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Tissue typing

Tissue typing, also known as human leukocyte antigen (HLA) typing, is a laboratory procedure that identifies specific proteins on the surface of cells to determine compatibility between a donor and recipient in organ, tissue, or stem cell transplantation.^[1] These proteins, encoded by genes in the major histocompatibility complex (MHC), help the immune system distinguish self from non-self, and mismatches can trigger rejection of the transplanted material.^[2] The process is essential for minimizing the risk of acute and chronic rejection, thereby improving transplant success rates and reducing the need for immunosuppressive drugs.^[3] Tissue typing originated in the 1950s with serological methods following Jean Dausset's discovery of the first HLA antigen in 1958. The primary goal of tissue typing is to match HLA antigens, particularly classes I (HLA-A, HLA-B, HLA-C) and II (HLA-DR, HLA-DQ, HLA-DP), which are inherited from parents and exhibit extensive variability, with over 43,000 known alleles as of 2025.^[4]^[3] For solid organ transplants like kidneys or livers, typing typically focuses on six key antigens (two each from A, B, and DR loci), where a perfect match is rare outside of identical twins and occurs in about 25% of sibling pairs.^[1] In bone marrow or stem cell transplants, a more comprehensive match of 8 to 10 HLA markers is targeted, with 9/10 or 10/10 matches considered ideal to prevent graft-versus-host disease.^[5] Compatibility is assessed through additional tests, including crossmatching to detect pre-existing antibodies in the recipient that could attack donor cells, and panel reactive antibody (PRA) testing to gauge overall sensitization levels.^[2] Tissue typing is performed via blood samples, cheek swabs, or saliva, using advanced molecular techniques such as polymerase chain reaction (PCR) and next-generation sequencing for high-resolution allele identification.^[2] These methods allow for rapid processing—routine tests handle about 20 samples in six hours—enabling timely decisions for deceased donor transplants through STAT protocols.^[3] Despite improvements, challenges persist, including the rarity of exact matches for highly sensitized patients and limitations in fully predicting immune responses, which can lead to strategies like paired kidney exchanges to facilitate incompatible donations.^[3] Overall, tissue typing has revolutionized transplantation by enhancing patient outcomes and expanding donor pools, with ongoing advancements in sequencing and machine learning further refining matching accuracy.^[2]

Introduction

Definition

Tissue typing, also known as HLA typing or histocompatibility testing, is a laboratory procedure designed to identify and match human leukocyte antigens (HLA)—proteins on the surface of nearly all nucleated cells, particularly white blood cells—between potential donors and recipients to assess compatibility for transplantation.^[6]^[7] The primary purpose of this testing is to evaluate histocompatibility, or the degree to which donor and recipient tissues are immunologically compatible, thereby minimizing the risk of adverse immune responses in procedures such as organ or tissue grafts.^[8]^[9] HLA typing serves as the core component of tissue typing, focusing on these antigens inherited from parents to determine an individual's unique HLA profile.^[1]^[6] The basic process of tissue typing begins with collecting samples, typically blood drawn from a vein or, alternatively, saliva via a cheek swab, from which white blood cells or DNA is isolated for analysis.^[7]^[9] These samples are then processed in specialized laboratories to detect and characterize the specific HLA types, enabling a comparison between donor and recipient profiles for matching.^[10]^[2] In distinction from blood typing, which identifies ABO and Rh antigens on red blood cells to prevent immediate transfusion reactions, tissue typing targets HLA proteins to address longer-term immune compatibility issues in solid organ and cellular transplants.^[7]^[11] This focused assessment of HLA is essential for optimizing transplant outcomes by reducing the likelihood of rejection.^[6]^[5]

Historical Development

The discovery of tissue typing began in the 1950s with foundational work on histocompatibility antigens by Jean Dausset, who identified the first human leukocyte antigen, later designated HLA-A, in 1958 through studies of leukocyte agglutination in patients post-blood transfusions.^[12] Dausset's research demonstrated that these antigens played a critical role in transplant rejection, building on earlier animal models of histocompatibility and establishing the genetic basis for immune responses to foreign tissues.^[13] His pioneering efforts in defining the human major histocompatibility complex (MHC) earned him a share of the 1980 Nobel Prize in Physiology or Medicine, alongside George D. Snell and Baruj Benacerraf, for elucidating the genetic factors regulating antigen formation and immune regulation.^[14] In the 1960s, serological methods for HLA typing advanced significantly, with Rose Payne independently reporting leukocyte antibodies in multiparous women in 1958, which facilitated the development of complement-dependent cytotoxicity assays for antigen detection by the early 1960s.^[12] These techniques enabled precise matching of donor-recipient pairs, culminating in the first successful HLA-matched kidney transplants in the mid-1960s, such as those performed following the identification of HLA-A1 and HLA-A2 specificities.^[15] Concurrently, the World Health Organization (WHO) organized the first International Histocompatibility Workshop in 1964, which standardized serological testing and laid the groundwork for the HLA Nomenclature Committee established in 1968 to systematically name antigens based on serologic specificities.^[16] By the 1970s, HLA typing became integrated into routine transplant protocols, with matching at HLA-A and HLA-B loci adopted as standard practice to reduce rejection rates in kidney transplantation, as evidenced by improved graft survival in matched versus mismatched cases.^[17] Dausset's ongoing contributions emphasized the linkage of HLA genes on chromosome 6, influencing global efforts to map the MHC.^[18] The 1980s marked a shift toward molecular methods, with the introduction of polymerase chain reaction (PCR) techniques in the late 1980s enabling DNA-based HLA typing, which offered greater resolution than serological approaches and transformed histocompatibility testing for transplantation.^[19]

Biological Basis

Human Leukocyte Antigens (HLA)

Human leukocyte antigens (HLA) are a group of cell surface proteins encoded by genes within the major histocompatibility complex (MHC) on the short arm of chromosome 6 at locus 6p21.3.^[20] These proteins play a central role in tissue typing by distinguishing self from non-self cells. HLA molecules are divided into two main classes based on their structure and function: class I and class II. Class I molecules, encoded by the HLA-A, HLA-B, and HLA-C loci, consist of a heavy α-chain non-covalently associated with β2-microglobulin and are expressed on nearly all nucleated cells.^[21] Class II molecules, encoded by the HLA-DR, HLA-DQ, and HLA-DP loci, comprise α- and β-chains and are primarily expressed on antigen-presenting cells such as dendritic cells, macrophages, and B cells.^[21] The HLA system exhibits extraordinary genetic diversity, with over 42,000 known alleles identified across its loci as of November 2025.^[4] This polymorphism arises from evolutionary pressures, including balancing selection driven by pathogen diversity, which favors heterozygous individuals for broader immune recognition.^[22] HLA genes follow codominant inheritance, meaning both maternal and paternal alleles are expressed on cell surfaces, contributing to individual variability.^[23] The high degree of polymorphism, particularly in the peptide-binding regions, ensures a wide repertoire of antigen presentation capabilities across populations.^[24] HLA nomenclature, standardized by the World Health Organization Nomenclature Committee for Factors of the HLA System, uses a systematic format to denote alleles.^[25] The designation follows the pattern HLA-locusallele group:protein sequence, such as HLA-A01:01, where the locus indicates the gene (e.g., A, B, DRB1), the two-digit allele group specifies synonymous nucleotide differences in exons encoding the antigen recognition site, and the two-digit protein sequence denotes changes in the amino acid sequence. Additional fields, like :01:01, further resolve synonymous changes outside the antigen recognition domain or intronic variations. In tissue typing, HLA compatibility is evaluated at different resolution levels to assess matching for applications such as transplantation. Low-resolution typing identifies broad serological equivalents (first field, e.g., A01), intermediate-resolution distinguishes allele groups and protein variants (second and third fields, e.g., A01:01), and high-resolution (allele-specific) typing resolves full sequences including synonymous changes (fourth field or beyond, e.g., A*01:01:01).

Role in Immune Response

Human leukocyte antigen (HLA) class I molecules, expressed on nearly all nucleated cells, present intracellular peptides derived from endogenous proteins to CD8+ cytotoxic T cells, enabling the immune system to detect and eliminate infected or malignant cells.^[26] These peptides, typically 8-10 amino acids long, are generated by proteasomal degradation in the cytosol and transported into the endoplasmic reticulum via the transporter associated with antigen processing (TAP), where they bind to HLA class I for surface presentation.^[26] In contrast, HLA class II molecules, primarily expressed on professional antigen-presenting cells (APCs) such as dendritic cells, macrophages, and B cells, display exogenous peptides to CD4+ helper T cells, facilitating coordination of adaptive immune responses including antibody production and macrophage activation.^[26] Exogenous antigens are internalized by endocytosis, processed in endosomal compartments, and loaded onto HLA class II molecules after removal of the invariant chain, allowing recognition by CD4+ T cells to amplify immunity against extracellular pathogens.^[26] In transplantation, HLA molecules drive allorecognition, where recipient T cells perceive donor HLA as foreign, triggering graft rejection through direct and indirect pathways. Direct allorecognition occurs when recipient T cells recognize intact donor HLA-peptide complexes on passenger donor APCs within the graft, eliciting a robust, early response that activates both CD4+ and CD8+ T cells and is primarily responsible for acute rejection episodes within the first weeks post-transplant.^[27] Indirect allorecognition involves recipient APCs processing donor HLA-derived peptides and presenting them in the context of self-HLA molecules to recipient T cells, promoting a more sustained CD4+ T cell response that contributes to chronic rejection through mechanisms like alloantibody production and vascular damage over months to years.^[27] These pathways underscore the high frequency of alloreactive T cells—up to 10% of the T cell repertoire may respond to a single mismatched HLA allele—highlighting the potency of HLA-driven immunity in allogeneic settings.^[27] HLA mismatches between donor and recipient exacerbate rejection risks by amplifying T cell activation and alloantibody formation, with each additional mismatch linearly increasing the hazard of graft failure. For instance, in kidney transplantation, a single HLA mismatch raises the risk of transplant failure by 13%, while six mismatches elevate it by 64%, affecting both acute cellular rejection via direct T cell cytotoxicity and chronic antibody-mediated rejection through indirect pathway-driven humoral responses.^[28] Matching HLA loci, particularly HLA-A, -B, and -DR, minimizes these consequences by reducing alloreactive T cell priming and subsequent inflammation, endothelial injury, and fibrosis in the graft.^[28] Beyond transplantation, HLA variations influence susceptibility to autoimmunity and infections by modulating peptide presentation efficiency and T cell selection. The HLA region, including specific class II alleles such as HLA-DRB104:01, confers increased risk for rheumatoid arthritis by preferentially presenting arthritogenic self-peptides to autoreactive CD4+ T cells, explaining up to 30% of disease heritability in some populations.^[29] Conversely, certain HLA class I alleles like HLA-B57:01 protect against HIV progression by enhancing presentation of viral peptides to CD8+ T cells, reducing viral load and delaying disease onset in carriers.^[29] These associations illustrate HLA's broader role in balancing immune vigilance against self-tolerance and pathogen defense.^[29]

Methods of Tissue Typing

Serological Methods

Serological methods for tissue typing primarily rely on the complement-dependent cytotoxicity (CDC) assay, which detects human leukocyte antigens (HLA) expressed on the surface of lymphocytes using specific antibodies. In this technique, HLA-specific antibodies—derived from alloantisera or monoclonal sources—bind to the target HLA molecules on viable lymphocytes, activating the complement system and leading to cell membrane damage and lysis if the antigen-antibody match occurs.^[30] This principle, first described by Terasaki and McClelland in 1964, allows for the identification of HLA specificities through the observation of cytotoxic reactions, making it a cornerstone of early histocompatibility testing.^[30] The procedure begins with the isolation of lymphocytes from peripheral blood, typically separating T cells for class I HLA typing or B cells for class II. These cells are then incubated with a panel of typing sera containing known anti-HLA antibodies in microplates, such as Terasaki trays, at around 22°C for 30 minutes to permit antibody binding. Rabbit or human complement is subsequently added, and the mixture is incubated for an additional 60-90 minutes at 37°C to facilitate complement activation and potential cell death. Cytotoxicity is assessed microscopically after staining with a vital dye like eosin or trypan blue; dead cells take up the dye and appear bright against live cells, with reactions scored on a scale from 1 (no lysis) to 8 (complete lysis), where scores of 2 or higher indicate a positive reaction for that HLA specificity.^[30] This step-wise process enables the assignment of HLA types at a basic serological level, often requiring multiple sera to resolve specificities due to potential cross-reactivity.^[31] Serological methods, particularly CDC, dominated HLA typing from the 1960s through the 1990s, serving as the standard for matching donors and recipients in organ and bone marrow transplantation during this era. Introduced in the early 1960s, the microlymphocytotoxicity variant revolutionized the field by allowing high-throughput testing with small sample volumes, facilitating widespread adoption in clinical histocompatibility laboratories worldwide.^[31] By the 1970s, refinements like the addition of anti-human globulin (AHG) enhanced sensitivity for detecting low-titer antibodies, further solidifying its role in transplant programs until molecular techniques emerged.^[30] A key advantage of serological typing is its cost-effectiveness and suitability for low-resolution typing, providing rapid results (within hours) using readily available reagents and viable cells that mimic in vivo conditions without genetic manipulation.^[30] It remains valuable in resource-limited settings for initial screening and as a complement to more advanced methods. However, these techniques are labor-intensive, requiring skilled personnel for cell preparation and subjective microscopic interpretation, which can introduce variability.^[32] Moreover, serological methods cannot detect HLA alleles that lack surface expression, such as null alleles or those with cryptic epitopes not recognized by available antisera, leading to incomplete typing and potential mismatches in transplantation.^[24] Cross-reactivity among antisera also contributes to ambiguities, with error rates up to 25% reported for certain loci like HLA-B.^[31]

Molecular Methods

Molecular methods for tissue typing primarily involve DNA-based techniques to identify human leukocyte antigen (HLA) alleles with high precision, surpassing the limitations of serological approaches by directly analyzing genetic sequences. These methods extract genomic DNA from patient samples and apply polymerase chain reaction (PCR) amplification followed by detection strategies to characterize HLA loci such as HLA-A, -B, -C, -DRB1, and -DQB1. They enable typing at various resolution levels, defined by the IMGT/HLA nomenclature: 2-digit resolution specifies the allele group (e.g., HLA-A02), 4-digit adds protein-level specificity (e.g., HLA-A02:01), 6-digit includes synonymous coding changes (e.g., HLA-A02:01:01), and 8-digit provides full intronic and untranslated region details (e.g., HLA-A02:01:01:01).^[33]^[34] A foundational technique is PCR with sequence-specific oligonucleotide probing (PCR-SSOP) or sequence-specific priming (PCR-SSP), both developed in the early 1990s for allele-level detection. In PCR-SSOP, target HLA exons are amplified via PCR, then hybridized to immobilized sequence-specific oligonucleotide probes on membranes or beads, allowing detection of alleles through positive hybridization signals; this method supports intermediate resolution (typically 4-digit) and is suitable for batch processing in clinical labs.^[35]^[10] PCR-SSP, conversely, uses allele-specific primers in multiplex PCR reactions, where amplification occurs only for matching alleles, visualized by gel electrophoresis; it offers rapid, cost-effective typing at similar resolution but is best for smaller sample sets due to primer design limitations.^[35]^[10] Both techniques resolve ambiguities in heterozygous samples better than serological methods but may miss novel alleles not covered by predefined probes or primers.^[36] Sanger sequencing, or sequence-based typing (SBT), provides high-resolution (4- to 6-digit) analysis by amplifying polymorphic HLA exons with universal primers, followed by bidirectional dideoxy sequencing to determine nucleotide sequences. This approach excels in identifying exact mismatches in exons encoding antigen-binding sites, crucial for transplantation compatibility, though it often requires additional steps to resolve phase ambiguities in heterozygous loci.^[10]^[36] Adopted widely since the late 1990s, Sanger SBT remains a gold standard for confirmatory testing despite its labor-intensive nature and higher cost for low-throughput settings.^[37] Next-generation sequencing (NGS) represents a high-throughput advancement, enabling 8-digit resolution across full HLA genes by massively parallel sequencing of long-range PCR amplicons or captured regions, minimizing ambiguities through haplotype phasing algorithms. Platforms like Illumina MiSeq sequence multiple samples simultaneously, covering introns and untranslated regions to detect rare variants, with turnaround times of 2-3 days.^[38]^[10] Introduced in clinical labs around 2010, NGS has become preferred for its comprehensive coverage and ability to handle complex polymorphisms, though it demands robust bioinformatics for data interpretation.^[38]^[37] Common sample types for these molecular methods include genomic DNA extracted from peripheral blood (preferred for high yield) or non-invasive buccal swabs, which provide sufficient material (15-80 ng) while avoiding venipuncture risks, especially for pediatric or remote donors.^[7]^[39] Automation in histocompatibility labs enhances reproducibility, with robotic liquid handlers performing PCR setup, library preparation, and normalization for up to 96 samples, reducing hands-on time and errors in NGS workflows.^[39]^[10]

Applications

Organ and Tissue Transplantation

In solid organ transplantation, tissue typing plays a crucial role in assessing compatibility between donor and recipient to minimize immune-mediated rejection. The primary focus is on matching human leukocyte antigens (HLA) at key loci, particularly HLA-A, HLA-B, and HLA-DR, as mismatches at these sites are strongly associated with increased risk of acute rejection and reduced graft survival.^[40] Complement-dependent cytotoxicity or flow cytometry crossmatch tests are performed to detect pre-formed donor-specific antibodies in the recipient, which could trigger hyperacute rejection if present.^[41] Matching criteria vary by organ due to differences in ischemia tolerance and clinical urgency. For kidneys, up to 4-6 HLA mismatches can be tolerated, allowing broader donor pools, though outcomes improve with fewer mismatches; in contrast, hearts and livers often receive transplants with 0-2 mismatches prioritized when possible, as time constraints from deceased donors limit extensive matching.^[40] Living donors enable more precise HLA assessment and selection, contributing to superior long-term results compared to deceased donors, where logistical factors may result in higher mismatch rates.^[42] Graft outcomes are markedly better with 0-2 HLA-A, -B, and -DR mismatches, with rejection incidence as low as 4.4% and 5-year survival rates reaching 100% in sensitized kidney recipients, versus 31.3% rejection and 74% survival with 5-6 mismatches.^[40] Analysis of United Network for Organ Sharing (UNOS) registry data from the early 1990s confirms that each additional HLA mismatch increases the hazard ratio for graft failure by approximately 1.06, underscoring the survival benefit of optimized matching; more recent data indicate overall 5-year graft survival rates of 80-90% for living donor kidneys and 66-82% for deceased donor kidneys.^[43]^[44]^[45] In tissue banking, HLA typing ensures compatibility for allografts such as corneas, skin, and bones, reducing rejection risk in recipients. Corneal transplants often proceed with partial HLA matches due to the tissue's immune-privileged status, while skin grafts prioritize HLA-A, -B, and -DR compatibility to support integration and vascularization without excessive immunosuppression; for bone grafts, HLA matching is not routinely required, particularly for structural allografts, due to lack of proven benefit in incorporation.^[2]^[46]

Hematopoietic Stem Cell Transplantation

In hematopoietic stem cell transplantation (HSCT), tissue typing plays a pivotal role in selecting donors to prevent immune-mediated complications such as graft rejection and graft-versus-host disease (GVHD). The process focuses on high-resolution human leukocyte antigen (HLA) matching to ensure compatibility between donor and recipient, with the goal of replicating the natural immune tolerance seen in syngeneic transplants. Sibling donors are ideal, as they have a 25% chance of being fully HLA-identical, inheriting the same haplotypes from parents, which minimizes alloreactivity and supports engraftment without additional immunosuppression.^[7]^[47] For unrelated donors, matching requirements emphasize an 8/8 HLA match at high-resolution for loci A, B, C, and DRB1, or preferably a 10/10 match incorporating DQB1 to optimize survival and reduce non-relapse mortality.^[48]^[49] Mismatches at these loci heighten GVHD risk, where donor T cells recognize recipient tissues as foreign, leading to severe acute or chronic forms; for example, allele-level mismatches at HLA-A, B, or DRB1 independently increase overall mortality, while HLA-DQB1 mismatches show a similar trend primarily through antigen disparities.^[50] To mitigate this, typing incorporates permissive mismatches, particularly at HLA-DPB1, where certain epitope-compatible disparities (e.g., T-cell epitope group 1 mismatches) do not significantly elevate GVHD or mortality risks compared to non-permissive ones.^[51]^[52] International registries like the National Marrow Donor Program (NMDP) and World Marrow Donor Association (WMDA) maintain global databases of over 44 million HLA-typed volunteers as of 2023, enabling efficient donor searches and confirmatory typing to identify 8/8 or better matches, especially for patients from underrepresented ethnic groups where match likelihood is lower.^[53]^[54] When fully matched unrelated donors are unavailable, haploidentical HSCT from half-matched family members (sharing ~5/10 HLA loci) combined with post-transplant cyclophosphamide (PTCy) has emerged as a standard alternative; PTCy selectively depletes alloreactive T cells, achieving low rates of severe acute GVHD (typically 10-15% grade III/IV) without compromising relapse protection.^[55]^[56] HLA-matched sibling donors yield superior outcomes, with 1-year overall survival often exceeding 80% for low-risk hematologic malignancies. In unrelated donor settings, 8/8 matches achieve approximately 50-60% 1-year survival, while single mismatches reduce it further due to elevated GVHD and relapse risks. In haploidentical settings with PTCy, 1-year GVHD-free, relapse-free survival approaches 50%, comparable to matched unrelated donors while expanding access for urgent cases.^[57]^[55]

Challenges and Advances

Limitations of Current Methods

Current methods of tissue typing, particularly next-generation sequencing (NGS), face technical challenges such as allelic ambiguities, which stem from the high polymorphism of HLA genes and incomplete sequencing coverage of introns, untranslated regions, and other non-exonic areas. These ambiguities can result in hundreds of possible allele combinations per locus, complicating precise genotype assignment without supplementary testing. Additionally, phase problems in heterozygous loci arise due to difficulties in determining cis-trans configurations of polymorphisms on the same chromosome, often requiring family segregation studies or long-read sequencing to resolve.^[58]^[59] Biologically, the extreme diversity of HLA alleles poses significant hurdles, especially rare variants prevalent in ethnically diverse populations that are underrepresented in reference databases, leading to potential misidentification or failure to detect matches. Non-HLA factors, including minor histocompatibility antigens like those encoded by the Y chromosome (H-Y) or other polymorphic genes, further contribute to immune responses and rejection, as they elicit T-cell activation independent of HLA compatibility.^[17]^[60] Logistically, achieving high-resolution typing demands substantial time—often days to weeks—and high costs, estimated at hundreds of dollars per sample, which restricts routine application in resource-limited settings and delays transplant matching. Access disparities disproportionately affect underrepresented ethnic groups, where lower registry representation and higher frequencies of unique alleles reduce match likelihood and exacerbate inequities in transplant outcomes.^[61]^[62] Error sources include sample contamination, which can introduce extraneous DNA and yield false allele calls, particularly in low-input scenarios like buccal swabs. Interpretation variability across laboratories, influenced by differences in software algorithms, reference panels, and reporting standards, further undermines result reliability and comparability.^[63]^[64] These limitations collectively heighten the risk of HLA mismatches in transplants, with studies indicating increased incidence of acute rejection for mismatches at key loci like HLA-A, -B, or -DR, ultimately compromising graft survival.^[65]

Recent Developments

Since the 2010s, third-generation sequencing (TGS) technologies, particularly long-read platforms like PacBio SMRT sequencing, have revolutionized HLA typing by enabling the determination of full-length HLA haplotypes without the ambiguities common in short-read methods. These approaches generate ultra-long reads that span entire HLA genes, allowing for accurate phasing and resolution of complex heterozygous regions that previously required labor-intensive assembly. For instance, a 2019 workflow using PacBio demonstrated high-resolution typing of HLA class I and II loci with over 99% accuracy in allele assignment across diverse samples, eliminating the need for imputation and improving transplant matching precision.^[66] Similarly, nanopore sequencing, another TGS method, has been applied to achieve rapid, portable HLA typing, with studies showing its utility in resolving novel alleles in immunogenetics research.^[67] Advancements in automation and artificial intelligence have further streamlined HLA allele calling, reducing turnaround times and enhancing accuracy in high-throughput settings. Machine learning algorithms, such as DEEPHLA, employ convolutional neural networks to impute HLA genotypes from whole-exome sequencing data, achieving allele-level resolution comparable to specialized typing while handling multi-ancestry cohorts.^[68] Point-of-care rapid typing kits have also emerged, including real-time PCR-based systems like QTYPE, which deliver results for 11 HLA loci in under one hour with minimal hands-on time, facilitating bedside decision-making in transplantation.^[69] Additionally, assays for specific alleles, such as a near point-of-care test for HLA-B57:01, provide economical genotyping in clinical specimens within minutes, expanding access in resource-limited environments.^[70] Beyond transplantation, HLA typing has found expanded applications in predicting drug hypersensitivity reactions, notably the association between HLA-B57:01 and abacavir-induced hypersensitivity in HIV patients, where prospective screening has nearly eliminated severe reactions. Guidelines now recommend HLA-B57:01 testing prior to abacavir initiation, with meta-analyses confirming its 100% negative predictive value and significant risk reduction.^[71]^[72] This pharmacogenomic use exemplifies how high-resolution typing informs personalized medicine, preventing adverse events across diverse populations.^[73] Global efforts to maintain comprehensive HLA databases, such as the IPD-IMGT/HLA repository, have accelerated with quarterly updates incorporating thousands of new alleles, reaching over 42,000 alleles as of September 2025 to support worldwide standardization.^[74] Initiatives addressing equity in diverse allele catalogs emphasize including underrepresented ancestries to mitigate biases in transplant matching and therapeutic development, with studies highlighting how allele frequency variations by race affect eligibility for HLA-restricted immunotherapies.^[75]^[76] Looking ahead, gene editing technologies like CRISPR-Cas9 hold promise for creating universal donors by disrupting HLA expression, potentially bypassing traditional typing needs in allogeneic therapies. Recent trials have tested CRISPR-edited kidneys with biallelic knockouts of HLA-A and HLA-B, aiming to reduce rejection without immunosuppression, while hypoimmunogenic iPSCs generated via HLA gene editing demonstrate enhanced compatibility in preclinical models.^[77]^[78] These innovations could transform tissue typing by shifting focus from matching to engineered universality, though challenges in off-target effects remain.^[79]

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HLA typing by SSO and SSP methods - PubMed
This chapter provides an overview of the SSO and SSP methods in relation to HLA typing. Publication types. Review. MeSH terms. Base Sequence; DNA Primers / ...
[36]
HLA DNA typing: past, present, and future - PubMed
HLA DNA typing uses methods like RFLP, PCR, SSO, and next-generation sequencing. The first method used RFLP analysis, and PCR allowed for amplification of ...
[37]
The Past, Present, and Future of HLA Typing in Transplantation
Numerous studies have identified HLA matching as a key determinate to improve patient outcomes from transplantation.
[38]
Next generation sequencing and its place in the advancement of ...
Feb 5, 2021 · Next Generation Sequencing (NGS), the latest molecular technology introduced in clinical tissue typing laboratories, has demonstrated advantages ...
[39]
HLA typing using PCR and NGS technology - News-Medical.net
Oct 16, 2024 · NGS library preparation for HLA typing uses long-range PCR amplicons that span the entire gene sequence, allowing for high-resolution typing.
[40]
HLA Mismatching Strategies for Solid Organ Transplantation - PMC
HLA matching provides numerous benefits in organ transplantation including better graft function, fewer rejection episodes, longer graft survival, ...
[41]
Human leukocyte antigen typing and crossmatch - NIH
Complement-dependent cytotoxicity crossmatch (CDC-XM) can be done for B and T lymphocytes. Sensitivity is limited if the relevant antibody is in low titres, ...
[42]
The Risk of Transplant Failure With HLA Mismatch in First Adult ...
When using 0-mismatched full siblings as a reference, living-donor kidneys reduce the hazard of failure by approximately 34% when compared with deceased donors.
[43]
The Impact of HLA Mismatches on the Survival of First Cadaveric ...
Sep 22, 1994 · As a consequence, projected five-year graft survival could potentially increase from 58.5 percent to 62.9 percent. This would be associated with ...
[44]
What is the impact of human leukocyte antigen mismatching on graft ...
May 18, 2018 · HLA per mismatch was significant associated with increased risks of overall graft failure (hazard ratio (HR), 1.06; 95% confidence interval (CI) ...
[45]
HLA Sensitization and Allograft Bone Graft Incorporation - PMC - NIH
Although HLA sensitization does not appear to delay structural allograft bone incorporation, further followup is required to determine if there is an ...
[46]
Recommendations for Donor HLA Assessment and Matching ... - PMC
The recipient and related donor should be ≥ 4/8 match at HLA-A, -B, -C and -DRB1, with only one mismatch per locus. A significant risk of graft failure exists ...
[47]
How to select the best available related or unrelated donor of ...
Jun 1, 2016 · In most European centers the gold standard is to look for an HLA-A, -B, -C, -DRB1, and -DQB1-matched donor, a so-called 10/10 match. An ...Abstract · Introduction · Searching for 'HLA-compatible... · Conclusion
[48]
A clinician's guide to HLA matching in allogeneic hematopoietic ...
In this review, we provide an up to date resource to educate and remind clinicians of: 1) Why HLA matching matters, including reviewing the role HLA molecules ...
[49]
High-resolution HLA matching in hematopoietic stem cell ...
Key Points. HLA mismatches at the allele and antigen level (possibly with the exception of HLA-DQB1) should be treated equally in donor selection.HLA misma.Abstract · Introduction · Patients and methods · Results
[50]
Permissive HLA-DPB1 mismatches in HCT depend on ... - PubMed
Feb 18, 2021 · Permissive HLA-DPB1 mismatches between patients and their unrelated donors are associated with improved outcomes compared with nonpermissive mismatches.
[51]
High-risk HLA alleles for severe acute graft-versus-host disease and ...
In comparison to HLA-C allele match, patient mismatched HLA-C*14:02 showed the highest risk of severe acute graft-versus-host disease (HR, 3.61, P<0.001) and ...
[52]
https://pmc.ncbi.nlm.nih.gov/articles/PMC5004392/
[53]
30 years of global collaboration in transplantation and cellular therapy
Sep 26, 2025 · WMDA is committed to donor safety, ethical treatment, and the integrity of stem cell products in transplantation and cellular therapies. As a ...<|separator|>
[54]
Post-Transplantation Cyclophosphamide-Based Graft-versus-Host ...
Jun 21, 2023 · A phase 2 study indicated the potential superiority of a post-transplantation regimen of cyclophosphamide, tacrolimus, and mycophenolate mofetil.
[55]
Haploidentical Hematopoietic Stem Cell Transplantation with Post ...
In adult recipients high-dose post-transplant cyclophosphamide (PTCY) is increasingly used to mitigate the risks of graft failure and graft-versus-host disease ...
[56]
HLA-Mismatch Is Associated With Worse Outcomes After Unrelated ...
... versus-host disease (GVHD). Results. Adjusted one and three-year OS was better in 8/8 vs. 7/8 matched recipients (54.7% vs. 48.8%, p=0.01 and 37.4% vs. 30.9 ...
[57]
Resolving Ambiguities in Deceased Donor HLA Typing: Next ...
Oct 15, 2024 · The ambiguities were significantly reduced from hundreds detected in rtPCR to 4 or fewer possible allele combinations with NGS. Eleven cases ...
[58]
Clinical validation of next generation sequencing for HLA typing ...
The complexity of the HLA region leads to an inability to phase heterozygous positions thus additional testing is required to achieve allele level typing.
[59]
Non-HLA Genetics and Application to Living Donor Candidates - PMC
Sep 5, 2025 · Non-HLA genetic mismatches, including single nucleotide variants affecting minor histocompatibility antigens, can drive alloimmune responses, ...Variants Affecting Immune... · Table 1 · Apol1 Renal Risk Variants...
[60]
Cost-efficient high-throughput HLA typing by MiSeq amplicon ...
Jan 24, 2014 · Many registries with limited resources have had to find a trade-off between cost and resolution and extent of typing for newly recruited donors ...
[61]
Effect of HLA restriction on racial and ethnic disparities in access to ...
Jul 16, 2025 · In addition to HLA-associated disparities, studies suggest some racially and ethnically minoritized people with cancer are less likely to meet ...
[62]
[PDF] SOURCES OF ERROR IN SEROLOGIC AND IMMUNOLOGIC LAB
Remember that contaminated blood specimens, reagents or supplies may interfere with the test reagents, or supplies may interfere with the test results. Page 19 ...
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Interpreting Anti-HLA Antibody Testing Data: A Practical Guide ... - NIH
Laboratory variability exists because of differences in the SAB product itself depending on the bead manufacturer, batch, or lot (19-21). Manufacturers have ...
[64]
HLA Mismatching Strategies for Solid Organ Transplantation
HLA matching provides numerous benefits in organ transplantation including better graft function, fewer rejection episodes, longer graft survival, and the ...
[65]
High-Resolution Full-Length HLA Typing Method Using ... - PacBio
Sep 22, 2019 · To overcome these limitations, we here described end-to-end workflow for sequencing of HLA class I and class II genes using third generation ...
[66]
A long road/read to rapid high-resolution HLA typing - NIH
May 1, 2020 · Here, we provide a concise review of nanopore sequencing with a focus on its potential benefit for HLA typing and immunogenetics research.
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A multi-task convolutional deep learning method for HLA allelic ...
Jan 10, 2021 · Here, we developed DEEP*HLA, a multi-task convolutional deep learning method to accurately impute genotypes of HLA genes from SNV-level data.
[68]
Real-Time PCR-Based HLA Typing | QTYPE - CareDx
QTYPE is a rapid, real-time PCR-based HLA typing method for 11 loci, providing results in less than 1 hour with less than 10 minutes of hands-on time.Missing: point- | Show results with:point-
[69]
Rapid Near Point-of-Care Assay for HLA-B*57:01 Genotype ...
This rapid and economical assay accurately detects HLA-B*57:01 in clinical specimens. Use of this assay could expand access to HLA-B*57:01 genotyping.
[70]
HLA-B*57:01 Testing - StatPearls - NCBI Bookshelf
Oct 6, 2024 · The recommendation is that patients receive an alternative NRTI to abacavir if they have the HLA-B*57:01 allele to avoid the possibility of a ...
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Diagnostic accuracy of HLA-B*57:01 screening for the ... - PubMed
Pooled analysis of risk ratio showed that prospective HLA-B*57:01 testing significantly reduced the incidence of abacavir-induced hypersensitivity. Conclusion: ...<|separator|>
[72]
HLA-B*5701 Screening for Hypersensitivity to Abacavir
Feb 7, 2008 · This study was designed to establish the effectiveness of prospective HLA-B*5701 screening to prevent the hypersensitivity reaction to abacavir.
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The IPD-IMGT/HLA Database - PMC - PubMed Central
Nov 9, 2022 · Since the first release, the database has been updated every 3 months for a total of 95 releases. During this time, the database has continually ...
[74]
Ensuring equity in the era of HLA-restricted cancer therapeutics - NIH
Nov 28, 2022 · As additional cancer therapies targeting antigens presented by specific HLA alleles are developed, it is important to recognize that HLA allele ...
[75]
Eligibility for Human Leukocyte Antigen–Based Therapeutics by ...
Oct 26, 2023 · The frequency of the HLA-A*02:01 allele in the population varied, with 11.9% (95% CI, 11.8%-12.0%) in African or African American individuals ...
[76]
NCT07053462 | CRISPR-Edited HLA Donor Kidney Transplant to ...
Jul 8, 2025 · This clinical trial investigates the transplantation of donor kidneys that have been genetically modified ex vivo using CRISPR-Cas9 genome editing to reduce ...
[77]
HLA matching or CRISPR editing of HLA class I/II enables ... - Nature
Oct 13, 2025 · Stringent matching of HLA class I and II restores efficacy but is clinically impractical. Using non-viral CRISPR editing we disrupt B2M and ...
[78]
Development of immunocompatible pluripotent stem cells via ... - NIH
Jan 7, 2019 · In this study, we used CRISPR/Cas9 to knockout HLA-B from inducible pluripotent stem cells (iPSCs) with heterogenous HLA-B and showed that the HLA-B knockout ...