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Tissue typing
Tissue typing
Tissue typing
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Tissue typing is a procedure in which the tissues of a prospective donor and recipient are tested for compatibility prior to transplantation. Mismatched donor and recipient tissues can lead to rejection of the tissues. There are multiple methods of tissue typing.

Overview

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Mapping of HLA loci on chromosome 6

During tissue typing, an individual's human leukocyte antigens (HLA) are identified.[1] HLA molecules are presented on the surface of cells and facilitate interactions between immune cells (such as dendritic cells and T cells) that lead to adaptive immune responses.[2] If HLA from the donor is recognized by the recipient's immune system as different from the recipient's own HLA, an immune response against the donor tissues can be triggered.[3] More specifically, HLA mismatches between organ donors and recipients can lead to the development of anti-HLA donor-specific antibodies (DSAs).[4] DSAs are strongly associated with the rejection of donor tissues in the recipient, and their presence is considered an indicator of antibody-mediated rejection.[5] When donor and recipient HLA are matched, donor tissues are significantly more likely to be accepted by the recipient's immune system.[3] During tissue typing, a number of HLA genes should be typed in both the donor and recipient, including HLA Class I A, B, and C genes, as well as HLA Class II DRB1, DRB3, DRB4, DRB5, DQA1, DQB1, DPA1, and DPB1 genes.[6] HLA typing is made more difficult by the fact that the HLA region is the most genetically variable region in the human genome.[7]

Methods of tissue typing

[edit]
This diagram shows serological typing. In the top half of the diagram, the correct antibody for the HLA type of the cell was added, so complement activation occurred, leading to cell lysis. Cell lysis indicates that the antibody added matched the HLA type of the cell, so the HLA type of the cell is then known. In the bottom half of the diagram, an HLA antibody that did not match the cell's HLA type was added, so there was no complement activation, and no cell lysis occurred.

One of the first methods of tissue typing was through serological typing. In this technique, a donor's blood cells are HLA typed by mixing them with serum containing anti-HLA antibodies. If the antibodies recognize their epitope on the donor's HLA then complement activation occurs leads to cell lysis and death, allowing the cells to take up a dye (trypan blue). This allows for identification of the cells' HLA based indirectly on the specificity of the known antibodies in the serum. This method has been used widely since it is simple, quick, and low-cost; however, the huge variability in HLA alleles means that serum containing antibodies specific to the HLA of the cells being tested may not be available.[6][3] Serological typing does not give a clear picture of the HLA region and does not always result in successful HLA typing, so many laboratories have stopped using it in favor of more effective methods.[6][8]

Recently, other more effective approaches have emerged, including the use of polymerase chain reaction (PCR) based on sequence-specific primers (SSP) or sequence-specific oligonucleotide probes (SSOP).[3][6] However, SSP-PCR can be both time and resource consuming.[8] SSOP-PCR is better for HLA typing large numbers of individuals, for example, large numbers of donors for bone marrow registries.[8] RT-PCR is another approach to HLA typing that is fast and versatile, but it is expensive.[6]

Reference strand-mediated conformational analysis (RSCA) is yet another method used for HLA typing. In this method, an unknown HLA sample is mixed with a reference allele and run in a gel by electrophoresis.[8] RSCA is limited by the number of HLA reference alleles available since the HLA region is so diverse.[8]

Direct DNA sequencing is currently considered the best method of HLA typing, either by Sanger sequencing or next generation sequencing, though it can also be time-consuming and is one of the more expensive methods.[6][8] RNA sequencing can also be used, but many labs do not as RNA is unstable and prone to degradation.[8]

See also

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References

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Tissue typing

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Tissue typing, also known as (HLA) typing, is a procedure that identifies specific proteins on the surface of cells to determine compatibility between a donor and recipient in organ, tissue, or transplantation. These proteins, encoded by genes in the (MHC), help the distinguish self from non-self, and mismatches can trigger rejection of the transplanted material. 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. 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-B, ) and II (, HLA-DQ, HLA-DP), which are inherited from parents and exhibit extensive variability, with over 43,000 known alleles as of 2025. 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. In or transplants, a more comprehensive match of 8 to 10 HLA markers is targeted, with 9/10 or 10/10 matches considered ideal to prevent . Compatibility is assessed through additional tests, including to detect pre-existing antibodies in the recipient that could attack donor cells, and (PRA) testing to gauge overall sensitization levels. Tissue typing is performed via blood samples, cheek swabs, or saliva, using advanced molecular techniques such as (PCR) and next-generation sequencing for high-resolution identification. 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. 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 exchanges to facilitate incompatible donations. Overall, tissue typing has revolutionized transplantation by enhancing patient outcomes and expanding donor pools, with ongoing advancements in sequencing and further refining matching accuracy.

Introduction

Definition

Tissue typing, also known as HLA typing or testing, is a procedure designed to identify and match leukocyte antigens (HLA)—proteins on the surface of nearly all nucleated cells, particularly —between potential donors and recipients to assess compatibility for transplantation. The primary purpose of this testing is to evaluate , 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. 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. The basic process of tissue typing begins with collecting samples, typically drawn from a or, alternatively, via a swab, from which or DNA is isolated for analysis. 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. 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. This focused assessment of HLA is essential for optimizing transplant outcomes by reducing the likelihood of rejection.

Historical Development

The discovery of tissue typing began in the 1950s with foundational work on antigens by Jean Dausset, who identified the first , later designated , in 1958 through studies of leukocyte agglutination in patients post-blood transfusions. Dausset's research demonstrated that these antigens played a critical role in , building on earlier animal models of and establishing the genetic basis for immune responses to foreign tissues. His pioneering efforts in defining the (MHC) earned him a share of the 1980 in Physiology or Medicine, alongside George D. Snell and , for elucidating the genetic factors regulating antigen formation and immune regulation. 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 assays for detection by the early 1960s. These techniques enabled precise matching of donor-recipient pairs, culminating in the first successful HLA-matched transplants in the mid-1960s, such as those performed following the identification of HLA-A1 and HLA-A2 specificities. Concurrently, the (WHO) organized the first International Workshop in 1964, which standardized serological testing and laid the groundwork for the HLA Nomenclature Committee established in 1968 to systematically name s based on serologic specificities. By the 1970s, HLA typing became integrated into routine transplant protocols, with matching at and HLA-B loci adopted as standard practice to reduce rejection rates in , as evidenced by improved graft survival in matched versus mismatched cases. Dausset's ongoing contributions emphasized the linkage of HLA genes on , influencing global efforts to map the MHC. The 1980s marked a shift toward molecular methods, with the introduction of (PCR) techniques in the late 1980s enabling DNA-based HLA typing, which offered greater resolution than serological approaches and transformed testing for transplantation.

Biological Basis

Human Leukocyte Antigens (HLA)

Human leukocyte antigens (HLA) are a group of cell surface proteins encoded by genes within the (MHC) on the short arm of at locus 6p21.3. 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. Class II molecules, encoded by the , 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. The HLA system exhibits extraordinary , with over 42,000 known alleles identified across its loci as of November 2025. This polymorphism arises from evolutionary pressures, including balancing selection driven by diversity, which favors heterozygous individuals for broader immune recognition. HLA genes follow codominant , meaning both maternal and paternal alleles are expressed on cell surfaces, contributing to individual variability. The high degree of polymorphism, particularly in the peptide-binding regions, ensures a wide repertoire of capabilities across populations. HLA nomenclature, standardized by the Nomenclature Committee for Factors of the HLA System, uses a systematic format to denote alleles. The designation follows the pattern HLA-locusallele group:protein sequence, such as HLA-A01:01, where the locus indicates the (e.g., A, B, DRB1), the two-digit allele group specifies synonymous differences in exons encoding the antigen recognition site, and the two-digit protein sequence denotes changes in the 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 + cytotoxic T cells, enabling the to detect and eliminate infected or malignant cells. These peptides, typically 8-10 long, are generated by proteasomal degradation in the and transported into the via the transporter associated with (TAP), where they bind to HLA class I for surface presentation. In contrast, HLA class II molecules, primarily expressed on professional antigen-presenting cells (APCs) such as dendritic cells, s, and B cells, display exogenous peptides to + helper T cells, facilitating coordination of adaptive immune responses including antibody production and macrophage activation. Exogenous antigens are internalized by , processed in endosomal compartments, and loaded onto HLA class II molecules after removal of the invariant chain, allowing recognition by + T cells to amplify immunity against extracellular pathogens. 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 + and + T cells and is primarily responsible for acute rejection episodes within the first weeks post-transplant. 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 + T cell response that contributes to chronic rejection through mechanisms like alloantibody production and vascular damage over months to years. 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 —highlighting the potency of HLA-driven immunity in allogeneic settings. 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 . For instance, in , a single HLA mismatch raises the risk of transplant 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. Matching HLA loci, particularly , -B, and -DR, minimizes these consequences by reducing alloreactive T cell priming and subsequent , endothelial injury, and in the graft. 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 by preferentially presenting arthritogenic self-peptides to autoreactive + T cells, explaining up to 30% of disease heritability in some populations. Conversely, certain HLA class I alleles like HLA-B57:01 protect against progression by enhancing presentation of viral peptides to CD8+ T cells, reducing and delaying disease onset in carriers. These associations illustrate HLA's broader role in balancing immune vigilance against self-tolerance and pathogen defense.

Methods of Tissue Typing

Serological Methods

Serological methods for tissue typing primarily rely on the (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 and leading to cell membrane damage and if the antigen-antibody match occurs. 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 testing. 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 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 . is assessed microscopically after staining with a vital dye like or trypan blue; dead cells take up the dye and appear bright against live cells, with reactions scored on a scale from 1 (no ) to 8 (complete ), where scores of 2 or higher indicate a positive reaction for that HLA specificity. 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 . Serological methods, particularly CDC, dominated HLA typing from the through the , serving as the standard for matching donors and recipients in organ and transplantation during this era. Introduced in the early , the microlymphocytotoxicity variant revolutionized the field by allowing high-throughput testing with small sample volumes, facilitating widespread adoption in clinical histocompatibility laboratories worldwide. 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. 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 conditions without genetic manipulation. 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. 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. among antisera also contributes to ambiguities, with error rates up to 25% reported for certain loci like HLA-B.

Molecular Methods

Molecular methods for tissue typing primarily involve DNA-based techniques to identify (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 (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 : 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). A foundational technique is PCR with sequence-specific probing (PCR-SSOP) or sequence-specific priming (PCR-SSP), both developed in the early for allele-level detection. In PCR-SSOP, target HLA exons are amplified via PCR, then hybridized to immobilized sequence-specific 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. PCR-SSP, conversely, uses allele-specific primers in multiplex PCR reactions, where amplification occurs only for matching alleles, visualized by ; it offers rapid, cost-effective typing at similar resolution but is best for smaller sample sets due to primer design limitations. Both techniques resolve ambiguities in heterozygous samples better than serological methods but may miss novel alleles not covered by predefined probes or primers. 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. 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. 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. 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. 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. 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.

Applications

Organ and Tissue Transplantation

In solid , 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-B, and , as mismatches at these sites are strongly associated with increased risk of acute rejection and reduced graft survival. Complement-dependent cytotoxicity or crossmatch tests are performed to detect pre-formed donor-specific antibodies in the recipient, which could trigger hyperacute rejection if present. 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. 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. Graft outcomes are markedly better with 0-2 , -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. Analysis of (UNOS) registry data from the early 1990s confirms that each additional HLA mismatch increases the 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. In tissue banking, HLA typing ensures compatibility for allografts such as corneas, , and , 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 ; for bone grafts, HLA matching is not routinely required, particularly for structural allografts, due to lack of proven benefit in incorporation.

Hematopoietic Stem Cell Transplantation

In (HSCT), tissue typing plays a pivotal role in selecting donors to prevent immune-mediated complications such as graft rejection and (GVHD). The process focuses on high-resolution (HLA) matching to ensure compatibility between donor and recipient, with the goal of replicating the natural 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 . 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. 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. 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. International registries like the (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. When fully matched unrelated donors are unavailable, haploidentical HSCT from half-matched family members (sharing ~5/10 HLA loci) combined with post-transplant (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. HLA-matched sibling donors yield superior outcomes, with 1-year overall often exceeding 80% for low-risk hematologic malignancies. In unrelated donor settings, 8/8 matches achieve approximately 50-60% 1-year , while single mismatches reduce it further due to elevated GVHD and risks. In haploidentical settings with PTCy, 1-year GVHD-free, -free approaches 50%, comparable to matched unrelated donors while expanding access for urgent cases.

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 combinations per locus, complicating precise assignment without supplementary testing. Additionally, phase problems in heterozygous loci arise due to difficulties in determining cis-trans configurations of polymorphisms on the same , often requiring family segregation studies or long-read sequencing to resolve. 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 antigens like those encoded by the (H-Y) or other polymorphic genes, further contribute to immune responses and rejection, as they elicit T-cell activation independent of HLA compatibility. 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 . 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. 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. 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.

Recent Developments

Since the 2010s, (TGS) technologies, particularly long-read platforms like PacBio SMRT sequencing, have revolutionized HLA 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 of HLA class I and II loci with over 99% accuracy in assignment across diverse samples, eliminating the need for imputation and improving transplant matching precision. Similarly, , another TGS method, has been applied to achieve rapid, portable HLA , with studies showing its utility in resolving novel alleles in immunogenetics research. Advancements in automation and have further streamlined HLA allele calling, reducing turnaround times and enhancing accuracy in high-throughput settings. 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. 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. Additionally, assays for specific alleles, such as a near point-of-care test for HLA-B57:01, provide economical in clinical specimens within minutes, expanding access in resource-limited environments. 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 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. This pharmacogenomic use exemplifies how high-resolution typing informs , preventing adverse events across diverse populations. Global efforts to maintain comprehensive HLA databases, such as the IPD-IMGT/HLA repository, have accelerated with quarterly updates incorporating thousands of new , reaching over 42,000 as of September 2025 to support worldwide . Initiatives addressing equity in diverse allele catalogs emphasize including underrepresented ancestries to mitigate biases in transplant matching and therapeutic development, with studies highlighting how variations by race affect eligibility for HLA-restricted immunotherapies. 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 and HLA-B, aiming to reduce rejection without , while hypoimmunogenic iPSCs generated via HLA gene editing demonstrate enhanced compatibility in preclinical models. These innovations could transform tissue typing by shifting focus from matching to engineered universality, though challenges in off-target effects remain.

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