at Specific Research Questions
| Scientific Components: Projects Directed at Specific Research Questions |
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The following sections include articles summarizing the status of planning activity and overall work scope for individual Workshop projects. These summaries will be updated periodically, as project time-lines are developed and formal scientific workshop projects are begun in 1999. As Workshop studies progress and data generated and submitted, these articles will chart work-in-progress and present relevant and timely results. Reports from individual components will also be posted on the 13th IHWC website. Please refer to the web site for a complete summary of component activities to date. HLA and Disease (Erik Thorsby, Chair): The primary aim of the HLA and Disease Component is to undertake studies to identify other genes within the HLA region that are involved in disease resistance or susceptibility. The seven diseases to be studied, and the chair of each project, include: Ankylosing spondylitis (Antoine Toubert); Celiac Disease (Cristina Mazzilli); Hemachromatosis and Psoriasis (Joe Williamson); Narcolepsy (Emmanuel Mignot); Rheumatoid Arthritis (Lee Nelson and Jean-Francois Eliaou); and Type 1 Diabetes (Sophie Caillat-Zucman). Dr. Thorsby has convened meetings of the Disease Component Committee in Atlanta, Strasbourg and Vancouver to discuss protocols for individual disease studies, selection of case-control material, plan for the development of SNP and microsatellite typing approaches, and methods of data recording and analysis. An announcement of individual disease component studies, individual protocols, proposals for specific techniques and reagents, as well as other relevant information for laboratories interested in participating in this project are available on the website, or by fax request at 206-667-6969. The committee will be meeting in Paris, Feb. 5, 1999, and an update of their plans and recommendations will be available in early March. Erik Thorsby or FAX, 47-22-20-3693. (e-mail contact, lisbeth.berger@labmed.uio.no) HLA Expression in Cancer (Soldano Ferrone, Chair): The HLA Expression in Cancer Component will study the molecular mechanisms responsible for the loss of HLA class I alloantigens expressed on the surface of cells undergoing malignant transformation. Committee members met in Vancouver on Saturday, October 10, 1998 to plan specific component projects. Following a review of planning activities that have taken place in recent months, the committee discussed the grant application that will be submitted as part of a Program Project (John Hansen, P.I.). The proposed studies for this component will focus on the analysis of the frequency of HLA class I antigen downregulation in surgically removed breast carcinoma, cervical carcinoma, colon carcinoma, head and neck carcinoma, lung carcinoma, melanoma and prostate carcinoma lesions. Coordinators for these diseases are Maria Worsham, Peter Stern, Federico Garrido, Manita Feenstra, Edmond Yunis, Catherine Stavropoulos-Giokas and Pan Zheng, respectively. The anti-HLA class I heavy chain monoclonal antibody HC-10 and the anti-beta2-mu mAb L368 will be initially utilized in these studies to stain formalin fixed tissues. In addition, HLA-A2 antigen downregulation will be analyzed in the above-mentioned cancers using frozen tissue sections. It was also decided that another workshop planning session will be held next April at the EFI meeting in Creta, Greece. If you are interested in participating in the HLA and Cancer component of the workshop or would like more information about the proposed projects, please contact Soldano Ferrone by e-mail at: Soldano.Ferrone@roswellpark.org, or fax, 914-594-4176. NK Receptors (Bo Dupont, Chair): The goals of the NK Receptors Component are to 1) determine the specificity of NK receptors for HLA and define the genetics of NK receptor genes, 2) determine the KIR and CD94/NKG2 phenotype in HLA typed populations, 3) determine KIR haplotypes and genotypes by family study, and 4) identify KIR homozygous individuals. This work will be accomplished by studying KIR-CD94/NKG2 phenotypes and genotypes in marrow graft donor-recipient pairs and correlating with graft rejection, GVHD, risk of leukemic relapse and survival. We will also clone NK receptors and determine NK receptor repertoire by use of HLA homozygous B-LCL and 721.221-HLA transfectants. (212-717-3128, fax) Hematopoietic Cell Transplantation (Effie Petersdorf, Chair): A working group, composed of transplant experts, HLA specialists and biostatisticians, has been assembled to begin planning the clinical and laboratory studies that will comprise the Hematopoietic Cell Transplantation (HCT) Component. The working group met in Vancouver, Heidelberg, and Miami Beach recently to continue organization of the project. The goals of this component are to ascertain the limits of HLA incompatibility in unrelated and related stem cell transplantation, to identify specific allele mismatches that are well-tolerated, and to address the relevance of new genes as possible transplantation determinants. For the June 2001 analysis, the working group will examine the impact of HLA-A*0201 allele mismatches and single nucleotide polymorphisms (SNPs) in CML transplants. Plans for study material include 1) peripheral blood mononuclear cells (preferable) or DNA (minimal requirement) submitted from transplant centers, tissue typing laboratories and registries from HCT patients and donors, 2) clinical outcome data, 3) high resolution DNA typing of HLA class I and II genes, 4) mHag (HA-1) typing of HLA-A*0201-positive transplants, and 5) SNP analysis using workshop protocols developed by Dan Geraghty. The international workshop is an ideal venue for investigating the clinical relevance of mismatching for specific HLA allele combinations, since the study requires populations of ethnically and racially diverse transplant recipients and donors. Our proposal is to begin these studies as part of the 13th IHWC, and subsequently build upon this platform for future genomic analyses. Hence, we have a long-range plan for ongoing studies. The importance of collecting and preserving DNA (or more ideally, cells) cannot be over-emphasized. In order to assure a collection of material for future genetic studies, we urge all transplant centers and laboratories to actively save DNA and cells on all of their prospective transplants. If laboratories require help in storing this material, please contact Effie Petersdorf immediately. The 13th IHWC is now preparing plans for funding of this project including funds for required storage of samples. Laboratories can participate in several ways. First, contributing DNA/cells to the international repository will require on-going commitment from all participants. The total number of samples needed will depend on specific HLA allele frequencies in various transplant populations, but conservative estimates suggest a minimum of 5,000 transplants. We can reach this goal only if there is a world-wide effort to contribute cells/DNA, clinical outcome data, and HLA typing results. The mechanism for collection of clinical outcome data is still being discussed; the IHWC would like to avoid duplication of effort and in this regard, is eager to work with registries which have an existing report mechanism for data collection. Finally, we need laboratories who can perform high resolution typing of HLA genes and who are interested in characterizing new genes. Please let Effie Petersdorf know what you are interested in or are capable of typing! Effie Petersdorf can be reached at: epetersd@fhcrc.org, or fax, 206-667-6969. The Human Diversity/Anthropology Committee met in Vancouver on October 10, 1998 to continue project planning. The goals of the Human Diversity Component are to estimate allele and haplotype frequencies for HLA class I and class II loci in various populations, to create an ongoing database of study results, to analyze frequency data using a variety of statistical methods, and to create a sample repository for sample accession. Populations for study will be defined by language and geography as in previous workshops. HLA-A, B, C, DRB, DQB1, DQA1, DPB1 and DPA1 allele-level typing will be performed by high resolution methods. These methods must be reliable, simple and robust in order to maximize the number of participating laboratories, using standardized reagents to facilitate data capture and analysis. Three different molecular typing methods are being considered: 1) SSOP typing for class I and class II (see SSOP summary, above; 2) reverse line blot typing for class I; and 3) ARMS-PCR for class I and class II. Laboratories interested in the reverse line blot and/or ARMS-PCR typing methods should visit the Human Diversity Component section of the 13th IHWC web site for more information and relevant questionnaire. More information about these two alternative technologies can also be obtained by e-mail by contacting Dr. Henry Erlich (reverse line blot) at: henry.erlich@roche.com or by contacting Dr. Julia Bodmer (ARMS-PCR) at julia@icrf.icnet.uk. |
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