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Clinical Relevance of HLA Epitope Antigenicity and Immunogenicity

Clinical Relevance of HLA Epitope Antigenicity and Immunogenicity. Rene Duquesnoy University of Pittsburgh Medical Center. 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?

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Clinical Relevance of HLA Epitope Antigenicity and Immunogenicity

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  1. Clinical Relevance of HLA Epitope Antigenicity and Immunogenicity Rene Duquesnoy University of Pittsburgh Medical Center

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

  4. HLA Mismatch Immunogenicity • Mismatched HLA antigens have different epitope “loads” • HLA epitopes have different degrees of immunogenicity A better understanding of HLA immunogenicity will permit a permissible mismatch strategy for non-sensitized transplant patients

  5. KIDNEY ALLOGRAFT SURVIVAL AND HLA CLASS I MATCHING AT THE AMINO ACID TRIPLET LEVEL Duquesnoy, RJ , Takemoto S, de Lange P, Doxiadis IIN, Schreuder GMT , Persijn, G and Claas FJH: Transplantation 75:884-889, 2003

  6. Effect of HLA-A,B Triplet Mismatching on Graft Survival of Zero-HLA-DR Mismatched Kidneys in Eurotransplant Low epitope “load”

  7. HLAMatchmaker Predicts Antibody Formation to HLA Mismatches

  8. Volume 77(8)             27 April 2004             pp 1236-1239 THE NUMBER OF AMINO ACID TRIPLET DIFFERENCES BETWEEN PATIENT AND DONOR IS PREDICTIVE FOR THE ANTIBODY REACTIVITY AGAINST MISMATCHED HUMAN LEUKOCYTE ANTIGENS Dankers, Marlies K. A; Witvliet, Marian D; Roelen, Dave L; De Lange, Peter; Korfage, Nelleke; Persijn, Guido G.; Duquesnoy, René; Doxiadis, Ilias I. N; Claas, Frans H. J. Department of Immunohematology and Blood Transfusion, Leiden University Medical Center

  9. Volume 77(8)             27 April 2004             pp 1236-1239 THE NUMBER OF AMINO ACID TRIPLET DIFFERENCES BETWEEN PATIENT AND DONOR IS PREDICTIVE FOR THE ANTIBODY REACTIVITY AGAINST MISMATCHED HUMAN LEUKOCYTE ANTIGENS Dankers, Marlies K. A; Witvliet, Marian D; Roelen, Dave L; De Lange, Peter; Korfage, Nelleke; Persijn, Guido G.; Duquesnoy, René; Doxiadis, Ilias I. N; Claas, Frans H. J. Department of Immunohematology and Blood Transfusion, Leiden University Medical Center

  10. Class II Epitope Load and Immunogenicity Duquesnoy et al “Retransplant Candidates Have Donor-Specific Antibodies that React with Structurally Defined HLA-DR,DQ,DP Epitopes”. Transplant immunology, 18:352-360, 2008

  11. Anti-DRB1 and Anti-DRB3/4/5 Antibodies after Kidney Transplantation *p< 0.01

  12. Anti-DQ and anti-DRB1 Antibodies after Kidney Transplantation *p< 0.01

  13. The Epitope “Load” Determines the Immunogenicity of a Mismatched HLA Antigen

  14. How Important is DRB1 Matching in Kidney Transplantation?

  15. HLA Class II Matching • DRB1 is “standard” • DRB3/4/5 • Antibodies to DR51, DR52 and DR53 • DQB1 and DQA1 • Relevance of DQB matching in transplantation • Patients make antibodies to DQB and DQA epitopes • DPA1 and DPB1 • Relevance of DP matching • Anti-DP antibodies in transplantation

  16. A DR Antigen Mismatch Represents an Extra Epitope Load DRB1+ DRB3/4/5+ DQB+DQA+DPB+DPA

  17. Conventional Matching for a DR7,DR18 Patient Which is the “best” mismatch?

  18. Allele Based Compatibility for DR7,DR18 Patient All are common DR-DQ haplotypes

  19. Epitope-Based Compatibility for DR7,DR18 Patient All are common DR-DQ haplotypes Are DR8, DR9 and DR17 more “desirable” mismatches?

  20. Epitope-based HLA Class II Compatibility • Epitope compatibility information requires high-resolution DRB, DQ and DP types • It is possible to identify DR mismatches with relatively low epitope loads • Such mismatches may reduce anti-class II antibody responses and perhaps benefit transplant outcome ?

  21. HLA Mismatch Immunogenicity • Mismatched HLA antigens have different epitope loads • HLA epitopes have different degrees of immunogenicity

  22. Frequencies of antibodies to donor DQB eplet mismatches Duquesnoy et al Transplant immunology, 18:352-360, 2008

  23. Frequencies of antibodies to donor DQA eplet mismatches Duquesnoy et al Transplant immunology, 18:352-360, 2008

  24. Dominant Eplets Reacting with anti-HLA-DP Antibodies * 55DE is similar to the 57DE eplet on DR11 All 55DE-reactive sera reacted also with DR11 Duquesnoy et al Transplant immunology, 18:352-360, 2008

  25. The Antibody Response to an HLA Mismatch is Restricted to a Limited Number of Epitopes

  26. SERUM ANALYSIS AFTER TRANSPLANT NEPHRECTOMY REVEALS RESTRICTED ANTIBODY SPECIFICITY PATTERNS AGAINST STRUCTURALLY DEFINED HLA CLASS I MISMATCHES Adeyi et al. Transplant Immunology, 14: 53-62, 2005

  27. Thirty Patients With Rejected Kidney Transplants Underwent Allograft Nephrectomy 100% 80% PRA 60% 40% 20% 0% Before Tx Pre-AlloNx. Post-AlloNx Adeyi et al. Transplant Immunology, 14: 53-62, 2005

  28. Donor Epitopes:   A3: 62Qe,66rNv,70aQs,76Vd,80gTl,144tKr,149aAh,151aHe,163dT A31: 56R,62Qe,66rNv,74iD,76Vd,80gTl,193Av   B55: 131S   B63: 45Ma,66rNm,70aSa,74Y,131S Adeyi et al. Transplant Immunology, 14: 53-62, 2005

  29. Donor Epitopes (serum-reactive epitopes are shown in underlined bold font) A3: 62Qe,66rNv,70aQs,76Vd,80gTl,144tKr,149aAh,151aHe,163dT A31: 56R,62Qe,66rNv,74iD,76Vd,80gTl,193Av B55: 131S B63: 45Ma,66rNm,70aSa,74Y,131S Adeyi et al. Transplant Immunology, 14: 53-62, 2005

  30. Donor Epitopes (serum-reactive epitopes are shown in underlined bold font) A3: 62Qe,66rNv,70aQs,76Vd,80gTl,144tKr,149aAh,151aHe,163dT A31: 56R,62Qe,66rNv,74iD,76Vd,80gTl,193Av B55: 131S B63: 45Ma,66rNm,70aSa,74Y,131S Unacceptable epitopes identify unacceptable antigens e.g. 45Ma is present on B13, B46, B57,B62, B63. B75, B76, B76 Adeyi et al. Transplant Immunology, 14: 53-62, 2005

  31. Donor Epitopes: B13: 41T,45Ma,76En,80rTa,82aLr,144tQl,163E 82aLr is expressed by all Bw4-associated HLA-B antigens +A23, A24, A25 and A32 144tQl is unique for HLA-B13 After six months: the anti-76En and anti-82aLr antibodies have disappeared, Only anti-144tQl antibodies are detected Adeyi et al. Transplant Immunology, 14: 53-62, 2005

  32. Relative Immunogenicity of Eplets How often do mismatched eplets induce specific antibodies? 14th International HLA Workshop Project Analysis of donor-specific antibodies in patients whose rejected kidney transplants had been removed

  33. Preliminary Results: Eplet Immunogenicity in 62 Cases Duquesnoy, RJ and Claas FHJ: Progress Report of 14th International Histocompatibility Workshop Project on the Structural Basis of HLA Compatibility, Tissue Antigens, 69 (Suppl. 1): 1-5, 2007

  34. 15th International Workshop Project on Epitope Immunogenicity • Analyze post-allograft nephrectomy sera for antibodies against donor class I and class II epitopes • Serum screening with single alleles (Luminex) and by CDC • So far, 40 laboratories worldwide will contribute informative cases • For more information go to http://www.15ihiws.org/project.php?n=13 To participate please contact Frans Claas or Rene Duquesnoy

  35. HLA Mismatch Immunogenicity • Mismatched HLA antigens have different epitope loads • HLA epitopes have different degrees of immunogenicity A better understanding of HLA immunogenicity will permit a permissible mismatch strategy for non-sensitized transplant patients

  36. New Website http://www.HLAMatchmaker.net • Introductory articles and tutorials • HLAMatchmaker related publications • From UPMC • From other institutions • Free downloads of all programs • Class I and class II matching • Antibody analysis • Other programs • Contacts and communications

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