Dr. Petersdorf opened the meeting with a summary of the research objectives. The overall goal is to build a resource for scientific inquiry into the genomics of transplantation. The five specific aims are:
1) Establish an international inventory of cells/DNA available for characterization of HLA alleles and other genomic testing.
2) Characterize HLA allele mismatches in racially diverse patients and their unrelated donors.
3) Determine whether complete allele matching is necessary for optimal transplant outcome.
4. Define SNPs and microsatellite polymorphism in HLA allele matched and mismatched donor-recipient pairs and begin to identify those with relevance for GVHD and survival.
5. Define allele mismatches that are well tolerated.
The U24 Resource
The 13th International Histocompatibility Working Group has established a resource to facilitate studies in genomics of transplantation. The resources are:
1. Create a renewable resource of DNA/cells on all allogeneic transplants. (23%)
cell transformation and expansion
storage of DNA, PBL, LCL
n=13002. Provide technical expertise for complete and precise genotyping (15%)
allele typing for HLA class I, DP3. Establish database and links to facilitate clinical outcomes analyses (36%)
collection, auditing, and management of clinical data and links to HLA database4. Assure adequate staff to support laboratory and database needs (26%)
Typing Progress
Significant progress has been made by participating labs. As of February 14, 2001, a total of 2301 unrelated donor-recipient pairs have been identified by participating laboratories. These transplant pairs meet eligibility criteria for inclusion into the first phase of the workshop analyses: unrelated transplant, CML diagnosis, DNA/PBL/LCL available for additional typing.
These tallys represent the minimal number of contributions. Regions will update the total numbers of pairs and we anticipate that the study population will well exceed 2381. The estimated number of pairs needing HLA high resolution typing represents a minimum estimate of 630 pairs or 1260 samples to be forwarded to the Core Research Laboratory (CRL) for completion of HLA-A, B, C, DPB1 sequencing. Participants were strongly encouraged to identify material for which IHWG resources are needed early in order to avoid a large amount of sequencing immediately before the workshop. All typing performed by the CRL for this component requires complete clinical outcome data. Samples for which clinical data is missing or incomplete will not be sequenced. Sequencing data will be reported to the contributing lab. There will be no charges for the sequencing.
Significant progress has been made by the CRL since the initiation of U24 funding, September 1, 2000:
Collection and Management of Clinical Data
The IBMTR has distributed four questionnaires to non-US transplant centers to 1) determine the level of participation in the Transplant Component studies, 2) obtain consent to release transplant data to the IHWG, and 3) determine the location and nature of recipient/donor samples available for the project. Sherrie Simpson from the IBMTR described the questionnaire. In total, over 150 transplant centers were queried of which 88 have responded. The IBMTR will next forward to the IHWG the identification numbers for which complete clinical outcome data is available. The IHWG will forward these IDs to the participating laboratories. Laboratories will prioritize these samples for typing.
Human Subjects
A committee has already been formed by the IHWG to review, recommend and oversee all facets of research pertaining to the protection of human rights. Each laboratory and transplant center submitting data, DNA/PBL/LCL to the IHWG must assure in writing that the material obtained from donors abided by IRB-approved consenting processes. Retrospective samples which lack this cannot be included in the workshop studies.
Time Table
Present - September, 2001
Continue identifying samples
Complete high resolution typing, microsatellite testing
Report data
November, 2001
Preliminary analysis of:
match/mismatch rates for each locus; multi-locus mismatch rates
allele, antigen, haplotype frequencies
Outcomes Analysis
December, 2001-February, 2002
Continue to report typing
March 2002
Analysis of allele, antigen, haplotypes, match/mismatch rates, clinical outcome
Results to participants; specific working groups for
analysis/ presentation/discussion at workshop
May, 2002 Workshop
Discussion of results: interpretation, future hypotheses/
questions to be addressed/changes in study design
