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18s Medical Research Society Young Investigator Communications YI-Y46 for other risk factors. eNOS Asp298 was not associated with EH and there was no correlationbetween this variant and BP in either EH or normotensive subjects. Y I CLINICAL XENOTRANSPLANTATION OF PORCINE ORGANS: IMMUNE BARRIERS BEYOND HYPERACUTE REJECTION Conclusions: Three common variants of the NOS 3 gene (two in the promoter and a third, which predicts an eNOS variant, eNOS Asp298) have the potential to influence expression or function of the encoded e w e . Homozygosity for eNOS Asp298 was a risk factor for atherosclerotic CAD in this UK population. Studies investigating the biochemistry of this novel variant are in progress. A DORLING AND RI LECHLER Department of Immunology, Royal Postgraduate Medical School, Hmersmith Hospital, London W12 ONN, England The use of organs from animal donors (xenotransplantation) is a potential solution to the chronic shortage of allogeneic organs and currently the pig is thought to be the most suitable donor for man. However, porcine organs are rejected rapidly by a vascular process called hyperacute rejection (HAR) which has so far prevented clinical xenotransplantation. It is likely that this barrier will be overcome in the near future by the application of novel strategies, probably involving the use of organs from transgenic pigs. Data from animal models indicates that multiple other immune mechanisms will contribute to the rejection of xenografts once HAR has been bypassed. Little was known of these 'post-HAR' immune-mediated events in the specific human anti-pig combination at the start of this work. We have described two aspects of these mechanisms. First, the phenomenon of 'accommodation', whereby xenografts acquire in vivo resistance to HAR and delayed xenograft rejection, has been explored in an in vitro model utilising immortalised porcine endothelial cells. The results indicate that human anti-pig antibodies induce a concentration-dependent and time-dependent change in porcine endothelial cells compatible with the development of accommodation. Secondly, the in vitro human anti-porcine T cell response has been documented in detail, with particular emphasis on quantitative and qualitative comparisons with the in vitro T cell alloresponse. The results of this work, which indicate that the response to porcine xenografts is likely to be significantly stronger than that against allografts, have important implications for the level of conventional immunosuppression that may be necessary to prevent xenograft rejection, and provide an important basis for the development of strategies to promote xenograft-specific immunosuppression and tolerance. Y2 A VARIANT OF THE ENDOTHELIAL NITRIC OXIDE SYNTHASE GENE IS A RISK FACTOR FOR CORONARY ATHEROSCLEROSIS. AD HINGORANI, C LIANG, J FATIBENE, A PARSONS, R HOPPER,D TRUTWEIN, NG STEPHENS, KM O'SHAUGHNESSY, MJ BROWN. Clinical PharmacologyUnit, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK Background: Endotheliumderived nitric oxide (eN0) is a potent vasodilator with anti-aggregatory and anti-proliferative effects. eN0 is synthesised from arginine by endothelial nitric oxide synthase (eNOS), encoded by the NOS 3 gene on chromosome 7. A reduction in bioactive eN0 may contribute to the development of ischemic heart disease and essential hypertension (EH),both of which.have a heritable component. We hypothesised that polymorphic variants of the NOS 3 gene might be responsible for reduced NO production and thereby predsiposeto these diseases. Methods: DNA variants of the NOS 3 gene were sought using single strand conformation polymorphism analysis and DNA sequencing. Genotype and allele frequencies of the four bi-allelic polymorphisms identified were determined in unrelated population controls. Case-control studies were used to assess the relationship between a G+T 894 polymorphism and coronary artery disease (CAD) and EH. Results: Two variants were identified in the gene promoter at -1468 (T+A) and -922 (A+G) bp from the transcription start site. and another (A-S) was located 30 bp from the start of exon 12. The fourth variant (894 G+T), in exon 7 of the gene, predicts a Glu+Asp amino acid substitution at codon 298. There was an excess of eNOS Asp298 homozygotes among CAD cases compared to healthy controls ( 3 6 % ~10%. p<O.OoOl). In comparison to Glu298 homozygotes, the odds ratio for coronary artery disease in Asp298 homozygotes was 4.2 (95% CI: 2.3-7.7) increasing to 7.6 (95% CI: 2.3-17.9) after adjustment Y3 IDENTIFICATION OF CD8+ CYTOTOXIC T LYMPHOCYTES (CTL) SPECIFIC FOR Plasmodium foldpanan AND Mycohacteriiim riibercirlosisIN NATURALLY INFECTED HUMANS A LALVANI. M AIWO, R BROOKES, and AVS HILL Nuffield Department of Clinical Medicine. University of Oxford. John Radcliffe Hospital, Oxford OX3 9DU CD8+ CTL are a crucial element of immunity to viruses. Evidence from animal models points to a protective role for CTL against M . tuberculosis and the liver stage of P.folcipamn, yet CTL specific for mycobacterial or protozoal pathogens have not been identified in man. Using a reverse immunogenetic approach, selected preerythrocytic antigens of P.,fulcipanun and secreted antigens of M. tubercwlosis were scarined with HLA class 1 allelespecific peptide motifs. Approximately 200 peptides congruent with these motifs were synthesized. Pools of peptides, sorted by HLA class I motifs, were used to stimulate peripheral blood lymphocytes in titro from donors with the corresponding HLA class I type. CTL cognate for a candidate epitope preferentially proliferate and are detected by assays of effector function. The "Cr release CTL assay was used and, for tuberculosis, a highly sensitive ELISPOT assay for single cell peptide-specific interferongamma release was developed. P. folcipamn-derived peptides were screened in naturally exposed partially immune Africans in the Gambia. Extending the molecular analysis of the protective association of HLA-B53 with severe malaria which yielded 3 Cn epitopes, this work identified 8, largely conserved, CI'L epitopes from 4 pre-erythrocytic antigens restricted by several different HLA class I alleles. These epitopes were also recognised in Tanzanians in an area of more intense P. foldpunan transmission and the C l l recognised endogenously processed antigen. 2 CD8+ (JIZ epitopes were identified in ESAT-6, a secreted antigen specific for M. tuberculosis complex but absent in BCG. CTL exhibited MHC class I-restricted peptidespecific interfaon-gamma release and lytic activity and recognised endogenously processed antigen. CD8+ CTL were detected only in healthy contacts and patients with lymphadenitis (where the bacillus is contained by a vigorous host response) but in none of the patients with pulmonary or extrapulmonary disease, suggesting that CD8+ CTL are associated with protection. These studies establish that CD8+ Cn specific for non-viral intracellular pathogens are induced during natural infection in man. This work endorses current efforts to develop mL-inducing vaccines against P. fakiponon and M. tuberculosis and identifies candidate antigens for inclusion in subunit vaccines. Y4 TWO-STAGE GENOME-WIDE SEARCH I N INFLAMMATORY B O W E L DISEASE: S T R O N G E V I D E N C E F O R S U S C E P T I B I L I T Y LOCI ON CHROMOSOMES 3,7 AND 12 Jack Satsa i1.3, Miles Parkefii.3, Eduoard Louis'*3, Ken WelsQ, John I Bel?', Derek P Jewel1 . Nuffield Departments of Medicine' and Sur ery', Oxford Radcliffe Hospiyls, Oxford and the Wellcome g u s t Centre for Human Genetics , Oxford Concordance rates in siblings and twin pairs have provided strong evidence that genetic predisposition is important in the gthogenesis of the inflammatory bowel diseases (IBD). owever, neither Crohn's disease (CD) nor ulcerative colitis (UC) has a simple Mendelian pattern of inheritance; the model which seems most pertinent to inflammatory bowel disease is that of a heterogeneous group of polygenic disorders. In the present study, a systematic two-stage search of the human enome for suscepiibility genes in inflammatory bowel &ease was performed, involving 186 affected siblin pairs. In the first stage, 89 sibling pairs wi%i IBD were genotyped at 260 microsatellite markers spanning the 22 autosomes, using fluorescence labelled primers for polymerase chain reaction, and semi-automated DNA fragment sizing technology. Allele sharing