Cord Blood Establishing a National Hematopoietic Stem Cell Bank Program (2005) / Chapter Skim
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Appendix F: HLA Overview
Appendix F: HLA Overview
Pages 242-272
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From page 242... ...
Department of Oncology Georgetown University Medical Center Washington, DC January 3, 2005 KEY OBSERVATIONS ON HLA AND HEMOTOPOIETIC STEM CELL TRANSPLANTATION The following bulleted list is a summary of key facts about HLA that are described in more detail in the paragraphs below. · Major histocompatibility complex encodes proteins, HLA molecules, that control tissue rejection.
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From page 243... ...
· Seventy percent of patients with fatal blood diseases treated with hematopoietic stem cell transplant require an unrelated donor and are served by registry and cord blood banks around the world. · A registry/bank must possess sophisticated algorithms for storing and matching to address the complexity of HLA assignments received on volunteer donors/cord blood units.
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From page 244... ...
. Genes encoding these cell surface molecules are located in a cluster on chromosome 6 named the major histocompatibility complex (MHC)
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From page 245... ...
. HLA Genes The genes for the HLA-A, -B, -C, -DR, -DQ, and -DP molecules are found next to one another within the MHC on chromosome 6 (68)
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From page 246... ...
. An HLA typing result provides a genotype (HLA alleles carried)
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From page 247... ...
Allele and Haplotype Frequencies The frequencies of HLA alleles and haplotypes found in individuals differ among ethnic/racial groups (9,38,43,77)
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From page 248... ...
When large databases of HLA typed individuals are analyzed, only a small percent of potential HLA phenotypes are found. Using serologic assignments from the National Marrow Donor Program, of the predicted 19,536,660 HLA-A, -B, -DR phenotypes, only 1.6 percent were observed (52)
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From page 249... ...
, National Marrow Donor Program (NMDP) , SouthEastern Organ Procurement Foundation (SEOPF)
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From page 250... ...
This means that a cell expressing a new HLA allele with unique serologic epitopes must be defined using pre-existing serologic types (e.g., B* 8201 is defined as a combination of B45 and B22 serologic specificities)
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From page 251... ...
. The digits indicate that the two alleles differ in DNA sequence, but that the amino acid sequence of the HLA proteins specified by the two alleles do not differ (i.e., differing by silent or synonymous substitutions)
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From page 252... ...
Because serologic HLA typing had limitations in the consistency of test results, searches for potential HLA matched donors might have to include alternative phenotype searches to identify donors who may have been serologically mistyped. This will become less common as more and more DNAtyped donors are listed in the registry files.
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From page 253... ...
0305 or etc. aThe National Marrow Donor Program has a 24 letter code that includes specific alleles.
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From page 254... ...
High-resolution testing is frequently carried out by the transplant center to determine the degree of the HLA match between a patient and a specific potential donor. Allele Level DNA-based typing identifies the specific allele carried by an individual (e.g., DRB1*
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From page 255... ...
Correlation of DNA-Based and Serologic Types Although a single serologic specificity was once thought to define the product of a single HLA allele, we now know that a single serologic specificity is associated with multiple allelic products (Table F-4)
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From page 256... ...
02XX DNA-based, low tions of serologic determinants which do not fit within previously defined serologic specificities. These allelic products would be serologically typed as "blanks" or might be identified as carrying one of two or more specificities.
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From page 257... ...
Since most HLA alleles encode proteins which differ from one another in the amino acid sequence of the antigen binding domains, most are theoretically capable of stimulating alloreactive T cells. SOURCES OF HEMATOPOIETIC STEM CELL DONORS Related Donors In order to avoid allorecognition, physicians attempt to identify hematopoietic stem cell donors who are "HLA compatible" with their donors.
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From page 258... ...
The HLA phenotypes available worldwide are summarized within the database of Bone Marrow Donors Worldwide (BMDW; http:// www.bmdw.leidenuniv.nl)
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From page 259... ...
Six of 6 refers to matching for 2 assignments at each of 3 loci; 5 of 6 is matching for 5 of the potential 6 assignments. The extent of allele matching within a 6/6 antigen match can vary (Table F-7)
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From page 260... ...
HLA Matching to Optimize Outcome in Marrow Transplantation There are 12 HLA loci that could potentially impact outcome: A, B, C, DRA, DRB1, DRB3, DRB4, DRB5, DQA1, DQB1, DPA1, DPB1. Various studies on marrow transplants using allele level typing for a subset of these loci to evaluate their impact on transplant outcome have somewhat different results (16, 54, 65, 66, 70, 74, 82)
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From page 261... ...
Additional histocompatibility testing may be performed to include a higher level of resolution for the three primary HLA loci or to test additional histocompatibility loci such as HLA-C and -DQB1. Donors who appear to be potential HLA matches based on transplant center matching TABLE F-8 Examples of HLA Typing Assignments Carried by Volunteer Donors on Registries Recruitment Typinga Typing Method, Resolution A1,2, B7,8 Serology A and B, DR testing not done A1,2, B7,8, DRB1*
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From page 262... ...
potentially matched donors if available and if resources are not limited for additional testing in step 3. 3 -- Additional HLA testing High- or intermediate-resolution DNA-based testing of to evaluate match with HLA loci to determine match.
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From page 263... ...
For example, data for additional HLA loci may be added or the resolution of existing HLA types may be altered during confirmatory typing. Since an HLA typing may be obtained by serology or DNA and at various levels of resolution, comparison of patient and donor assignments is a complex process (45, 53, 55)
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From page 264... ...
. Selection of six antigen matched donors did not result in allele matching throughout the HLA complex in 92 percent of the cases, in 50 percent if DP was ignored (29)
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From page 265... ...
The level of allele matching in the 5/6 matched pairs is lower than 6/6 antigen matched pairs; however, the lower percentage of matching did not derive solely from the known mismatch. For example, in the 5/6 matched pairs in which the known mismatch was at the HLA-A locus (n = 203)
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From page 266... ...
These studies likely overestimate the likelihood of finding matches because, in practice, many transplant centers define an acceptable match at an allele level of resolution. RESEARCH Registries/Cord Blood Banks as Repositories of Extensive HLA Data As large repositories of HLA and often clinical data, registries/banks should have the resources to analyze this information to direct registry recruitment (e.g., evaluate HLA diversity to serve searching patients)
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From page 267... ...
2004. Impact of HLA class I and class II high resolution matching on outcomes of unrelated donor bone marrow transplantation: HLA-C mismatching is as sociated with a strong adverse effect on transplant outcome.
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From page 268... ...
1999. A special report: histocompatibility testing guidelines for hematopoietic stem cell transplantation using volunteer donors.
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From page 269... ...
2001. Maintaining updated DNA-based HLA assignments in the National Marrow Donor Program bone marrow registry.
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From page 270... ...
2002. Positive serum crossmatch as predictor for graft failure in HLA-mismatched allogeneic blood stem cell transplantation.
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From page 271... ...
1997. HLA gene and haplotype frequencies in bone marrow donors worldwide registries.
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From page 272... ...
2004. A T-cell epitope encoded by a subset of HLA-DPB1 alleles determines nonpermissive mismatches for hematologic stem cell transplantation.
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