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G Gallagher

Publications and source records attributed to G Gallagher.

At least 37 records · Page 2Linked to original sources
PubMed1999

Cytokine gene polymorphism in human disease: on-line databases.

The pathologies of many infectious, autoimmune and malignant diseases are influenced by the profiles of cytokine production in pro-inflammatory (TH1) and anti-inflammatory (TH2) T cells. Interindividual differences in cytokine profiles appear to be due, at least in part, to allelic polymorphism within regulatory regions of cytokine gene. Many studies have examined the relationship between cytokine gene polymorphism, cytokine gene expression in vitro, and the susceptibility to and clinical severity of diseases. A review of the findings of these studies is presented. An on-line version featuring appropriate updates is accessible from the World Wide Web site, http://www.pam.bris.ac.uk/services/GAI/cytokine4.htm.

Cytokines↗
PubMed1999

Microsatellite alleles and single nucleotide polymorphisms (SNP) combine to form four major haplotype families at the human interleukin-10 (IL-10) locus.

Interleukin-10 (IL-10) is a pivotal immunoregulatory cytokine, influencing many aspects of the immune response. The IL-10 gene is located on chromosome 1 at 1q31-32 and is highly polymorphic. One microsatellite and three single nucleotide polymorphisms (SNPs) have been recorded within the 1.2 kb immediately upstream of the gene, with an additional microsatellite present at 4 kb upstream. The relationship between these two classes of polymorphism is poorly defined in the IL-10 gene. Haplotypes have been presented comprising alleles from the two microsatellite loci, and independently from the three SNPs, but these have not yet been brought together to define unified halpotypes. In the present report we describe the 29 IL-10 haplotypes found in 56 Dutch European families and show that they fall into four major haplotype groups, each of which spans the 4 kb upstream of the IL-10 gene and has a different distribution of IL10.G alleles. In addition, we describe three novel single nucleotide polymorphisms in the human IL-10 gene and suggest how they relate to these four haplotype families.

Alleles↗
PubMed1999

Analysis of genetic polymorphisms at the interleukin-10 and tumour necrosis factor loci in early-onset periodontitis.

Early onset periodontitis (EOP) is considered to have a substantial genetic basis, although the gene or genes involved have not been elucidated. The aim of the present study was to investigate possible links between generalized EOP (GEOP) and genes regulating expression of the cytokines tumour necrosis factor (TNF) and interleukin-10 (IL-10). Microsatellite marker DNA sequences corresponding to phenotypic variations in cytokine response were analysed. Genotypic variations in cytokine response have been shown in vitro for TNF and IL-10, and specific alleles are implicated in diseases such as systemic lupus erythmatosus (SLE) and rheumatoid arthritis (RA). Two microsatellites at the IL-10 locus, IL10.R and IL10.G, and 1 microsatellite at the TNF locus, TNFa, were typed for 77 GEOP patients in the West of Scotland. Due to the highly polymorphic nature of the microsatellite loci, a statistical comparison with ethnically matched healthy controls (TNFa, n = 91, IL10.R, n = 94, IL10.G, n = 102) was conducted using a Monte Carlo simulation for each marker. No significant differences were observed for any of the 3 markers, although there were possible indications of trends similar to those observed in SLE for the IL10.G marker. In conclusion, no links were found between GEOP and microsatellites at TNFa, IL10.R or IL10.G loci.

Adult↗
PubMed1998

Interleukin 10 secretion in relation to human IL-10 locus haplotypes.

Stimulation of human blood cultures with bacterial lipopolysaccharide (LPS) shows large inter-individual variation in interleukin 10 (IL-10) secretion, which has been shown to have a genetic component of over 70%. Alleles at two microsatellite loci in the 4 kb immediately upstream of the human IL-10 transcription initiation site in 132 individuals from 56 Dutch families were defined and assigned as haplotypes. LPS-induced IL-10 secretion was measured by ELISA and related to the IL-10 promoter haplotypes present in 78 unrelated individuals obtained from these families. Analysis showed that LPS-induced IL-10 secretion from unrelated individuals varied with IL-10 promoter haplotypes (P = 0.024; Kruskal-Wallis test). Two observations were made in relation to secreted IL-10 levels and promoter haplotypes; first, those haplotypes containing the allele IL10.R3 were associated with lower IL-10 secretion than haplotypes containing any other IL10.R allele. Second, the haplotype IL10.R2/IL10.G14 was associated with highest IL-10 secretion overall, whereas the haplotype IL10.R3/IL10.G7 was associated with lowest IL-10 secretion. These data demonstrate that the ability to secrete IL-10 can vary in man according to the genetic composition of the IL-10 locus.

Alleles↗
PubMed1997

Polymorphisms in the TNF gene cluster and MHC serotypes in the West of Scotland.

We examined the distribution of polymorphic elements within the tumor necrosis factor (TNF) gene cluster in 105 unrelated individuals and determined their relationship to class I and class II major histocompatibility complex (MHC) antigens, and to the highly polymorphic microsatellites TNFa and TNFb. The data demonstrate the contribution of elements within the TNF cluster to two extended haplotypes which are recognized to straddle the MHC. The A1.B8.DR3 haplotype appears to contain the TNF alleles TNFa2, TNFb3, LT.Nco-1.B*1, and TNF-308.2, while the A3.B7.DR2 haplotype is associated with the TNF alleles TNFa11, TNFb6, TNFc1, LT.Nco-1.B*2, LT.AspH1.1, TNF-308.1, and TNFe1. The presence of other extended associations which covered smaller parts of the MHC was also suggested. In most cases, the associations described here were in keeping with previously described extended haplotypes which dominate the structure of the MHC, but these did not always match completely. Taken together, these data suggest that the structure of the TNF locus is well integrated into the rest of the MHC but that important ethnic differences may exist.

Cohort Studies↗
PubMed1997

Mapping of the human IL10 gene and further characterization of the 5' flanking sequence.

Interleukin-10 (IL-10) is an important regulatory cytokine whose involvement extends into diverse areas of the human immune system. Recent characterization of the promoter and 5' flanking regions has demonstrated the presence of positive and negative regulatory segments in the promoter. In addition, the characterization of two dinucleotide repeat elements immediately upstream of the gene has shown that there is considerable polymorphism directly associated with the human IL10 gene. In the present report, we describe the mapping of the human IL10 gene to a discrete area of chromosome 1, the definition of a potential cytokine-responsive segment 3 - 4 kilobases upstream of the transcription initiation site, and the identification of two new point mutations in the immediate promoter region with their distribution in a panel of 75 unrelated healthy individuals. These data should further the understanding of how the IL10 gene is controlled in humans and how its function may vary between individuals.

Base Sequence↗
PubMed1997

Immuno-localisation of tumour necrosis factor and its receptors in temporal arteritis.

Temporal arteritis (TA) is an acute vasculitis characterised by destruction of arterial architecture following infiltration of the arterial wall by macrophages, giant cells and lymphocytes. Using immunohistochemical techniques, tumour necrosis factor (TNF) was demonstrated in up to 60% of the cells in all areas of inflamed arteries. More cells staining for TNF were detected in the intima and media of inflamed vessels than control uninflamed arteries (P < 0.003 and P < 0.001, respectively). In TA, TNF was localised to giant cells and macrophages, suggesting that its predominant source is from the monocyte lineage, but, occasionally, TNF staining was found in areas infiltrated by T cells. Many endothelial cells also contained TNF, but there were no differences between the number of endothelial cells staining in inflamed and normal blood vessels. Of the two TNF receptors, the p75 receptor was sparsely represented in the inflamed vessels in TA. By comparison, the p55 receptor was widely detected on endothelial cells and infiltrating mononuclear cells close to the internal elastic lamina (IEL). Endothelial cells from normal vessels also stained for both TNF receptors, but normal smooth muscle cells in the vessel media expressed the p55 receptor, indicating that they are capable of responding to locally secreted TNF. Localisation of TNF receptors and TNF in close proximity to the IEL suggests that TNF could be involved in the leucocyte infiltration and arterial wall destruction characteristic of TA.

Biopsy, Needle↗
PubMed1997

Association between polymorphisms at the human IL-10 locus and systemic lupus erythematosus.

Recent studies have shown elevated IL-10 levels in several rheumatic autoimmune diseases, and particularly in systemic lupus erythematosus (SLE). Such changes may have a genetic basis. We studied two novel polymorphic dinucleotide repeats in the IL-10 promoter region (IL10.G and IL10.R) in order to investigate their possible significance in association with this condition in a group of 56 Caucasian SLE patients compared with 102 ethnically matched controls. The results show that there is an allelic imbalance between SLE patients and controls at the IL10.G microsatellite; this observation is supported by a significant difference in genotype distribution. The nature of autoantibody production and the presence or absence of renal involvement also appeared to be associated with certain IL10.G microsatellite alleles, although the small size of individual clinical sub-groupings may have influenced this result. No association with the IL10.R microsatellite was observed. Overall, the differences observed at the IL10.G microsatellite between SLE patients and controls suggest that the IL-10 locus contributes to the genetic background important for the development of this disease. Although the moderate sample size described in this study requires that the results be interpreted carefully, they provide an interesting and useful framework for future study.

Alleles↗
PubMed1997

Association of the TNFa2 microsatellite allele with the presence of colorectal cancer.

Independently, our two groups collaborating in this report performed association studies to consider the influence of the TNF region within the human MHC on the presence of colorectal cancer. In the Glasgow Study, 84 colorectal cancer patients were compared with 91 controls at the TNFa microsatellite locus. Analysis of individual alleles by Fisher's exact test revealed a significant overrepresentation of the TNFa2 allele in the colorectal cancer group, after correcting for multiple comparisons. In the Essen Study, 47 colorectal cancer patients were compared with 117 matched controls, and the hypothesis of TNFa2 overrepresentation in colorectal cancer was confirmed. These data provide evidence for the involvement of the TNF locus in the pathogenetic etiology of colorectal cancer.

Alleles↗
PubMed1997

Tumor necrosis factor locus polymorphisms in rheumatoid arthritis.

We examined six polymorphic elements in the tumor necrosis factor (TNF) locus and determined their allelic distribution in 98 Caucasian rheumatoid arthritis patients in comparison with 91 ethnically-matched controls. Polymorphic elements at four biallelic sites were distributed similarly between patients and controls, irrespective of the presence or absence of DR4. Differences were observed between the two groups at the TNFa and TNFe loci, but these were consistent with extended MHC haplotypes known to be present in rheumatoid arthritis patients. Therefore, this study suggests that there is little, if any, independent contribution of the TNF locus to the genetic background for rheumatoid arthritis susceptibility.

Adult↗
PubMed1996

Increased monocyte cytokine production in association with systemic complications in acute pancreatitis.

Tumour necrosis factor (TNF) alpha, interleukin (IL) 1 beta, IL-6 and IL-8 are thought to play a central role in the pathophysiology of sepsis but their role in acute pancreatitis is unknown. In the present study, monocytes were isolated from the peripheral blood of 26 patients with moderate or severe acute pancreatitis without biliary sepsis. Secretion of these cytokines in vitro was measured at intervals during the first week of illness. Sixteen patients developed systemic complications. Peak TNF-alpha secretion was significantly higher in patients who developed systemic complications (median (interquartile range (i.q.r.)) 18.5 (5.5-28.5) ng/ml) than in those with an uncomplicated course (3.7 (2.3-6.4) ng/ml, P < 0.01). Similarly, peak IL-6 and peak IL-8 secretion were significantly higher in the complicated group (IL-6: complicated median (i.q.r.) 48.9 (12.1-71.0) ng/ml, uncomplicated 16.3 (14.2-37.9) ng/ml, P < 0.05; IL-8: complicated 748 (643-901) ng/ml, uncomplicated 608 (496-749) ng/ml), P < 0.05). No significant difference in peak IL-1 beta secretion was observed between the two groups. Systemic complications of acute pancreatitis are associated with a significant increase in monocyte secretion of TNF-alpha, IL-6 and IL-8 suggesting that, as in sepsis, these cytokines play a central role in the pathophysiology of the disease.

Acute Disease↗
PubMed1995

The development of a novel immunotherapy model of human ovarian cancer in human PBL-severe combined immunodeficient (SCID) mice.

The reported ability of SCID mice to accept xenografts of both human tumors and peripheral blood lymphocytes (PBL) provides the potential for the development of novel immunotherapy models in these animals. This study describes the development of a novel small animal model of human ovarian cancer. This was achieved by engrafting a human ovarian cancer cell line (Ovan-4) into the peritoneal cavity of immunodeficient SCID and immune reconstituted human PBL-SCID mice. When transplanted to SCID mice this cell line exhibited growth characteristics similar to the clinical disease observed in patients with implantation of metastatic nodules onto the interior surface of the peritoneal wall. Reconstituted human PBL-SCID mice challenged with identical numbers of Ovan-4 cells exhibited a significant increase in survival time, suggesting a role for cells of the human immune system in preventing the development of this type of malignancy in vivo. Furthermore, vaccination of human PBL-SCID mice against Ovan-4 produced tumour-specific human antibodies in the serum of these animals. Animals reconstituted with CD8-depleted PBL exhibited increased serum immunoglobulin levels and produced enhanced anti-Ovan-4 activity after vaccination. Subsequent challenge of these animals with Ovan-4 revealed a further increase in survival time. These results suggest that human antibodies may have a role in immunity against ovarian cancer and could be of therapeutic value in this type of disease.

Animals↗