with the equivalent condition in remission. The impairment of growth velocity was significantly greater in relapse of large bowel Crohn's disease and ulcerative colitis than in small bowel Crohn's disease alone, although for the subgroups in stage 1 puberty (prepubertal) the differences were not significant. Inadequate growth in chronic inflammatory bowel disease is currently ascribed to inadequate nutrition and TNF alpha may contribute to this through its cachexia inducing effects. It may, in addition, diminish pituitary growth hormone release. These results suggest that production of TNF alpha may be associated with growth failure in relapse of colonic inflammatory bowel disease.

Adolescent↗
PubMed1991

T cell receptor V beta expression by mucosal T cells.

Immunohistochemistry with monoclonal antibodies to the T cell receptor V beta regions 5, 6, 8 and 12 was used to determine whether normal intestinal lymphocytes that are potentially exposed to many bacterially derived superantigens show any preferential expression of particular V beta regions compared with the blood. No difference between V beta expression in the mucosa and the blood was observed, suggesting that they share a common pool of alpha beta T cells and that there is no expansion of alpha beta T cells in response to bacterial "superantigens" in the gut. The T cell receptor V beta expressed by the activated T cells in the lamina propria of bowel from patients with Crohn's disease was also studied. There was no increase in V beta 8 expression in these cells, suggesting that the increase in V beta 8 observed in the blood and mesenteric nodes of patients with Crohn's disease is not of primary importance in the aetiology of the disease. Finally, V beta expression by mucosal T cells in coeliac disease was studied. There was no difference in V beta use by T cells in coeliac disease and those in the blood and normal jejunum.

Adolescent↗
PubMed1991

Histopathology and immunohistochemistry of the caecum in children with the Trichuris dysentery syndrome.

Caecal biopsy specimens from Jamaican children with the Trichuris dysentery syndrome (TDS) and age matched Jamaican controls were investigated by immunohistochemistry and by light microscopy. Biopsy specimens from all children (with TDS and controls) showed a mild to moderate increase in inflammatory cells. Except in the vicinity of the worm, where the epithelium was flattened, there was no other epithelial abnormality. Compared with controls, children with TDS had increased IgM lamina propria plasma cells and decreased intraepithelial T cells. There was also an increase in crypt epithelial cell proliferation. Lamina propria T cells (both activated and non-activated) were no more common in children with the Trichuris syndrome than controls. Epithelial cell HLA-DR and VLA-1 expression (which are increased in other colitides) were the same in both groups. Despite the presence of large worm burdens and chronic dysentery, therefore, only minor changes were seen in the caecal mucosa of children with TDS.

Antigens, CD↗
PubMed1990

Cytotoxic alpha/beta+ and gamma/delta+ T cells in murine intestinal epithelium.

Murine intraepithelial lymphocytes (IEL) consist of two main populations. Approximately half are Thy-1+, most of which are CD3+, T cell receptor (TcR) alpha/beta+, and the remainder are Thy-1-, most of which are CD3+, TcR alpha/beta- (presumably TcR gamma/delta+). In redirected cytotoxicity assays, TcR alpha/beta+ IEL are potent cytotoxic effectors. Thy-1-, CD3+, TcR alpha/beta- IEL isolated from athymic mice are also cytotoxic. Thus, regardless of TcR usage or Thy-1 expression, IEL are cytotoxic effectors.

Animals↗
PubMed1990

Selective death of T cell receptor gamma/delta+ intraepithelial lymphocytes by apoptosis.

In mice, the majority of T cells expressing the gamma/delta T cell receptor (TcR) are found at mucosal surfaces, especially the intestinal epithelium. Here we show that in vitro, the majority of TcR gamma/delta+ intraepithelial lymphocytes, but not TcR alpha/beta+ intraepithelial lymphocytes, undergo rapid and selective programmed cell death by apoptosis.

Animals↗
PubMed1990

Expression of the VLA family of integrins in human intestine.

The distribution of cells expressing the integrins VLA-1 to 6 in human intestine was examined by alkaline phosphatase immunohistochemistry using monoclonal antibodies specific for the individual alpha-chains of the VLA heterodimer. VLA-2,3, and 6 were expressed on all epithelial cells in the small and large bowel. VLA-1 was expressed on crypt cells in the small and large bowel, but was only weakly expressed or was absent on villus epithelial cells in the small bowel and colonic surface epithelial cells. All epithelia were negative for VLA-4 and VLA-5. Intraepithelial lymphocytes were VLA-1+ and VLA-4+. VLA-1,3, and 5 were expressed uniformly by muscularis propria, muscularis mucosae, pericrypt cells, and smooth muscle fibres within the villi. By contrast, VLA-2 and 4 were present only in pericrypt cells and fibres within the villi; they were absent from the muscularis mucosae. VLA-1,3,5, and 6 were expressed by endothelium. Staining of muscle fibres and endothelium in the lamina propria made it difficult to determine the extent of VLA expression on lamina propria lymphocytes. However, VLA-1+ cells with lymphoid morphology were only rarely seen. All mononuclear cells in the lamina propria were VLA-4+.

Antibodies, Monoclonal↗