HLA in research: Recent trends and innovations

The Human Leukocyte Antigen (HLA) system is a set of genes that play important roles in health and disease, serving as a flag for ‘self’ and ‘non-self’ cells. As such, HLA molecules have implications in several biomedical research areas, from immunology to transplantation and precision medicine. In this article, we explore what HLA typing is, why it matters, and how HLA research is shaping our understanding of autoimmune diseases, infectious diseases, stem cell transplantation, and cancer.

The Human Leukocyte Antigen (HLA) system, also known as the major histocompatibility complex (MHC), is one of the most complex and variable regions of the human genome.¹ The system encodes cell surface proteins that are essential for immune system regulation and antigen presentation. The HLA molecules are divided into class I (HLA-A, HLA-B, HLA-C) and class II (HLA-DR, HLA-DQ, HLA-DP).² 

These molecules help the immune system distinguish between the body’s own cells and tissues (‘self’) and foreign substances such as pathogens and transplanted cells (‘non-self’), playing a pivotal role in immune response, disease susceptibility, and transplantation outcomes.^1,2

HLA typing is the process of identifying the specific HLA genes and alleles present in an individual. This information is critical for^3–5:

• Matching organ and stem cell donors with recipients
• Understanding genetic predisposition to diseases
• Developing and testing immunotherapies
• Advancing research on HLA and its role in disease mechanisms

The HLA gene family is extremely diverse, with over 28,000 class I and more than 12,000 class II alleles identified in the human genome.⁶ This diversity makes HLA in research both fascinating and challenging.

HLA research has transformed our understanding of how immune cells interact with other cells in our body and how the immune system prevents diseases.

Research has revealed strong associations between specific HLA alleles and autoimmune diseases. Several HLA alleles have been found to predispose individuals to various autoimmune conditions:

These associations help researchers understand the mechanisms of immune system dysregulation and guide the development of diagnostic biomarkers and targeted therapies.11 HLA typing is now routinely used in the diagnostic workup for certain autoimmune conditions.

Research has shown that HLA molecules play a central role in how the body responds to infections. Certain HLA alleles can increase or decrease susceptibility to viral infections such as HIV, hepatitis B and C, and SARS-CoV-2.^12,13

• HLA class I molecules present viral peptides to CD8+ T cells, driving cytotoxic responses.¹²
• HLA class II molecules activate CD4+ T cells, supporting antibody production and memory responses.¹²

Understanding these interactions enables the prediction of disease outcomes and the design of effective vaccines and therapies.

HLA research is vital for successful hematopoietic stem cell transplantation (HSCT). HLA matching between donor and recipient reduces the risk of graft rejection, graft-versus-host disease (GVHD), and other complications.¹⁴ 

Advances in HLA typing have improved donor selection, making transplantations safer and more effective. The number and type of mismatches affect transplant outcomes, and research on permissible mismatches and immune modulation is expanding donor options.¹⁴ Therefore, HLA-typed cells are essential for preclinical testing and cross-reactivity studies before transplantation.

HLA research is driving breakthroughs in cancer immunotherapy. Tumor-reactive T cells recognize cancer cells through HLA molecules, and the effectiveness of therapies like adoptive cell transfer depends on the  compatibility.^15,16 HLA typing helps identify patients likely to respond to immunotherapies, and HLA-typed cells are used to test new cancer treatments and minimize off-target effects.17,18 In addition, certain alleles serve as biomarkers for predicting cancer treatment outcomes.^17,19,20

The landscape of translational research is advancing rapidly, with several new developments in technology and methodology for developing personalized treatment and HLA-guided therapy. Human primary cells with known HLA types provide a physiologically relevant platform for drug testing and immunological studies. This offers an enhanced translational potential compared to animal models .²¹ These pre-typed cell models have become invaluable tools in various research applications.

Research has revealed strong associations between specific HLA alleles and autoimmune diseases. Several HLA alleles have been found to predispose individuals to various autoimmune conditions:

• Precision medicine: HLA typing enables the development of therapies tailored to an individual’s genetic makeup, improving efficacy and reducing side effects of treatments.^5,22 
• Immunogenetics: Identifying genetic predisposition to diseases guides the design of targeted interventions.⁴
• HLA-guided therapy: Therapies such as adoptive T cell transfer, checkpoint inhibitors, and peptide vaccines are increasingly designed based on HLA genotype.^23,24

The diversity and complexity of the HLA system create several challenges. The system is extremely polymorphic, with thousands of HLA alleles.⁶ In addition, HLA molecules vary in peptide-binding properties, affecting immune responses.⁴ 
This genetic complexity and structural diversity complicate typing and matching. Accurate and high-throughput HLA typing requires advanced technology and expertise, which can be costly.²⁵ Moreover, traditional cell models often lack the diversity and specificity needed to study HLA-driven responses.²⁶

• Human relevance: Pre-typed primary cells mimic the human immune environment, enabling more translational research.
• Diversity: Large inventories of HLA-typed cells allow for the study of rare alleles and population-specific responses.
• Efficiency: Pre-typed cells save time and resources, accelerating research and development.

There are several emerging trends and methodologies in HLA research, with HLA-typed cells becoming increasingly vital tools for researchers.

• Immunotherapies: They enable precise testing of T cell-based therapies and immune checkpoint inhibitors, allowing researchers to predict responses across diverse patient populations.^23,27
• Transplantation: These cells facilitate in vitro compatibility testing, helping refine matching protocols and develop strategies to overcome HLA mismatch.²⁸
• Vaccine development: Using HLA-typed cells allows for the identification and validation of epitopes that can trigger immune responses across multiple HLA types, leading to more universally effective vaccines.²⁷
• Drug screening and toxicity testing: They provide a more accurate prediction of immune-related adverse events and drug hypersensitivity reactions than traditional models.²⁹

• Integration of HLA-typed cells: Standardized protocols are being developed to ensure reproducibility and reliability in translational research.^30,31
• Collaborative databases: Sharing data through initiatives such as the IPD-IMGT/HLA Database⁶ accelerates discovery and application across the biomedical community.

We are committed to empowering you with the tools and expertise you need to advance your research. Here’s how we can help you:

• High-quality HLA-typed cells: Choose from a broad range of HLA-typed human primary cells and PBMCs from over 100 donors, with complete 4-digit resolution typing for HLA-A, HLA-B, HLA-C, HLA-DPA1/DPB1, HLA-DQA1/DQB1, and HLA-DRB1/DRB345.
• Customized cell culture media: Our specialized media robust cell growth and function, ensuring reliable results.
• Expert scientific support: Our cell culture specialists are ready to assist you with protocol optimization, troubleshooting, and custom solutions for your research.

References

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