Over 99% of our genes are the same – HLA type is a crucial part of the difference
Figure 1. typeHLA sample report: clearly presented, easy to interpret
Many clinical studies fail their primary endpoints because they do not reach statistical significance on their core hypothesis. Studies usually cover individuals with a broad distribution of HLA types. However, when a study is stratified based on detailed HLA typing data, previously unseen statistically significant trends can become visible. This can change failure of a study overall into success in a sub-group, helping you to protect your investment.
Equally adverse events, such as drug immunogenicity, may be HLA linked. Where such events become a problem for your study overall, it’s good to know HLA associations where they do exist, giving you better choices for progressing your work.
(whole Class I panel reported)
(can be ordered individually)
(whole Class II panel reported)
Fully resolved 4 digit (allelic level) typing with no degeneracy in most cases
4 digit (allelic level) typing but with some degeneracy
Can be ordered for each locus individually, and in combination with multi-locus typing
Link J et al.* (2014) “Human Leukocyte Antigen Genes and Interferon Beta Preparations Influence Risk of Developing Neutralizing Anti-Drug Antibodies in Multiple Sclerosis”
*Department of Clinical Neuroscience / Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
PLoS ONE 9(3): e90479. doi:10.1371/journal.pone.0090479
Figure 3. Absolute risk for development of neutralizing anti-drug antibodies (NAbs) and biologically relevant titers.
Calculation of the absolute risk was used to estimate how DRB1*04 and DRB1*15 carriage impacts the risk for the outcomes of NAb positivity (bars on grey floor) and biologically relevant titers (bars on white floor) when adjusted for the baseline risk. Baseline risk was the frequency of development of NAb (dark grey bars, grey floor) and biologically relevant titers (dark grey bars, white floor) for each IFNb preparation in the Swedish NAb registry. Compared to the baseline risks, DRB1*15 carriage increased the absolute risk for both outcomes in s.c. IFNb-1a treated patients (grey bars) and to a lesser extent in patients receiving i.m. IFNb-1a (light grey bars), whereas DRB1*15 carriage lowered the risk for both outcomes in patients receiving IFNb-1b (white bars). In DRB1*04 carriers the reversed relationship was observed, with an increased absolute risk for both outcomes in IFNb-1b treated patients. Moreover, the absolute risk for NAb positivity and biologically relevant titers was constantly lower for i.m. IFNb-1a than for the two s.c. IFNb preparations, regardless of whether patients were positive or negative for DRB1*04 and DRB1*15.
Allelic-level Third Generation Sequencing (TGS) typing of full-length HLA genes ensures 4-digit typing is obtained, with no requirement for additional testing to resolve ambiguities. Where prior art PCR-based typing may return a type of: HLA-A*23:01/03/05/06, TGS would determine the exact allele present – e.g. HLA-A*23:01.
TGS HLA typing allows you to determine HLA types precisely, quickly, and in a single analysis, saving time and money, and removing doubt from HLA analysis.
Typing is carried out using a range of techniques, selected based on the individual sample and loci being typed. Major allele groups are resolved to 4 digits, with some degeneracy in allele resolution, e.g. HLA-A*23:01/03/05/06.
In PCR-SSO the genomic DNA is amplified using PCR, then incubated with a panel of different oligonucleotide probes, which have distinctive reactivities with different HLA-types. PCR-SSP uses specific primers designed such that a PCR product is either generated or not generated, based on specific polymorphisms in the HLA gene. SBT (Sequence-based typing) uses dye terminator sequencing of key regions of the HLA genes.
We accept genomic DNA, saliva samples, fresh or frozen whole blood or frozen cells, and will provide you with details of how to ship each of these to us. There is an order handling charge for samples sent as saliva, whole blood or frozen cells due to the additional processing needed for these sample types.
We offer a worldwide service, available for one sample or hundreds – our high throughput service enables us to process tens to hundreds of samples at a time. You can confidently send your samples from any location worldwide using our experience in shipping globally.
We have the following requirements for samples:
Note that samples provided as whole blood/PBMC/saliva are subject to an Order Handling Fee for each shipment. Samples supplied as gDNA are not subject to the Order Handling Fee.
Dr. Jennifer Kirchherr at the Duke Human Vaccine Institute in North Carolina, USA
“We looked at a range of companies offering tissue typing, and also at using an on-campus typing facility, and we found that ProImmune were able to offer us the best pricing and turnaround time.”
Dr. Navapon Techakriengkrai at Chulalongkorn University, Thailand
“I outsource my tissue typing to ProImmune because they provide me with the fastest service at the best price. Since the main theme of my research is on T cell immunology, HLA-type is inevitably needed. The customer service from ProImmune is of the best quality.”
An individual’s immune response to a foreign agent, such as a vaccine, drug or allergen, can be strongly influenced by their HLA tissue type. In addition there are numerous examples of diseases with known HLA association – for instance, Type 1 Diabetes is associated with HLA-DRB1*04:01, Multiple Sclerosis with HLA-DRB1*15:01 and protection from HIV infection with B*57:01 and B*35:01. It seems absurd, but HLA type is ignored in most clinical trials where the presence of a novel therapeutic is known to influence the immune response.
One of the most relevant examples is recombinant factor VIII, used to treat suffers of hemophilia. There is clear bias towards an anti-drug response in a subset of recipients with common HLA alleles. Efforts are underway to understand this bias fully, and to develop variants of Factor VIII that will be less immunogenic for these individuals.
Autoimmune diseases including Rheumatoid Arthritis (RA) show a strong association with HLA DRB1*01:01 and HLA-DRB1*04:01. A therapeutic target in RA is CD20, and the anti-CD20 antibody Rituxan® (Rituximab), (a chimeric mouse/human monoclonal antibody developed by IDEC Pharmaceuticals) is used in RA treatment. However, Rituxan® contains DR1 and DR4 restricted T cell epitopes, which in the RA population contribute to a high rate of reported immunogenicity.
These examples illustrate the case for understanding your patient population in terms of HLA type, and thus knowing at an early stage how your biologic may perform in different populations. Even if your clinical trial doesn’t result in your therapy going forward, you can maximize the amount of information you gain from the trial by having HLA typing data available.