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HLA Equivalency Tables Update 2020

Proposal Overview

Status: Board Approved

Sponsoring Committee: Histocompatibility

Strategic Goal: Improve waitlisted patient, living donor, and transplant recipient outcomes

Read the proposal (PDF; 01/2020)

View the Board Briefing Paper (PDF; 06/2020)

View the policy notice (PDF; 06/2020)

Contact: Betsy Gans

eye iconAt a glance

What is current policy and why change it?

Histocompatibility laboratories use commercially available kits to test transplant recipient and potential organ donor tissues for compatibility. This matching helps lower the risk that the recipient’s body will reject the transplant. The values used in this testing are included in tables in OPTN policy, so these values can be programmed into the OPTN computer system. As the science changes, the values used in the test kits need to be updated. This proposal updates the tables and adds an additional table with a new element that can further improve efficiency of tissue matching.   

What’s the proposal?

  • Updates to existing reference tables in OPTN Policy 4.10: Reference Tables of HLA Antigen Values and Split Equivalences.
  • Add new reference tables to be programmed into the OPTN computer systems, including the option for transplant hospital or histocompatibility labs to use an additional method that may make it easier to match candidate and donor tissue.
  • Set up future updates to these tables to go through an expedited policy process which allows these routine updates to be made quickly.

What’s the anticipated impact of this change?

  • What it’s expected to do
    • Update the existing reference tables to match the updated test kits.
    • Add an option to use a new element that can provide easier and more-efficient matching.
    • Shorten the length of time required to routinely update the reference tables.
  • What it won’t do
    • Change the Calculated Panel Reactive Antibodies (CPRA) calculation or frequency data used for the calculation.

Themes to consider

  •  Appropriateness of using expedited process for future updates.
  •  Addition of optional new element that increases efficiency and makes it easier to match tissues.

Terms you need to know

  • Calculated Panel Reactive Antibodies – Calculation that shows the percentage chance a recipient will not match with a donor’s tissue.  The higher the percentage the more “sensitized” a recipient is.
  • Human leukocyte antigen (HLA) complex – a group of genes that helps the immune system distinguish the body's own proteins from proteins made by foreign invaders such as viruses and bacteria.
  •  Click here to search the OPTN glossary.

Comments

Valia Bravo-Egana | 01/24/2020

This proposal is particularly important in current times when more and more labs have access to higher resolution HLA typing to assess matching between donors and recipients. With the advent of new technologies that provide a much deeper understanding of the HLA genes and proteins, it is very important that, the histocompatibility community has an efficient and quick way to include this information to be considered by the Programs when assessing matching and compatibility. I think this is long due and feel glad and thankful for this initiative.

Geof Land | 01/25/2020

These are welcome changes to listing patient and donor typings in UNOS, I support them.

Steven Geier | 01/27/2020

The proposed HLA Equivalency Tables Updates are very important to keep the tables up to date.

Marcelo FernandezVina | 01/27/2020

a) For DPB1 tables recommend using P groups that are accepted by the W.H.O. official nomenclature. The P groups include alleles with identical structure om the beta-1 domain. These are W.H.O. Nomenclature Committee and UNOS would not have to go through the approval process when new alleles are described. b) Why some DPB1* alleles are crossed and others are not? e.g. 104:01, 105:01, 124:01. 126:01 are not crossed while 350 and 351:01 are. These are equivalent to DPB1*03:01, 04:01, 04:02. The use of P equivalencies would make the application uniform. c) The DPB1 epitopes 55=57 EAE and AAE are equivalent and indistinguishable. It is worth focusing at residues 56-57 and just have the epitopes AE, EE and ED. This is a simpler way for listing DP avoids based on epitopes. d) It would be even more simple if DPB1 serotypes were reduced to DP1, 2, 3, and 4 as suggested by Cano P, Fernández-Viña M. (Two sequence dimorphisms of DPB1 define the immunodominant serologic epitopes of HLA-DP. Hum Immunol. 2009 Oct;70(10):836-43. doi: 10.1016/j.humimm.2009.07.011. Epub 2009 Jul 25. PubMed PMID: 19635517). The addition of DP10 would account for almost all DP serotypes. f) DPA1 is not taken into consideration although the DPA1 encoded epitopes are as immunogenic or more immunogenic than some DPB1 epitopes. g) B*48:02 has a close serotype corresponding to B71 (see HLA Dictionary; https://www.ebi.ac.uk/ipd/imgt/hla/). Listing as B48 is misleading since the allele lacks the most immundominat epitopes present in B48 (B*48:01 being the prototype).

Danny Youngs | 01/27/2020

Overall the changes are good, and the Epitope-based Unacceptable Antigen Assignment for DPB1 is very useful, but there is an omission: DPB1*99:01 is missing from both the 55AAE and 84GGPM sections of Table 4-15. It's unfortunate that the Additional Unacceptable Antigen Equivalences to be used in CPRA (Table 4-17) still exists. When will CPRA be based on actual DR51/52/53 results, and not on associated DRB1 typing?

Olga Charnaya | 01/29/2020

Highly support this change and looking forward to studying the effectiveness of DPB1 eplet based UA designation. As technology advances and more labs are moving to high-resolution HLA typing for solid organ transplant we should make every effort to utilize the new information being generated to optimize patient care and outcomes.

Idoia Gimferrer | 01/29/2020

DQB1*03:04 allele is missing from table 4-13. Although DQB1*03:04 is a DQ7 by WHO, it has epitope 55PPA shared with DQB1*03:02 (8).

Massimo Mangiola | 02/03/2020

I want to first extend my thank you to the Histocompatibility Committee members for working on this very much needed update and especially for their willingness to take the first steps needed to introduce the eplet concept into the UNOS system. I have few comments on the eplet component of this proposal. 1) Name. I would refer to these polymorphic residues as to EPLETS, not epitopes, since the epitope is a mostly unknown and much larger area which contains the eplet(s) but also includes several self-residues. Since you are planning on using an "eplet nomenclature" you should refer to these as eplets, not epitopes. 2) Nomenclature. I think we need to start this project by using current nomenclature. Although I can agree that the Epitope Registry (https://www.epregistry.com.br) has not been yet officially approved as the "current nomenclature", to date it is the only eplet database and, in the interim, is virtually the official HLA eplet nomenclature. Three (3) of the eplets in the residues area 55-57 are listed with a name that reflects the polymorphic residues, not the eplet: 55AAE = 55A 55DED = 57D 55DEE = 56EE The possible downside of NOT using the nomenclature as it appears in the Epitope Registry is that many users may not find the eplet in the UAs list. In fact, for the common 57D eplet, I would probably look for that, not 55DED. 3) Residues Used (two questions) I was wondering why you are limiting yourself to the polymorphic areas between AA55-AA57 and AA84-AA87? If you want to start with something, why not start with at least including the antibody-verified eplets? There are several known eplets on either side of these regions with some that have been verified by an antibody. I would recommend to add 35FV, 56A, 56E, 69E, 85GPM and 96K. I believe that, by adding at least all the 9 antibody-verified eplets, you will also have the opportunity to collect data on DP antibody patterns and their occurrence in the patient population.

OPTN Operations and Safety Committee | 02/14/2020

HLA Equivalency Table Update 2020 The Operations and Safety Committee (OSC) thanks the OPTN Histocompatibility Committee for their efforts in developing this public comment proposal for the HLA Equivalency Table Update. The Committee indicated the following sentiments for the proposal: 46% Strongly Support, 54% Support, 0% Neutral/Abstain, 0% Oppose, 0% Strongly Oppose

Region 4 | 02/20/2020

Strongly support (11), Support (9), Neutral/Abstain (2), Oppose (0), Strongly Oppose (0)

Region 8 | 02/20/2020

8 Strongly Support, 10 Support, 2 Neutral/Abstain, 0 Oppose, 0 Strongly Oppose

Region 6 | 02/21/2020

Strongly support (8), Support (9), Neutral/Abstain (0), Oppose (0), Strongly Oppose (0)

Region 5 | 02/21/2020

Strongly support (13), Support (8), Neutral/Abstain (1), Oppose (0), Strongly Oppose (0)

Region 2 | 02/28/2020

5 Strongly Support, 28 Support, 0 Neutral/Abstain, 0 Oppose, 0 Strongly Oppose

Region 1 | 03/10/2020

Strongly support (3), Support (5), Neutral/Abstain (0), Oppose (0), Strongly Oppose (0) No comments or questions

AMERICAN SOCIETY FOR HISTOCOMPATIBILITY AND IMMUNOGENETICS | 03/13/2020

ASHI values the opportunity to comment on the proposed updates and changes to the HLA Equivalency Tables (2020). ASHI supports the indicated updates to Tables 4-2 through 4-15. The proposed updates are necessary and appropriate based on evolution of HLA testing systems and recognized HLA alleles. ASHI also supports adoption of equivalency table updates via the Expedited Actions pathway. We are in agreement that these updates are typically non-controversial and a shorter approval process, with diversion to the standard review process for stated concerns via public comment, is attractive. ASHI also supports the formatting changes to Table 4-14 with the additional new table listing DPB1 alleles in a compact format. Regarding the use of DPB1 epitopes in unacceptable antigen assignment, ASHI is supportive. We believe that epitope-based UA assignment will be used by some centers, likely increasing over time as our laboratories educate clinical staff on this topic. We urge the Histocompatibility committee to carefully assess the impact of this optional unacceptable antigen assignment approach. While epitope analysis is well known in the HLA community, its clinical implementation is new and requires careful assessment of frequency of use and impact on crossmatch outcomes.

Malek Kamoun | 03/13/2020

Many thanks to the Histocompatibility Committee members for all the hard work; these proposed HLA Equivalency Tables Updates are very important. Below are a few comments regarding the content of these Tables. 1. HLA-DPB1: It appears that the list of Eplets is not comprehensive, in addition, many HLA-DB1* alleles that are listed in these Tables are not currently available in UNET. 2. HLA-DPA1* alleles should be included since several epitopes are as immunogenic as DPB1 epitopes. 3. There is no point of listing DQ3 any more 4. HLA-DRB3, 4, 5 alleles were previously listed in these Unacceptable Antigen Equivalences Tables to be used in the CPRA. Why are they not listed anymore? 5. HLA class I serotypes: It is very important to ensure that serologic equivalent of HLA alleles is carefully evaluated; for example B*48:02 has a close serotype corresponding to B71. Listing B*48:02 as B48 is not rigorous and could lead to problems since the allele lacks the most immmunodominant epitopes present in B48 (B*48:01). 6. Although the Histocompatibility Committee should be applauded for revising these Tables, the Committee should keep in mind the impact that these changes would have on the HLA lab in updating patients’ HLA unacceptable antigen in UNET which would involve a database utility interface change

Deborah Crowe | 03/13/2020

Overall, I agree with the updates to the equivalency tables. However, I fear there may still be confusion with the proper way to group the DPs. Some prefer P goups, or the serologic DP1,2,3,4 groups which focus on the immunodominant epitopes (Cano and Fernandiz-Vina Hum Immunol. 2009 Oct;70(10):836-43). Eplets are not Epitopes and this adds further confusion (see Massimo's comments). UNOS cannot force the use of one vendor's product to set a common nomenclature. I totally agree that a simpler nomenclature for DP is needed that correlates with serologic activity. We may need better consensus on the correct approach.

Loren Gragert | 03/17/2020

The committee should identify the source of the HLA frequencies used to truncate the list to common DPB1 alleles. Perhaps the common, intermediate, and well documented (CIWD) 3.0 allele list could serve as a citable source for a shortened DPB1 allele list. I agree with Marcelo Fernandez-Vina on the asymmetry in what should be P-group level antigen equivalency tables for DPB1. In Table 4-14 of the OPTN policies, a UA for DPB1*04:02 excludes donors with DPB1 antigens of 04:02, 105:01, 463:01, 571:01, 647:01, etc. But a UA of DPB1*105:01 only blocks a DPB1*105:01 donor, but the DPB1*105:01 gene encodes for the same protein as DPB1*04:02. That doesn’t seem to be consistent. Generation of the unacceptable antigen equivalency tables should scripted out based the IPD-IMGT/HLA sequence data files from here onward. It is impractical to curate these by hand. I support this experiment. The committee should develop clear guidance on when to select amino-acid-based DPB1 categories versus two-field allele categories. Depending on the amino acid motif, there will be different levels of interference for reactivity patterns. Some amino acid motifs will be present on fewer single antigen beads than other motifs. For example, the proposed 55EAE motif is only present on two beads in one of the more commonly used panels. I assume lab directors would also want to rule out putative epitopes found in other DPB1 hypervariable regions that cannot yet be selected? There should also be an effort to standardize the nomenclature for these amino acid motifs.

American Nephrology Nurses Association (ANNA) | 03/18/2020

ANNA supports this proposal.

Rene Duquesnoy | 03/19/2020

The proposed update of the HLA Equivalency Tables includes an option of using epitopes for assigning unacceptable antigens for DPB1. A table lists more than 1000 DPB1 alleles that can be considered unacceptable from recipient antibody reactivity patterns associated with certain DPB1 epitopes analogous to the seven antibody-verified eplets recorded in the International HLA Epitope Registry. Other antibody-verified DPB1 eplets are not included but this is nevertheless a good start about determining mismatch acceptability based on epitopes. Epitope-based assignments of unacceptable antigens was already considered in the 2016 review of the HLA equivalency tables but this new method was not pursued at that time. Now four years later, why has the epitope approach been applied only to DPB1? Many publications describe the beneficial effect of HLA eplet-based matching including the assessment of ABC, DR and DQ mismatch acceptability and other transplant programs worldwide have applied this concept. Why has the UNOS Histocompatibility Committee not expanded epitope-based matching to the other HLA loci? Instead, there continues to be an emphasis on HLA equivalency tables which are considered as “the expedited activation pathway in the future”. In the early days, HLA typing was done by serology but then the more accurate DNA testing methods revealed many allelic differences within the same antigen groups. During that transition time, it seemed useful to determine which alleles were equivalent to a given serologically defined antigen. But now with so many new alleles with amino acid sequence differences, how can their equivalents be determined, if any? What criteria are used to reach a decision? Perhaps, the equivalency dogma should be abandoned altogether. The widely used serum testing with SAB panels has offered new opportunities to identify antibody-specific HLA epitopes. Many highly reactive sera have specific antibodies that react with groups of alleles sharing the one or a few eplets. Often enough in class I and class II testing, two or more alleles corresponding to the same antigen react differently with patient’s antibodies because they have different eplet profiles and amino acid sequences. The identification of antibody-recognized eplets is a more precise method of determining mismatch acceptability of potential donors and can also include other alleles not available for testing. It should be used for all HLA loci important in transplantation. Rene Duquesnoy, University of Pittsburgh Medical Center

Region 11 | 03/19/2020

Strongly support (3), Support (12), Neutral/Abstain (2), Oppose (0), Strongly Oppose (0)

OPTN Region 3 | 03/22/2020

Vote: 6 strongly support, 12 support, 2 neutral/abstain, 0 oppose, 0 strongly oppose

OPTN Kidney Transplantation Committee | 03/23/2020

5 members Strongly Support. 4 members Support. The OPTN Kidney Transplantation Committee reviewed this proposal at their February 24th meeting. The committee strongly supports this proposal.

American Society of Transplant Surgeons | 03/23/2020

The American Society of Transplant Surgeons (ASTS) supports the OPTN policy proposal to expedite updates to HLA Equivalency Tables and to adopt the new DPB epitope strategy to optimize matching. This strategy will make assigning DPB alleles more efficient and more accurate. We believe these changes will promote patient safety and improve the overall system.

American Society of Transplantation | 03/23/2020

The American Society of transplantation supports this proposal as written without further comment.

OPTN Region 9 | 03/24/2020

Strongly support (1), Support (11), Neutral/Abstain (0), Oppose (0), Strongly Oppose (0)

Region 10 | 03/24/2020

5 Strongly Support, 7 Support, 2 Neutral/Abstain, 0 Oppose, 0 Strongly Oppose

Robert Goodman | 03/24/2020

I've read through the proposal and been on several conference calls discussing this proposal and support its approval.

Region 7 | 03/24/2020

6 Strongly Support, 6 Support, 3 Neutral/Abstain, 0 Oppose, 0 Strongly Oppose