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D Foell,
H Wittkowski,
Z Ren,
J Turton,
G Pang,
J Daebritz,
J Ehrchen,
J Heidemann,
T Borody,
J Roth, R Clancy
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ABSTRACT: Phagocyte-derived S100 proteins are endogenous activators of innate immune responses. S100A12 binds to the receptor for advanced glycation end-products, while complexes of S100A8/S100A9 (myeloid-related proteins, MRP8/14; calprotectin) are ligands of toll-like receptor 4. These S100 proteins can be detected in stool. In the present study we analyse the release of S100A12 and MRP8/14 from intestinal tissue. Specimens from patients with Crohn's disease (CD; n = 30), ulcerative colitis (UC; n = 30), irritable bowel syndrome (IBS; n = 30) or without inflammation (n = 30) were obtained during endoscopy. After 24 h culture, S100A12 and MRP8/14 were analysed in supernatants. Endoscopic, histological, laboratory and clinical disease activity measures were documented. We found an increased spontaneous release of S100A12 from tissue in inflammatory bowel disease (IBD). The release of S100A12 into the supernatants was 28-fold enhanced in inflamed tissue when compared to non-inflamed tissue (mean 46.9 vs. 1.7 ng/ml, p < 0.0001). In active CD, release of S100A12 and MRP8/14 was strongly dependent on localization, with little release from sites of active ileal inflammation compared to colonic inflammation. This difference was more pronounced for S100A12 than for MRP8/14. S100A12 and MRP8/14 provoked up-regulation of adhesion molecules and chemokines on human intestinal microvascular endothelial cells (HIMECs) isolated from normal colonic tissue. The direct release of phagocyte-derived S100 proteins from inflamed tissues may reflect secretion from infiltrating neutrophils (S100A12) and also monocytes or epithelial cells (MRP8/14). Via activation of pattern recognition receptors, these proteins promote inflammation in intestinal tissue. The enhanced mucosal release can explain the correlation of fecal markers with disease activity in IBD.
The Journal of Pathology 10/2008; 216(2):183-92. · 6.32 Impact Factor
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ABSTRACT: Support for a role of Mycobacterium avium subspecies paratuberculosis in Crohn's disease is largely based on epidemiological evidence, as no data on mechanisms linking the presence of M. avium subspecies paratuberculosis with gut damage is available.
To determine whether the presence of M. avium subspecies paratuberculosis contributes to the pathogenesis of Crohn's disease by promoting cytokine secretion within gut mucosa.
A total of 235 subjects were recruited: 63 with Crohn's disease, 53 with ulcerative colitis, 45 with irritable bowel syndrome and 74 normal controls. M. avium subspecies paratuberculosis status was defined by nested PCR using IS900 sequence. Gut mucosal organ cultures were established to detect cytokine secretion patterns.
Significantly higher tumour necrosis factor-alpha concentrations were found in culture supernatants for Crohn's disease compared to ulcerative colitis (p<0.05), irritable bowel syndrome (p<0.01) and controls (p<0.0001). When tumour necrosis factor-alpha levels were correlated with the presence of M. avium subspecies paratuberculosis, significantly greater concentrations were only found in M. avium subspecies paratuberculosis-positive Crohn's disease patients (p<0.05). Tumour necrosis factor-alpha levels in M. avium subspecies paratuberculosis-positive Crohn's disease were significantly higher than in M. avium subspecies paratuberculosis-positive ulcerative colitis (p<0.01), M. avium subspecies paratuberculosis-positive irritable bowel syndrome (p<0.05) and M. avium subspecies paratuberculosis-positive controls (p<0.01) and all M. avium subspecies paratuberculosis-negative specimens.
The data link M. avium subspecies paratuberculosis with a pathogenic mechanism in Crohn's disease and is consistent with abnormal macrophage handling of M. avium subspecies paratuberculosis.
Digestive and Liver Disease 05/2007; 39(5):445-51. · 3.05 Impact Factor
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ABSTRACT: Atherosclerosis is an inflammatory response, probably to a range of initiating causes. Chronic infection with Chlamydia pneumoniae (C.pn) has been suggested as one cause, but the nature of the association is controversial, in large part due to lack of an identified mechanism to link infection with the atherosclerotic process in man. This study examined 139 consecutive subjects with stable chest pain, with the aim of correlating the serological status of C.pn infection with the pattern of secretion of cytokines from CD4(+) T lymphocytes. C.pn seropositive subjects secreted significantly more interleukin (IL)-4 than did those who were C.pn seronegative (P = 0.02). No significant difference was noted for secreted interferon (IFN)-gamma. The amount of secreted IL-4, but not of secreted IFN-gamma, correlated positively with the extent of coronary artery disease (P = 0.006). A similar correlation with secreted IL-4 was not identified with Helicobacter pylori infection. These results support the hypothesis that C.pn infection contributes to the inflammatory process responsible for coronary artery atherosclerosis. The method used to detect cytokine secretion involves ligation of CD40L on blood CD4(+) T cells, which may have relevance to tissue events.
Clinical & Experimental Immunology 12/2006; 146(2):197-202. · 3.36 Impact Factor
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ABSTRACT: Current 'rescue' therapies provide inadequate Helicobacter pylori eradication rates because of antibiotic resistance.
To test the efficacy of a modified triple regimen combining rifabutin, pantoprazole and amoxicillin as rescue therapy for patients in whom eradication of H. pylori had failed standard clarithromycin-based triple therapy.
One hundred and thirty patients (mean age 51.7 +/- 14.8 years) who had failed one or more eradication attempts with omeprazole, clarithromycin and amoxicillin were treated for 12 days with rifabutin 150 mg daily, amoxicillin 1 g or 1.5 g t.d.s, and pantoprazole 80 mg t.d.s.
The intention-to-treat and per-protocol eradication rates were 90.8/90.8%. Metronidazole or/and clarithromycin resistance had no significant impact on H. pylori eradication rates. A higher overall eradication rate of 96.6% (95% CI: 92.1-101%) was obtained in patients treated with a regimen containing 1.5 g amoxicillin t.d.s compared with 90.7% (95% CI: 82-98.6%) using a regimen with 1 g amoxicillin t.d.s but the difference was not significant. Side-effects reported in 40% of patients were mild.
A 12-day course of low dose of rifabutin with an increased dose of amoxicillin and pantoprazole is well-tolerated and highly effective against dual-resistant H. pylori infection after failure of triple therapy.
Alimentary Pharmacology & Therapeutics 03/2006; 23(4):481-8. · 3.77 Impact Factor
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ABSTRACT: Orally administered live Lactobacillus acidophilus was assessed for its capacity to enhance clearance from the oral cavity of DBA/2 mice shown previously to be 'infection prone'. L. acidophilus fed to DBA/2 mice significantly shortened the duration of colonization of the oral cavity compared to controls. Enhanced clearance of Candida albicans correlated with both early mRNA gene expression for interleukin (IL)-4 and interferon (IFN)-gamma and expression of their secreted products in cultures of cervical lymph nodes stimulated with Candida antigen. In addition rapid clearance correlated with higher levels of IFN-gamma and nitric oxide in saliva. Delayed clearance, less pronounced levels of the cytokine response, saliva IFN-gamma and nitric oxide, and later mRNA expression for IL-4 and IFN-gamma relative to feeding with the L. acidophilus isolate were noted in mice fed a different Lactobacillus isolate (L. fermentum). These observations indicate significant variations in individual isolates to activate the common mucosal system.
Clinical & Experimental Immunology 08/2005; 141(1):29-36. · 3.36 Impact Factor
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ABSTRACT: The performance of commercial Helicobacter pylori diagnostic kits developed for particular geographic regions has often been found to be of poor diagnostic value when applied to other regions, possibly because of infections being caused by different H. pylori strains in different regions.
To evaluate the performance of an IgG2 anti-H. pylori enzyme-linked immunoassay test (Helirad Alert) for detection of H. pylori infection in both Australian and Hong Kong (Chinese) subjects.
Serum samples were tested for H. pylori specific IgG2 and IgG antibodies by enzyme-linked immunoassay kits using identical antigen preparation in 168 Australian and 160 Hong Kong (Chinese) subjects diagnosed with dyspepsia.
Using a cut-off value determined by analysis of H. pylori-negative Australian samples, the sensitivity, specificity and accuracy of the IgG2 assay were 77.8, 97.4 and 91.1%, respectively, for the Australian samples and 96.3, 83.8 and 90% for Hong Kong samples. For the IgG assay, sensitivity, specificity and accuracy were 87.0, 99.1 and 95.2% for Australian samples and 97.5, 75 and 86.3% for Hong Kong samples respectively. Receiver-operating characteristic analysis showed better discrimination of H. pylori status when the IgG2 assay was applied to Hong Kong samples, while the IgG assay was better in the Australian samples.
These data demonstrate that the Helirad Alert enzyme-linked immunoassay could provide a reliable method for screening H. pylori infection in both western and Chinese populations.
Alimentary Pharmacology & Therapeutics 02/2005; 21(1):83-9. · 3.77 Impact Factor
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ABSTRACT: A murine model of oral candidiasis was used to show that nitric oxide (NO) is involved in host resistance to infection with Candida albicans in infection-'resistant' BALB/c and infection-'prone' DBA/2 mice. Following infection, increased NO production was detected in saliva. Postinfection samples of saliva inhibited the growth of yeast in vitro. Treatment with NG-monomethyl-L-arginine (MMLA), an inhibitor of NO synthesis, led to reduced NO production, which correlated with an increase in C. albicans growth. Reduction in NO production following MMLA treatment correlated with an abrogation of interleukin-4 (IL-4), but not interferon-gamma (IFN-gamma), mRNA gene expression in regional lymph node cells. Down-regulation of IL-4 production was accompanied with an increase in IFN-gamma production in infection-'prone' DBA/2 mice. There was a functional relationship between IL-4 and NO production in that mice treated with anti-IL-4 monoclonal antibody showed a marked inhibition of NO production in saliva and in culture of cervical lymph node cells stimulated with C. albicans antigen. The results support previous conclusions that IL-4 is associated with resistance to oral candidiasis and suggest that NO is involved in controlling colonization of the oral mucosal surface with C. albicans.
Immunology 01/2002; 104(4):447-54. · 3.32 Impact Factor
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ABSTRACT: To determine if interleukin 2 (IL-2) alters epithelial transport and barrier function in cultured human small intestinal enterocytes.
Confluent monolayers of small intestinal cells derived from duodenal biopsies were treated with IL-2 0.2-50 U/ml for 24 hours prior to study. Transport measurements were performed under short circuited conditions in Ussing chambers, with and without the secretagogues forskolin and 3-isobutyl-1-methyl xanthine (IBMX). Serosal to mucosal flux of 3[H] mannitol (permeability) and 3[H] thymidine uptake (proliferation) were measured. IL-2 receptor and cystic fibrosis transmembrane conductance regulator (CFTR) mRNA were identified using reverse transcription-polymerase chain reaction (RT-PCR).
IL-2 did not alter baseline electrical parameters but caused a significant increase in cAMP dependent chloride secretion. The effect was mediated by the IL-2 receptor and paralleled a rapid increase in tyrosine phosphorylation, janus kinase 1, and signal transducers and activators of transcription (STATs) 1, 3, and 5. IL-2 significantly increased proliferation but at a lower dose than observed for enhanced secretion but did not alter permeability. IL-2 receptor beta and gammac chains and CFTR mRNA were identified by RT-PCR.
IL-2 treatment enhances cAMP stimulated chloride secretion and cellular proliferation in a human small intestinal cell line expressing a functional IL-2 receptor.
Gut 12/2001; 49(5):636-43. · 10.11 Impact Factor
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ABSTRACT: Persistent and recurrent infection of mucosal surfaces with Candida albicans is common, ranging from a nuisance to a life threatening clinical problem. No effective prophylactic or therapeutic vaccine has been developed. We have studied a mouse model of oral candida infection to identify regulatory and effector molecules of T cell activation as parameters of induced immunity, and here describe the use of this model to determine an optimal immunisation strategy. Oral immunisation with the blastospore yeast form (but not subcutaneous immunisation) induced clinical immunity, with a shift in parameters of cytokine response characterised by an early and sustained production of both IFN-gamma and IL-4 from antigen-stimulated cervical node T lymphocytes.
Vaccine 04/2001; 19(17-19):2516-21. · 3.77 Impact Factor
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ABSTRACT: The etiology and pathophysiology of stomach carcinoma is complex, and the mechanism whereby H. pylori directly or indirectly induces carcinoma remains unclear. In this study, interleukin (IL)-8, IL-4 and interferon (IFN)-gamma were measured in the tissue culture supernatant of gastric organ cultures from subjects with chronic gastritis with or without H. pylori infection, and with or without gastric cancer and gastric dysplasia.
Interleukin-8 levels were higher in cancer- and H. pylori-infected gastritis subjects than in H. pylori-negative subjects (12.95 +/- 3.16, 10.48 +/- 1.55 and 4.49 +/- 1.28 ng/mL, respectively). Elevated levels of IFN-gamma were detected in both H. pylori-infected and non-infected subjects with uncomplicated gastritis (72.23 +/- 19.0 and 34.61 +/- 5.30 pg/mL) and in non-infected dysplasia subjects (88 +/- 20.5 pg/mL). Background levels of IL-4 (< or = 9.4 pg/mL) in uncomplicated gastritis subjects and relatively high levels of IL-4 in dysplasia subjects (25.8 +/- 7.3 pg/mL) were detected. In contrast, trace amounts of IFN-gamma (16.01 +/- 0.35 pg/mL) and high levels of IL-4 (42.81 +/- 8.49 pg/mL) in gastric biopsy culture supernatants were found in cancer subjects. Mucosal IL-4 levels (but not IL-8 levels) correlated with infection and mucosal anti-H. pylori immunoglobulin G antibody.
The significant differences between gastritis with and without cancer and dysplasia indicated a shift from a Th1 to a Th2 helper cell pattern of cytokine secretion. This study has identified a local mucosal defect in gastric cancer. The near absence of IFN-gamma production from the mucosa at the margins of the tumor may be a critical factor in promoting growth of neoplastic cells.
Journal of Gastroenterology and Hepatology 02/2001; 16(2):142-8. · 2.87 Impact Factor
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ABSTRACT: Host protection against Candida albicans infection in a model of oral candidiasis involving infection-prone [DBA/2 (H-2(d))] and less infection-prone [BALB/c (H-2(d))] mouse strains was analyzed in terms of antibody and cellular responses, and in terms of cytokine patterns from regional lymph node cells. There was a selective expansion of gamma/delta(+) T-cell receptor cells, which correlated with the patterns of colonization in both mouse strains, with higher numbers of gamma/delta T cells detected in BALB/c mice. Antigen-induced T-cell proliferation was significantly higher in BALB/c mice than in DBA/2 mice. Higher levels of serum immunoglobulin G (IgG) and salivary IgA antibodies were detected in BALB/c mice than in DBA/2 mice, but only after the infection was cleared. The cervical lymph node cells from infected mice were assessed for interleukin-4 (IL-4), IL-12, and gamma interferon (IFN-gamma) mRNA gene expression by reverse transcription-PCR and protein production in the culture supernatants following restimulation in vitro. In BALB/c mice, an early increase in levels of IL-4, IFN-gamma, and IL-12 correlated with rapid elimination of C. albicans. In DBA/2 mice, where resolution of infection was delayed, IL-4 message expression was delayed and the IL-4 secretion level was lower. Neutralization of IL-4 by multiple injections of an anti-IL-4 monoclonal antibody in BALB/c mice resulted in increased carriage rate and delayed clearance of the yeasts. Collectively, the data suggest that the T-cell response to C. albicans in the regional lymph nodes which correlates best with rapid oral clearance of C. albicans is a balanced Th0 cytokine response involving early secretion of both IFN-gamma and IL-4.
Infection and Immunity 11/2000; 68(10):5771-7. · 4.16 Impact Factor
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ABSTRACT: Helicobacter pylori elicits a specific humoral and cellular immune response. There is increasing evidence that the type of T-cell response contributes to clinical outcome in H. pylori infection.
The host response to H. pylori infection in 34 subjects with chronic gastritis was examined in terms of T-cell proliferation and cytokine production in whole-blood cultures stimulated or unstimulated with H. pylori acid-glycine extract antigens (AGE).
The proliferative response in whole-blood cultures was similar for both H. pylori-positive and -negative subjects stimulated with H. pylori AGE. While an increase in interferon-gamma (IFN-gamma) production was observed from both H. pylori-positive and -negative subjects with gastritis, significantly higher levels of IFN-gamma were detected in the former when stimulated with H. pylori AGE. In contrast, interleukin 4 (IL-4) was undetectable regardless of antigen stimulation. However, if an in situ IL-4 antibody capture assay was used, antigen-independent production of IL-4 was detected, but there was no difference between H. pylori-positive and -negative subjects with gastritis. After eradication of H. pylori, antigen-induced production of IL-4 was increased, with no decrease in the levels of secretion of IFN-gamma. IL-4 production was dependent on CD4+ T cells, as addition of anti-CD4 but not anti-CD8 mouse monoclonal antibody or matched IgG isotype to the whole-blood culture inhibited the production of IL-4.
The results suggest that a shift toward a balanced Th1-Th2 response due to an increase in antigen-induced IL-4 production from CD4+ T cells follows eradication. We suggest that the downregulation of mucosal inflammation consequent on reduction in antigen levels or removal of downregulation after eradication of H. pylori contributes to this shift in cytokine balance.
Helicobacter 10/2000; 5(3):135-41. · 3.15 Impact Factor
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ABSTRACT: Helicobacter pylori infection is the commonest cause of gastritis. Different patterns of immune response to H. pylori infection and characteristics of bacteria are considered to contribute to clinical outcomes.
To determine characteristics of the host H. pylori relationship in subjects with non-ulcer dyspepsia and a histological diagnosis of gastritis.
Thirty-five subjects with chronic gastritis undergoing endoscopy (mean age 53 years, range 24-82, 14 male and 21 female) were studied, none of whom was on nonsteroidal anti-inflammatory drugs or antibiotics. H. pylori infection was determined by rapid urease test (CLOtest), culture, antibody and RT-PCR for Ure C, Cag A and 26 kDa gene and histology. Cytokine production of mucosal IL-6 and IL-8 were measured by ELISA.
Fifteen subjects were positive by CLOtest and/or bacterial culture. In these subjects histology showed numerous helical forms of H. pylori (Group I). Nine subjects were negative by CLOtest, bacterial culture, and mRNA for urease C fragment, but positive by PCR for the 26 kDa protein encoding gene. Histology in these subjects showed the presence of either coccoid forms (four), or scant helical forms (two), or mixed coccoid/helical forms (three) (Group II). Eleven subjects were negative by all methods of detection (Group III). IgG and IgA antibody levels in serum (p<0.05) and gastric tissue culture supernatant (p<0.001) were significantly higher in Group I than those in Group II or III. There were significant differences in the IgG serum and IgA supernatant antibody levels (p<0.01 and p<0.05) when Group II was compared to Group III. Supernatant IL-6 levels were significantly higher in Group I (p<0.01) than those from Groups II and III. IL-8 levels were higher in Group I (p<0.01) and Group II (p<0.05) when compared to Group III.
'H. pylori-negative' gastritis can be associated with a non-urease producing form of H. pylori, with a reduction in both local and systemic antibody levels and mucosal pro-inflammatory cytokines.
Australian and New Zealand journal of medicine 10/2000; 30(5):578-84.
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ABSTRACT: Neutrophils are central to the control of infection within the bronchial mucosa. To determine whether the link between bacterial and viral infection in the respiratory tract can be partly explained by acute reduction of neutrophil function, we examined the influence of influenza virus on lysozyme secretion by sputum neutrophils obtained from patients with bronchiectasis. Sputum neutrophils infected with influenza A virus had a significantly reduced capacity to secrete lysozyme but not myeloperoxidase. Influenza virus A strains were more effective in inhibiting lysozyme secretion than were influenza B virus strains. Reduction of bactericidal activity was similarly reduced by different strains of influenza A virus, but an influenza virus B strain had no effect. Our results show that downregulation of sputum neutrophil function characterized by lysozyme secretion and bactericidal activity could contribute to reduction in the capacity to control bacterial colonization in the respiratory tract following influenza virus infection.
American Journal of Respiratory and Critical Care Medicine 04/2000; 161(3 Pt 1):718-22. · 11.08 Impact Factor
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ABSTRACT: Recent work from our laboratory implicates T cells in the pathogenesis of alcoholic liver disease. We have studied the role of liver-associated T cells in acute hepatitis produced in control rats administered Concanavalin A (Con A) after adoptive transfer of T cells from alcohol-consuming animals.
Liver-associated T cells from ethanol-consuming rats were transferred via tail vein to nonethanol-consuming rats. They then received Con A (20 mg/kg body weight) intravenously. This produced a severe hepatitis. Serum was collected for the assay of alanine aminotransferase (ALT) and cytokines.
Hepatic necrosis was accompanied by an increase in plasma levels of ALT, interleukin-6, and tumor necrosis factor-alpha. These increases correlated with increased production of interleukin-6 and tumor necrosis factor-alpha in culture of liver-associated T cells stimulated or unstimulated with Con A. Immunohistology staining showed increased infiltration of inflammatory cells comprised of neutrophils and mononuclear cells, which included greater numbers of CD4+ T cells in the portal tract areas and around the central vein. Focal and lobular necrosis was seen with inflammatory cells in the necrotic area. Hepatocytes isolated from the liver showed increased apoptosis compared with rats that received liver-associated T cells from nonethanol-consuming rats. Injection of endotoxin LPS, in the same model, was associated with less hepatocyte injury indicating a distinct role for T cells as opposed to Kupffer cells in this model of liver disease.
Chronic ethanol consumption induces a lesion in a pool of liver-associated T cells which can mediate liver injury after polyclonal mitogen activation.
Alcoholism Clinical and Experimental Research 11/1999; 23(10):1660-7. · 3.34 Impact Factor
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ABSTRACT: Controversy exists as to whether the coccoid form of Helicobacter pylori can exist in a viable form. Conversion of helical to coccoid morphology occurs in culture over several days. In this study, the morphology was correlated with parameters of genetic integrity in the reference NCTC 11637 strain over 21 days of culture. The capacity to regrow colonies of helical form was demonstrated from a culture where the coccoid form constituted up to 95% and negligible urease activity could be detected. Urease enzyme activity and its mRNA decreased between day 0 and 10 while 26 kD mRNA and 16S rRNA were expressed unchanged for up to 14 and 21 days of culture, respectively. Expression of mRNA for the Cag A gene behaved in a similar fashion to that of urease. No evidence of DNA fragmentation was detected. These data suggest that a viable form of non-urease producing H. pylori exists after short to intermediate culture and that some if not all of these viable bacteria have coccoid morphology.
Microbios 02/1999; 97(388):153-63.
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ABSTRACT: The relationship between the development of acute hepatitis and the production of TNF-alpha IFN-gamma and IL-6 by liver-associated T lymphocytes following intravenous injection of concanavalin A (Con A) was studied in rats. Following a single injection of Con A, there was a dose and time-dependent correlation in the serum levels of serum alanine aminotransferase (ALT), IL-6, IFN-gamma and TNF-alpha. These increases correlated with an increase in the numbers of CD4+, CD8+ and CD25+ T cells in blood and CD4+ and CD25+ T cells in the liver perfusate, but not with CD8+ T cells in liver perfusate. Increased levels of IL-6, IFN-gamma and TNF-alpha were constitutively produced by liver-associated CD4+ T cells when cultured. In Con A-stimulated cultures, liver-associated CD4+ T cells secreted increasing levels of TNF-alpha in a time-dependent manner following Con A injection, but TNF-alpha production by peripheral blood lymphocytes was transient with peak levels detected at 1 h which then declined over 24 h. Histological examination of the liver revealed fatty change, hepatocyte degeneration and necrosis, with an associated cell infiltrate of neutrophils and CD4+ T cells both in the portal areas and around the central veins. These results support the hypothesis that Con A-induced liver damage is mediated by CD4+ T cells acting within the liver, at least in part through the secretion of TNF-alpha, IFN-gamma and IL-6.
Immunology and Cell Biology 01/1999; 76(6):542-9. · 3.66 Impact Factor
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R Clancy
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ABSTRACT: This innovative cross-discipline conference brought together an international cohort with widely different backgrounds to address 'hard' infections in a way that is unusual in the modern era. The success of this 'experiment' was reflected by the strong and enthusiastic support from all the attendees present, with the hope that this meeting will be the first of many. The meeting was introduced by a review of the parallel development of a scientific framework within which the clinical pressures of the day must be considered if therapeutic progress is to occur. The simple paradigm of infection driving an antibody response identified as protection, proved of value at the turn of the century when epidemic infectious diseases prevailed. Such a paradigm is hopelessly inadequate to cope with the new pressures of degenerative disease, neoplasia, and chronic inflammatory disease, which now dominate the clinical agenda and with which 'infection' is tenuously linked. The excitement of the discovery that many of our major health challenges are outcomes of interaction between microbes and the host response, was the theme of this meeting. Subtle variations in microbial pressure or host response, have focused attention on genetic background, compartmentalized response and microbe distribution, persistence of antigen, 'escape' forms of the microbe, inappropriate host responses which damage through hypersensitivity mechanisms, and perpetuation of disease through the triggering of autocrine or autoimmune mechanisms. Two particularly important factors are the role of dysfunctional T-lymphocytes and variable outcomes influenced by the 'dose-response' curve, which can determine up- or downregulation of the immune response. The various presentations given provided excellent models of these general principles, and will be discussed in this context.
IDrugs: the investigational drugs journal 09/1998; 1(4):421-3. · 2.28 Impact Factor
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ABSTRACT: The role of T-cell activation in alcoholic liver disease was investigated in rats fed alcohol and subsequently exposed to concanavalin A (Con A). Following Con A injection (20 mg/kg body weight), greater increases in liver-to-body weight ratio and ALT levels were observed at 12 and 24 hr in rats fed ethanol, compared with control rats fed sucrose. Furthermore, increases in serum interleukin-6 and tumor necrosis factor-alpha levels were noted in ethanol-fed rats, with maximal levels detected at 4 hr declining thereafter, but remaining above control levels at 24 hr. Analysis of T-cell subpopulations showed an increased percentage of CD4+, CD5+, and CD8+ T cells in blood from all groups, but not in liver perfusate. In contrast, a significant increase in the percentage of activated CD25+ T cells was detected in both blood and liver perfusate from rats fed ethanol even 24 hr after Con A injection. When CD4+ and CD8+ T cells from liver perfusate were cultured in the absence or presence of Con A, an increase in interleukin-6 and tumor necrosis factor-alpha production in supernatants was observed in ethanol-fed rats. In cultures stimulated with Con A, a 2- to 8-fold increase in cytokine production was detected, with intrahepatic CD4+ T cells being the major source. Immunohistological analysis revealed infiltration of CD4+ T cells around portal vein and central vein areas associated with fatty liver and severe hepatic necrosis. The results suggest that alcohol consumption induced a dysregulated T-cell population that mediated hepatic necrosis following polyclonal activation with Con A.
Alcoholism Clinical and Experimental Research 06/1998; 22(3):723-9. · 3.34 Impact Factor
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ABSTRACT: The relationship between the changes in liver pathology and the production of interleukin (IL)-1alpha, IL-6, and tumor necrosis factor-alpha (TNF-alpha) by intrahepatic mononuclear cells was studied in rats fed alcohol and subsequently exposed to lipopolysaccharide (LPS). Rats were fed 40% ethanol in drinking water, whereas control rats were provided with a chow diet with isocaloric or 2% sucrose drinking solutions for up to 20 weeks. Decreased IL-1alpha and TNF-alpha production in 24-hr culture supernatants of mononuclear cells isolated from liver perfusate was detected while IL-6 remained unchanged over 20 weeks. When animals were injected with LPS (1.0 microg/kg body weight), there was a 5-fold rise in ALT levels in the ethanol-fed group, but not in control groups. Increased IL-6 and TNF-alpha levels in the serum and supernatant of cultured intrahepatic mononuclear cells stimulated with or without LPS or concanavalin A was observed. There was a correlation between levels of ALT and TNF-alpha, but not IL-6. T cells and Kupffer cells were the major source of TNF-alpha in culture supernatants of hepatic perfusate mononuclear cells from ethanol-consuming rats injected LPS. In addition, pathological liver injury was evident, which suggests a pathogenic role for TNF-alpha in alcohol-induced liver disease.
Alcoholism Clinical and Experimental Research 02/1998; 22(1):150-6. · 3.34 Impact Factor
