Structurally Based HLA Matching: Are We Ready for Its Application in the Clinical Setting?

1. EFI Satellite Session, Wednesday April 2, 2008 Structurally Based HLA Matching: Are We Ready for Its Application in the Clinical Setting?

2. Matching: The Traditional Way • Count the number of A, B, DR antigen mismatches • Why do so many zero-antigen mismatches fail? • Why are many mismatches successful? • Determine unacceptable mismatches for highly sensitized patients • Why do see so many graft failures? • Why are many patients never transplanted? • Crossreactive antigen matching for platelet transfusions of refractory thrombocytopenic patients • Why are so many such transfusions unsuccessful? • Why do some non-crossreactive mismatches work so well?

3. New Developments in HLA • Complete typing for all HLA loci • Better methods for HLA antibody identification • HLA structure and polymorphisms • HLA and transplant immunity

4. HLA Effect on Transplantation • Humoral Immunity • Complement-dependent antibodies • Complement-independent antibodies • Cellular Immunity • Direct Allorecognition • Cytotoxic CD8 T-cells • Effector CD4 T-cells • Regulatory T-cells • Indirect Allorecognition • Effector CD4 T-cells • NK cells (KIR) • HLA-restricted Immune Responses • Anti-viral immunity • Cytotoxic CD8 T-cells • Recurrent autoimmune disease • Effector CD4 T-cells • Graft-versus-Host Reactivity • Mediated by donor T-cells • Transfusion associated lung injury (TRALI)

5. Antibody Responses to HLA • Class I HLA antigens • HLA-A and HLA-B • HLA-C • MICA • Class II HLA antigens • DRB1 • DRB3, 4, 5 • DQB and DQA • DPB and DPA

6. HLA Antibodies React With Epitopes Which Can Now Be Defined Structurally

7. Amino Acid Polymorphisms On The Molecular Surface Are Responsible for Epitopes That Induce Specific Alloantibodies How can we visualize the polymorphic residues?

8. Polymorphic Residues on Class I Antigens HLA-A2 HLA-B27 HLA-Cw3

9. Topography of Polymorphic Residues on HLA-DR and HLA-DQ Molecules HLA-DQ HLA-DR 1 1 1 1 2 2 2 2

10. The HLA type of the antibody producerdetermines what structural components of an immunizing HLA antigen can be “seen” as non-self Structural Matching Concept

11. Structural Basis of a HLA-B51 Mismatch Polymorphic Residues on B51

12. Structural Basis of a HLA-B51 Mismatch “Seen” by A2,A68; B27,B44 Polymorphic Residues on B51

13. Structural Basis of a HLA-B51 Mismatch “Seen” by A2,A68; B27,B44 “Seen” by A2,A68; B35,B44 Polymorphic Residues on B51

14. Structural Basis of a HLA-B51 Mismatch “Seen” by A2,A68; B27,B44 “Seen” by A2,A68; B35,B44 “Seen” by A2,A24; B7,B8 Polymorphic Residues on B51

15. Important Consideration Differentiate between Antigenicity of epitopes (reactivity with antibodies) and Immunogenicityof epitopes (induction of specific antibodies)

16. EFI Satellite Session Program • Rene Duquesnoy (Pittsburgh, Pennsylvania) “Introduction” (5 min) • Frans Claas (Leiden, The Netherlands) "Structural epitopes and acceptable mismatching for highly sensitized patients" (25 min) • Ivan Balasz (Stamford, Connecticut) "Epitope specificities of antibodies reactive with single HLA alleles in Luminex assays" (15 min) • Reyna Goodman (Cambridge, United Kingdom) "Predicting the immunogenicity of HLA class I alloantigens using structural epitope analysis determined by HLAMatchmaker” (15 min) • Rene Duquesnoy (Pittsburgh, Pennsylvania) "Clinical relevance of HLA epitope immunogenicity and antigenicity" (25 min) • Case presentations and discussion (35 min)