F
COMMISSIONED PAPER

HLA OVERVIEW

An analysis prepared for the Institute of Medicine, of the National Academies, for the Committee on Establishing a National Cord Blood Stem Cell Bank.

Carolyn Katovich Hurley, Ph.D.

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.

  • The genes that encode HLA molecules are highly polymorphic and the majority of nucleic acid substitutions alter the protein sequences in the key functional regions of the resultant HLA molecules.



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Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program F COMMISSIONED PAPER HLA OVERVIEW An analysis prepared for the Institute of Medicine, of the National Academies, for the Committee on Establishing a National Cord Blood Stem Cell Bank. Carolyn Katovich Hurley, Ph.D. 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. The genes that encode HLA molecules are highly polymorphic and the majority of nucleic acid substitutions alter the protein sequences in the key functional regions of the resultant HLA molecules.

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Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program Even single amino acid differences between HLA proteins can have a profound effect on their ability to present antigen, interact with T lymphocytes, and stimulate allorecognition (transplant rejection or graft vs host disease). The frequencies of specific HLA alleles and haplotypes (alleles on one chromosome) differ in different racial/ethnic groups but approximately two-thirds of the alleles and most theoretical haplotypes are rare. HLA typing uses either DNA-based methods to define which potential alleles are carried or serology to define which proteins are expressed by an individual. The ability of DNA-based typing to identify alleles varies depending on the method and reagents used. Typing of new volunteers for a registry is usually at low to intermediate resolution, narrowing down the potential alleles carried by an individual. Typing of a patient for transplant usually defines specific alleles carried by the patient. This is a newer method, and an increasing number of volunteer donors are typed by these methods. Serologic typing is low resolution; it does not define which of many alleles might be carried by an individual. Large numbers of volunteer donor typings on registries were obtained with this method. 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. Quality control of typing is also critical. While transplant centers differ in their definition of a “match,” the National Marrow Donor Program, has recommended matching for alleles at 4 HLA loci, HLA-A, -B, -C, -DRB1. When possible, DQB1 matching may provide additional benefit. The average patient searching the >5 million NMDP registry has an 85 percent chance of finding a 6 of 6 antigen match. Of the 6 of 6 antigen matches undergoing transplant, the probability of finding a 6 of 6 allele match is about 72 percent, a 10 of 10 allele match is about 50 percent, and a 12 of 12 match is 11 percent. The chance of finding a 6 of 6 antigen match for minorities is lower: 65 percent for an African American patient, and probability of allele matching has not yet been evaluated. The probability of match depends on allele and haplotype frequencies. Registries should possess the ability to evaluate the HLA characteristics of the database to improve knowledge of the HLA system and to enhance their ability to identify suitable donors for all patients.

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Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program THE HLA SYSTEM MHC-Encoded HLA Proteins In humans, proteins that controlled tissue compatibility were first detected on the surface of white blood cells using human-derived antibodies and were named human leukocyte antigens (HLA)(4, 13, 39, 76). Genes encoding these cell surface molecules are located in a cluster on chromosome 6 named the major histocompatibility complex (MHC) (Figure F-1). Two types of MHC-encoded (or HLA) molecules have been described, class I and class II. Class I molecules are expressed on the surface of essentially all nucleated cells. Humans express three different class I molecules: HLA-A, HLA-B, HLA-C. The class I molecules each consist of a single polypeptide encoded within the MHC, which associates with beta 2 microglobulin encoded on another chromosome (5). Class II molecules are expressed on the surface of cells of the immune system and they can be induced on some other cell types. Humans express three different class II molecules, HLA-DR, HLA-DQ, HLA-DP. Each class II molecule is comprised of an alpha and a beta polypeptide encoded within the MHC. Although the class I and class II molecules are composed of different polypeptide chains, they assume a very similar structure on the cell surface. The amino terminal residues of the MHC-encoded polypeptides form two alpha helices and a beta sheet, creating a groove that binds peptides. It is this region of the HLA molecule that performs the functions attributed to these proteins (5). Antigen Presentation Function The normal role of MHC molecules is to bind short peptides within their antigen binding grooves and to carry these peptides to the cell surface for recognition by T lymphocytes (40, 41). The peptides are found within the endoplasmic reticulum (endogenous peptides, class I) or in the endocytic pathway (exogenous peptides, class II) and derive from the degradation of normal cellular proteins or from any pathogens encountered by the cell. T cell recognition of peptides from pathogens or malignant cells triggers a cellular immune response. T lymphocytes usually ignore self peptides bound to an MHC molecule. Each MHC molecule binds a single peptide for transport to the cell surface. The peptides that bind to a particular MHC molecule must share common characteristics to allow the peptide to “fit” within the antigen binding cleft of the MHC molecule. Thus, only a subset of peptides are bound by the set of MHC molecules expressed by an individual. Since only a subset of peptides from any given pathogen will be bound by MHC and

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Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program FIGURE F-1 Human histocompatibility genes. targeted for T cell recognition, individuals may vary in their ability to mount immune responses to pathogens depending on the MHC molecules that they express (11). 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). The alpha (or heavy) chains of the class I molecules are encoded in the MHC; the second class I polypeptide chain, beta-2 microglobulin, is encoded on another chromosome. The genetic information needed to make a class II molecule is found in two different genes, a class II A (alpha) and a class II B (beta) gene. For example, a DQA1 gene and a DQB1 gene together provide the information needed to make a DQ molecule. Other class II A and B gene pairs include: DPA1 and DPB1, and DRA and DRB1. Some versions of chromosome 6 carry a second DRB gene, DRB3, DRB4, or DRB5. Its product can also associate with DRA to form a second DR molecule. Thus some individuals carry a copy of chromosome 6 that encodes two different DR molecules.

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Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program TABLE F-1 Alleles Identified at Each HLA Locus as of January 2005 (37) Gene Alleles Gene Alleles Gene Alleles Gene Alleles A 338 DRA 3 DRB4 13 DQB1 59 B 617 DRB1 383 DRB5 18 DPA1 22 C 179 DRB3 41 DQA1 28 DPB1 111 HLA Alleles HLA loci are the most polymorphic known in man (37). Several hundred alleles have been defined at some MHC-encoded loci (e.g., HLA-A, -B, -DRB1) (Figure F-1, Table F-1). The majority of these alleles carry nucleotide substitutions that change the amino acid sequence of the resultant protein which alters the antigen binding groove and T cell receptor contact residues of the MHC molecule (5). The extensive repertoire of alleles is likely due to the evolution of antigen presenting diversity at the level of the human population (46, 81). The majority of the polymorphism is hypothesized to have arisen by mutation followed by nonreciprocal exchange of short polymorphic regions among alleles. The latter process, referred to as gene conversion, spread the variations in nucleotide sequence among alleles. As a result, the HLA alleles are patchworks of polymorphic sequences, each sequence shared by some of the other alleles at the locus, embedded in a conserved framework (46). HLA Haplotypes Because the HLA genes are clustered on chromosome 6, the alleles on one chromosome are usually inherited as a haplotype. Any two children in a family have a one in four chance of receiving the same two chromosomes from their parents. Children receiving the same chromosome from one parent, but a different chromosome from the other parent, are haploidentical. The two chromosomes carrying the HLA genes sometimes exchange gene segments to “reshuffle” the HLA-A, -B, -C, -DR, -DQ, and -DP allele combinations that make up haplotypes. The frequency of recombination across the MHC from HLA-A to HLA-DPB1 is 2 to 2.5 percent, although recombination is concentrated in just a few segments in that region (e.g., recombination occurs between B and DRB loci but is unusual between DR and DQ loci) (12). An HLA typing result provides a genotype (HLA alleles carried) or

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Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program phenotype (HLA antigens expressed) but doesn’t identify which alleles are linked together on the chromosome as a haplotype. The only way to know for sure is through family segregation analysis. When family data are not available, the EM algorithm has been used to predict haplotypes (45,52). When two or more genes are on the same chromosome, they are said to be linked. When alleles of linked genes occur in haplotypes more frequently than would be expected on the basis of chance alone, those genes are said to be in linkage disequilibrium. The HLA gene complex is in linkage disequilibrium (7, 10). Apparently high disequilibrium across the DR-DQ subregion coupled with a lack of recombination have resulted in specific associations between DQA1 and DQB1 alleles and between DRB1 and DQ alleles. These associations may differ among individuals of different racial/ethnic backgrounds. At the level of class I–class II associations, the best known example of linkage disequilibrium is the HLA-A1, -Cw7, -B8, -DR3, -DR52, -DQ2 haplotype, which occurs approximately four times more frequently than would be expected by chance. It is thought that combinations such as this one (often called extended haplotypes) account for at least 30 percent of HLA allele combinations in whites. Allele and Haplotype Frequencies The frequencies of HLA alleles and haplotypes found in individuals differ among ethnic/racial groups (9,38,43,77). Some alleles and haplotypes are common to several populations; others may be predominantly confined to one particular population group. Most of the alleles are rarely observed. For example, in the United States, DRB1*03 (or DR3) is carried by 10–23 percent of four U.S. population groups (Table F-2) (77). The allele DRB1*0301 is common to most population groups, but DRB1*0302 TABLE F-2 DRB1*03 Allele Frequencies in Various U.S. Populations DRB1*03 allele U.S. Whites African Americans U.S.Hispanics Asian Americans DRB1*0301 100% 54% 83% 98% DRB1*0302   46% 15% 1% DRB1*0304       1% DRB1*0305     1%   DRB1*0307     1%   DRB1*0316     1%   Other DRB1*03   Frequency DRB1*03 23% 25% 17% 10% NOTE: The 22 other DRB1*03 alleles not found are present at <1 percent of the population (77).

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Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program is found primarily in the African American population. Most of the 28 DRB1*03 alleles (22 out of 28, 79 percent) were not observed in the testing, suggesting that they will be found in less than 1 percent of the population. The frequencies of HLA haplotypes found in individuals differ among ethnic/racial groups. Some haplotypes are common to several populations; others may be predominantly confined to one particular population group. Most of the theoretical haplotypes are rarely observed. The most common haplotype in whites (A1,B8,DR3) is the second most frequent haplotype in African Americans and the third most frequent haplotype in Latinos, but it is the 54th most frequent haplotype in Asian Americans (52). It is likely that not all potential haplotypes will be found. 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). Information of the frequencies of specific alleles and haplotypes (defined at allele level) in specific populations is limited (72). Populations have been studied through the International Histocompatibility Workshops, but the typing methods and resolution of testing have been inadequate to detect the full extent of HLA diversity (38, 42). Lack of allele level data seriously impacts our ability to predict the probability of finding an allele matched donor for patients and our ability to determine the most effective size for a registry or bank (44, 45). Understanding common haplotypes or allele associations is useful for predicting which alleles are most likely to be present in donors who have only low resolution typing information and no family data to define haplotypes. For this reason, information on the ethnic background of the volunteer donors is often provided in registries and umbilical cord blood banks. TISSUE TYPING Clinical Testing and Quality Control Testing to identify HLA allelic differences among individuals is classified as a high complexity assay by Clinical Laboratory Improvement Amendments (CLIA) guidelines (http://www.fda.gov/cdrh/CLIA/categorization.html). The complexity arises from the need to detect multiple loci, the similarity among loci and alleles, the complex nature of the polymorphism (multiple polymorphic motifs shared among alleles define an allele), and the continuing discovery of new alleles. HLA testing is routinely carried out by laboratories using either commercial and/or “home-made” reagents. The American Society for Histocompatibility and Immunogenetics (ASHI), the European Federation for Immunogenetics (EFI) and other orga-

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Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program nizations have standards for DNA-based HLA typing and an accreditation process (75). For example, extensive guidelines for quality control and quality assurance related to all stages of DNA-based HLA testing are described in the ASHI Standards for HLA Testing (ASHI, http://www.ashihla.org) (1). Additional ASHI guidelines apply for laboratories performing high-volume (>50,000 tests per year) HLA testing (i.e., large-scale registry typing). The ASHI program has accredited over 200 histocompatibility laboratories. The Health Care Financing Administration (HCFA), Joint Commission on Accreditation of Healthcare Organizations (JCAHO), National Marrow Donor Program (NMDP), SouthEastern Organ Procurement Foundation (SEOPF), United Network for Organ Sharing (UNOS); and the states of California, Florida, Oregon, and Washington grant deemed status to ASHI accredited labs. HLA Assignments—Nomenclature HLA assignments, testing methods, and reagents were developed through a series of International Histocompatibility Workshops, which began in 1964 and continue today (the 14th workshop is scheduled for December 2005; http://www.microbiol.unimelb.edu.au/micro/14ihiws/). The World Health Organization HLA Nomenclature Committee is responsible for the naming of HLA “types,” and their assignments are included on a web site (http://www.anthonynolan.org.uk/HIG) (50, 69). The names are based on the method of testing used to define HLA “types.” The naming system arose historically so that the nomenclature is difficult to understand. Testing Methodology—Serology The first method used for HLA typing was serology, and its use continues today (47). Serology detects different forms of the HLA proteins on the surface of peripheral blood lymphocytes. The assay uses antibodies, predominantly human alloantisera, in a microcytotoxicity assay. The alloantisera are obtained from humans who have been sensitized to HLA antigens by pregnancy or previous transplant. These antibodies are used as reagents to identify serologic specificities (or HLA types). The antibodies react with the HLA molecules present on the cell surface. The serologic specificities of the HLA antigens, HLA-A, -B, -C, -DR, and -DQ can be found on a Web site (http://www.anthonynolan.org.uk/HIG). Antibodies defining HLA-DP antigens are rare, so DP is not identified by serologic typing. Alloantisera are complex reagents containing multiple antibodies; they can react with more than one serologic epitope making interpretation of the results more of an “art.” Most serologic epitopes are thought to lie in the antigen binding region of the HLA molecule. Each serologic specificity (or HLA type) is designated by a letter indi-

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Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program cating the HLA antigen group and a number (e.g., A2, A34, B7, DR4). The number indicates the order in which the type was discovered. For example, B7 is a serologic specificity localized on an HLA-B molecule, while DR4 is a serologic specificity localized on an HLA-DR molecule. Some serologic specificities have been subdivided, defining broad and split classifications (e.g., B5 was subdivided into B51 and B52; DR6 into DR13 and DR14). Some antisera recognize amino acid sequences shared among allelic products. For example, B5-specific sera recognize a shared serologic epitope on molecules carrying either B51 or B52 serologic specificities. Because these serologic types were named as they were discovered, the naming system is confusing. The limited availability of alloantisera and the implementation of more powerful techniques to detect HLA differences among individuals (DNA-based typing) have resulted in the decision by the HLA community to discontinue the definition of new HLA serologic specificities. 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). Testing Methodology—DNA-Based Methods Most of the DNA-based assays rely on the polymerase chain reaction to amplify the HLA genes and the detection of nucleotide sequence differences among HLA alleles to predict “HLA types” (51). Techniques for testing include use of sequence specific oligonucleotide probes (SSOP), sequence specific primer (SSP) typing, and DNA sequencing (SBT, sequence based typing). Where SSOP and SSP typing methods only assess polymorphic regions of the amplified gene, SBT methods assess both the polymorphic and the invariant regions of the gene. SSOP and SSP are techniques used for testing of volunteer donors in a registry at the time of recruitment, while SBT is more often used for patient and potential donor typing. Most typing systems focus on polymorphisms in the gene encoding the antigen binding region of the MHC molecules. Depending on the two alleles carried by an individual and on the reagents, methods, and strategies used for the testing, a single individual tested in different laboratories may receive a variety of typing results. Even the same individual tested in the same laboratory at different times may receive differing assignments depending on how the reagents in the typing kit have changed over time and on the set of HLA alleles known to exist at the time that the test result was interpreted. Each HLA allele is designated by the name of the gene, followed by an asterisk and a four- to eight-digit number indicating the allele (http://www.anthonynolan.org.uk/HIG). For example, B*2701 is an allele of the HLA-B

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Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program gene. The first two numbers in the numerical designation of each allele are based on the similarity to other alleles and sometimes on the serologic type of the resultant protein molecule. For example, the HLA-A molecule expressed by the A*02010101 allele bears the A2 serological specificity defining the HLA-A2 molecule (or antigen). The A*0226 allele has a similar DNA sequence to other A*02 alleles; however, the HLA-A molecule specified by A*0226 has not been characterized using serology so no information is available on its serologic specificity. The second example illustrates an allele whose name is based on its similarity to other alleles, in this case, similarity to A*02010101, A*0202, A*0203 and so forth. New alleles which appear significantly different in nucleotide sequence from previously described alleles may receive a unique WHO assignment for the first two digits of their name. Thus, B*8101, which was frequently serologically typed as B7, received a unique designation setting it apart from the B*07, allele family. The third and fourth digits in an allele designation refer to the order in which the allele was discovered. For example, DRB1*030101 was the first DRB1*03 allele to be discovered and DRB1*030201 was the second. Some combinations of alleles share the first four digits of a six-digit designation (e.g., DRB1*110101 and DRB1*110102). 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). Some combinations of alleles are identified by eight-digit designations (e.g., DRB4*01030101 and DRB4*01030102). These alleles differ in DNA sequence only outside of their protein coding sequences (e.g., intron or 3’UTR differences). In some cases, these differences may affect the expression of the alleles. In the case of DRB4*0103102, the allele is not expressed due to a defect in a mRNA splice site. The addition of an AN@ indicates the presence of an allele which is not expressed as a normal HLA protein at the cell surface. The N may not always be included but is implied (ie., DRB4*01030102N = DRB4* 01030102). Other letters indicate HLA products that might be secreted (B*44020102S) or expressed at a low level (A*24020102L). Most DNA-based typing results narrow down but do not define the precise alleles carried by an individual. The results are various alternative genotypes (combinations of two alleles at a locus). Unfortunately, computer matching programs cannot accommodate listings of different possibilities for the allele present on a single chromosome, so registries such as the NMDP have adopted a “shorthand” nomenclature to indicate this typing result. Thus, in the NMDP database, the intermediate type DRB1*1101 or DRB1*1104 is labeled DRB1*11AD where AD is a code specifying 01 or 04. A Web site (http://www.nmdpresearch.org) lists this shorthand code.

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Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program Comparison of Typing Methods Serology was initially used for HLA typing. DNA-based typing was implemented in the late 1980s with the advent of the polymerase chain reaction and the availability of the nucleotide sequences of many HLA alleles. The advantages of DNA-based testing over the long-established serology assay are summarized in many publications (6, 57, 59). DNA-based assays are favored because they utilize synthetic reagents, use reagents of well defined specificity, do not require viable cells, and can detect all HLA diversity. For example, different HLA alleles defined by DNA typing can specify HLA proteins which are indistinguishable using serology. For example, an individual carrying the B*070201 allele would have the same serologic type (B7) as an individual carrying the B*0705 allele (B7). Because serologic reagents that are specific enough to define this subdivision (or Asplit@) are not available, serology can not distinguish between the two proteins specified by the two alleles, B*070201 and B*0705 (Figure F-1). There are many, many other examples of alleles defined using DNA typing which can not be individually identified using protein-based typing methods. 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 DNA-typed donors are listed in the registry files. Because the transition in typing methodology has taken place over a number of years, databases of HLA types (such as bone marrow registries) contain a mixture of serologic and DNA assignments. Some volunteer donor HLA types are a mixture of both serology and DNA assignments. Testing Resolution The ability to identify which HLA alleles are carried by an individual depends on the testing method and reagents used. Examples of the relationships among assignments are shown in Table F-3. Low Resolution at Serologic Broad The level of testing is achieved by serologic testing. A broad specificity is one that can be split further into two or more subtypes (or splits). For example, DR3 is a broad assignment that has been split into DR17 and DR18.

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Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program TABLE F-9 Steps in Donor Selection Steps in Donor Selection HLA Assignments 1—Recruitment of new volunteer Low to intermediate HLA-A, B, DRB1 2—Selection of volunteer as potential match Typing at time of selection is usually recruitment typing. A transplant center will select several (3–10) potentially matched donors if available and if resources are not limited for additional testing in step 3. 3—Additional HLA testing to evaluate match with patient. This step has various names (highresolution testing, confirmatory typing, DR typing) High- or intermediate-resolution DNA-based testing of HLA loci to determine match. Loci might include HLA-A, B, C, DRB1, DRB3/4/5, DQA1, DQB1, DPA1, DPB1; the NMDP recommends high-resolution testing of A, B, C, DRB1 for matching and DRB3/4/5 and DQB1 if possible. The testing might be carried out on a sample from the NMDP DNA repository or on a fresh donor sample. If the sample comes from the repository, a fresh donor sample must be tested to insure identity of the repository sample (see below). The testing may be carried out in stages. Serologic testing of HLA class I as a screen to select the best matched donor and/or to monitor expression of antigens. Some centers use serologic testing as an initial screen to select donors for higher resolution DNA-based testing of HLA loci. In addition, this assay might also be used to monitor the expression of some HLA antigens if null or nonexpressed HLA alleles are expected. Only HLA class I is tested; class II null alleles are usually not evaluated due to the poorer quality of the serology. 4—Workup (time at which a selected donor undergoes medical testing to evaluate if medically fit to donate) A fresh donor sample is required to confirm that the donor is indeed the person identified as a potential match and to confirm the HLA assignment. The DNA-based testing may be various levels of resolution for various HLA loci. It may, for example, confirm the identity using low resolution A, B, DRB1 testing or may retest alleles at these and other loci. The status of the patient might be considered in deciding on the resolution; high-risk patients might require a less stringent check of donor allele identity than low-risk patients because their urgent status indicates a rapid decision regarding transplant. The transplant center will check blood type at the time of transplant to confirm identity.

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Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program criteria are requested for confirmatory typing (CT). At this stage, a fresh blood sample from the donor and the patient are tested to confirm HLA identity. Quality control of the donor HLA database is critical to speed the search for donors and to identify all suitable matches. This quality control may include requiring HLA typing laboratory accreditation, establishing a registry program for proficiency testing at the time of recruitment typing (32, 60), comparison of recruitment typing to repeat CT (31), use of automated systems for HLA data entry and submission, and reanalysis of primary typing data in the registry (49). Selection of Potential HLA Matches by Registry Search Algorithms Two sets of criteria are used to determine the minimal HLA match between patient and a specific donor. The first set contains the criteria a registry or bank might have regarding how closely the donor must be matched to the patient to allow the donor to be used for transplant. In general, these guidelines are meant to protect the adult volunteer donor from undergoing the risks of donation for a transplant that is likely to fail. This also prevents cord blood units from being used for a transplant that is likely to fail. A second set of match criteria are dictated by the transplant center protocols and are usually more stringent than those used by the registry or bank. Since a volunteer donor or unit might be HLA typed several times (Table F-9), the registry must have an approach to incorporate and prioritize the updated information while maintaining older information in a history file. Since the newer HLA typing is usually, but not always, at a higher resolution, a computer algorithm (supplemented by staff review) should prioritize which HLA assignment to use in the match algorithm. 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). As an example, the allele A*0201 can be found within 844 different assignments submitted to the NMDP registry (Table F-10). Often the HLA typing result is converted into an assignment called a search determinant to provide a rapid comparison for finding a potentially matched donor (36). The goal is to identify all potentially matched donors yet to keep the list short and exclude suboptimal donors. The report listing potential donors is often sorted so that the best matched donors might be easily identified. Strategies to identify and prioritize mismatched donors on search reports are also complex.

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Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program PROBABILITY OF FINDING AN ALLELE MATCH FOR HLA LOCI The probability of finding an allele match for specific patients varies dramatically (2, 53). Patients with common alleles and common haplotypes will find many allele matched donors. The probability of a low resolution typed volunteer selected as a potential match carrying the same alleles as one of these patients is very high. In contrast, some patients have fairly common HLA alleles but they have uncommon haplotypes (the collection of alleles carried on a chromosome). In these cases it can be extremely difficult to find matched donors. Some patients have rare alleles and these are also difficult to find matches for unless the allele is found in a conserved haplotype. Within the NMDP registry, it is calculated that 85 percent of individuals find 6 of 6 antigen matches (31). In an evaluation of 1422 NMDP transplants matched at the 6/6 antigen level, 28 percent carried allele mismatches at HLA-A, -B and/or -DRB1 and most carried mismatches at other HLA loci, predominantly DP (29) (Table F-10). 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). Of the 6 of 6 antigen matches undergoing transplant, the probability of finding a 6 of 6 allele match is about 72 percent, a 10 of 10 allele match is about 50 percent, and a 12 of 12 match is 11 percent. The chance of finding a 6 of 6 TABLE F-10 Summary of HLA Matches at Each Locus in 6/6 Antigen Matched Donor-Recipient Pairs (n = 1422) from NMDP (29)     Mismatched at Allele Level (%)b Locus Matched at Allele Level (%)a Total Mismatchesb 1 Allele Mismatched 2 Alleles Mismatched A 1355 (92) 107 (8) 105 (7) 2 (0) B 1217 (86) 205 (14) 192 (14) 13 (1) C 986 (69) 436 (31) 382 (27) 54 (4) DRB1 1225 (86) 197 (14) 184 (13) 13 (1) DQA1d 1258 (88) 164 (12) 154 (11) 10 (1) DQB1d 1183 (83) 239 (17) 224 (16) 15 (1) DPA1d 791 (56) 631 (44) 563 (40) 68 (5) DPB1d 192 (14) 1230 (86) 794 (56) 436 (31) aBoth alleles at the locus are identical in donor and recipient. bOne or both alleles are mismatched. NOTE: These are patients with common types who may have undergone further testing to select the best donor.

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Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program TABLE F-11 Summary of HLA Matches at Each Locus in 5/6 Antigen Matched Donor-Recipient Pairs (n = 429) (29)   Matched at Allele Level (%)a     Antigen Mismatched Locusb Locus Total HLA-A (n = 203) HLA-B (n = 186) HLA-DRB1 (n = 40) A 180 (42) 0 (0) 146 (78) 34 (85) B 178 (41) 151 (74) 0 (0) 27 (68) C 136 (32) 106 (52) 14 (8) 16 (40) DRB1 328 (76) 183 (90) 145 (78) 0 (0) DQA1 338 (79) 184 (91) 150 (81) 4 (10) DQB1 299 (70) 165 (81) 130 (70) 4 (10) DPA1 224 (52) 107 (53) 96 (52) 21 (53) DPB1 45 (10) 23 (11) 17 (9) 5 (13) aBoth alleles at the locus are identical in donor and recipient. bThe mismatched antigen giving rise to the 5/6 match status. When the pairs were intentionally mismatched at a locus, there were no allele matches at that locus (e.g., the 203 pairs with HLA-A antigen mismatches had no pairs matched for HLA-A alleles). antigen match for minorities is lower, 65 percent for an African American patient, and probability of allele matching has not yet been evaluated. 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), only 74 percent of the HLA-B and 52 percent of the C loci were matched for both alleles (Table F-11). Likewise, in the 5/6 matched pairs with a known HLA-B antigen mismatch (n = 186), only 78 percent of the pairs were matched at the HLA-A locus and 8 percent at the HLA-C locus (29). Optimizing Registry Size to Find a Match Defining the optimal size of a registry is a public policy decision (44). Competing goals have to be balanced: (1) maximizing the number of patients who find a suitably matched donor, (2) providing comparable access to transplantation for patients regardless of race, and (3) containing costs. Definition of a “suitable match” must be defined based on the clinical outcome literature. The resolution of the registry typing will determine how accurately the probability of a match for searching patients can be predicted. The extensive diversity of HLA alleles and haplotypes makes it very

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Cord Blood: Establishing a National Hematopoietic Stem Cell Bank Program unlikely that a patient will match any given unrelated individual. This diversity requires a large donor registry to provide suitably HLA-matched donors for patients. If cord blood allows more mismatching, the required size of such a bank will likely be smaller (3). Even with over 9 million volunteer donors worldwide, there are still significant numbers of patients who fail to identify a donor (31). Racial/ethnic minority patients have a lower likelihood of finding an unrelated donor, resulting in part from a small number of minority volunteer donors available in registries and the greater HLA polymorphism for some of these groups (2). In the United States, there are more white patients than minorities failing to find a matched donor. Unfortunately, each additional volunteer added to a registry is less likely to carry a new set of HLA assignments and is more likely to carry a type already found in the registry (56). As a result, continued recruitment does improve the likelihood of finding an HLA-matched donor but still leaves many patients without a match. The number of patients without a donor will depend on the level of match required for a successful outcome. Published studies on the probability of finding a match are based on matching at a low resolution level, since most volunteers are typed at this level. 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), to refine search and matching algorithms, to create search tools, and to define matching requirements for optimal outcome (52, 71, 72). Access to expertise in informatics, population genetics, and histocompatibility is essential to capitalize on this wealth of information. REFERENCES 1. American Society for Histocompatibility and Immunogenetics Laboratory Manual, A. B. Hahn, G. A. Land, and R. M. Strothman, eds. American Society for Histocompatibility and Immunogenetics, 2000. New York. 2. Beatty, P. G., M. Mori, and E. Milford. 1995. Impact of racial genetic polymorphism on the probability of finding an HLA-matched donor. Transplantation 60:778–783.

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