HLA Matching at the Epitope Level: the Way to Go

1. HLA Matching at the Epitope Level: the Way to Go Rene J. Duquesnoy, PhD Professor Emeritus of PathologyUniversity of Pittsburgh Medical Center

2. Terasaki’s Impact • 1990ies: HLA antibodies recognize epitopes that can be defined by amino acid residues • Importance of HLA matching at the epitope level • Permissible mismatching improves long-term graft survival • 2003: His “Humoral Theory of Transplantation” which led to extensive studies demonstrating that HLA antibodies cause allograft rejection and organ transplant failure

3. HLA Antibodies Are Important in Transplantation • HLA antibodies cause allograft rejection and transplant failure • HLA antibodies recognize epitopes Therefore HLA epitopes are important in transplantation

4. HLA Epitopes are Defined by Polymorphic Amino Acid Residues HLA-A2 1 1 1 1 HLA-DQ HLA-DR 2 2 2 2

5. HLAMatchmaker is a Structurally Based Epitope Algorithmwww.HLAMatchmaker.net • HLA epitopes are defined by polymorphic amino acid configurations (“eplets” or previously “triplets” in alloantibody-accessible sites (i.e. a-helices and b-turns) on the HLA molecular surface • The HLA-A,B,C type of the patient represents six strings of self-eplets that cannot induce specific alloantibodies • Each donor HLA antigen represents a string of eplets • Compatibility is assessed by lining up donor eplet strings with patient eplet strings to determine differences between donor and patient The International HLA Epitope Registry is on http://epregistry.ufpi.br

6. Clinical Applications of HLA Epitopes • Epitope antigenicity: reactivity with antibody in different assays and in vivo • Epitope-based acceptable mismatching for sensitized patients (Eurotransplant) • Epitope immunogenicity: ability to induce specific antibodies • Effects of epitope loads of antigen mismatches on HLA antibody responses and transplant outcome

7. The Epitope Load of a HLA Mismatch Depends on HLA Type of RecipientExample: a single B51 mismatch

8. Epitope Loads and HLA Antibody Development

9. Each DR Antigen Mismatch Has an Extra Class II Epitope Load DRB1+ DRB3/4/5+ DQB+DQA+DPB+DPA

10. HLA-DR Conclusion: DR and DQ epitope mismatching outperforms traditional low-resolution antigen mismatching and high-resolution allele mismatching as a predictor of de novo Class II DSA development thereby improving long-term graft outcome

11. Clinical Relevance of HLA Epitope-Based Matching for Transplantation • Epitope antigenicity • Analyses of epitope specificities of antibodies enhance the determination of HLA mismatch acceptability for sensitized transplant candidates • Epitope loads of HLA antigen mismatches • Clinically useful in the post-transplant management of patients at risk for antibody-mediated rejection • May lead to permissible mismatch strategies for non-sensitized patients to reduce humoral rejection and increase transplant success • Avoid highly immunogenic epitopes

12. Paul: thank youfor including me in your FestschriftMy best wishes for you and your family