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Festschrift 2014, Los Angeles Nori Sasaki, MS Retired Santa Monica / Tokyo

HLA Epitopes are not Ready for Matching Transplants. Festschrift 2014, Los Angeles Nori Sasaki, MS Retired Santa Monica / Tokyo. Amino Acid Mismatch and Graft Survival.

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Festschrift 2014, Los Angeles Nori Sasaki, MS Retired Santa Monica / Tokyo

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  1. HLA Epitopes are not Ready for Matching Transplants Festschrift 2014, Los Angeles Nori Sasaki, MS Retired Santa Monica / Tokyo

  2. Amino Acid Mismatch and Graft Survival Terasaki PI, Park MS, Takemoto S, Cecka JM, E. Overview and epitope matching. In: Terasaki PI, editor. Clinical Transplants 1989, Los Angeles: UCLA Tissue Typing Laboratory: 1989. p. 499–516.

  3. Number of Amino Acid mm and 1-year Graft Survival Terasaki PI, Park MS, Takemoto S, Cecka JM. Overview and epitope matching. In: Terasaki PI, editor. Clinical Transplants 1989, Los Angeles: UCLA Tissue Typing Laboratory: 1989. p. 499–516.

  4. Number of Mismatched Amino Acids of the A-Locus and Graft Survival – UCLA registry (N=100,000) 1 year graft survival 3 year graft survival Number of transplants Terasaki PI, Takemoto S, Park MS, Cecka JM, Mickey MR. Molecular HLA matching. Transplant Proc. 1991 Feb;23(1 Pt 1):365-7.

  5. 5-Year Kidney Graft Survival. Primary DD Tx, 0 DR MM 0 to >=13 Triplet MM (TMM) Laux G, Mytillneos J, Opelz G. Critical evaluation of the amino acid triplet-epitope matching concept in cadaver kidney transplantation. Transplantation. 2004 Mar 27;77(6):902-7.

  6. 5-Year Kidney Graft Survival. Primary DD Tx, 0 DR MM 0 to >=12 Immunogenic Triplet MM (TMMI) Laux G, Mytillneos J, Opelz G. Critical evaluation of the amino acid triplet-epitope matching concept in cadaver kidney transplantation. Transplantation. 2004 Mar 27;77(6):902-7.

  7. Comparing frequencies of Mismatches at single aa position in TX cases Fail(under 2yr) vs Functioning(above 5yr) Primary DD Kidney TX - UNOS (1995 -2006) Mismatches of each loci giving the lowest 5 year graft survival Idica A, Sasaki N, Terasaki P. HLA matching by amino acid/positions in double and triple combinations. Clin Transpl. 2006:123-38.

  8. Comparing frequencies of Mismatches at single aa position in TX cases Fail(under 2yr) vs Functioning(above 5yr) Primary DD Kidney TX - UNOS (1995 -2006) Mismatches of each loci giving the lowest 5 year graft survival All the significance disappeared when these findings in primary DD tx was tried with primary LD tx Idica A, Sasaki N, Terasaki P. HLA matching by amino acid/positions in double and triple combinations. Clin Transpl. 2006:123-38.

  9. HLA Epitopes Publications • El-Awar, N. Lee JH, Tarsitani C, Terasaki PI. HLA class I epitopes: recognition of binding sites by mAbs or eluted alloantibody confirmed with single recombinant antigens. Hum Immunol., 2007. 68(3): p. 170-80. • El-Awar NR, Akaza T, Terasaki PI, Nguyen A. Human leukocyte antigen class I epitopes: update to 103 total epitopes, including the C locus. Transplantation 2007, 84(4):532-40. • Deng CT, El-Awar N, Ozawa M, Cai J, Lachmann N, Terasaki PI. Human leukocyte antigen class II DQ alpha and beta epitopes identified from sera of kidney allograft recipients. Transplantation 2008, 86(3):452-9. • El-Awar N, Terasaki PI, Nguyen A, Lias M, Conger N. New HLA class I epitopes defined by murine monoclonal antibodies. Hum Immunol. 2010, 71(5):456-61. • El-Awar N, Nguyen A, Almeshari K, Alawami M, Alzayer F, Alharbi M, Sasaki N, Terasaki PI.HLA class II DQA and DQB epitopes: recognition of the likely binding sites of HLA-DQ alloantibodies eluted from recombinant HLA-DQ single antigen cell lines. Hum Immunol. 2013 Sep;74(9):1141-52. El-Awar, N. 2013

  10. HLA Epitopes • 110 class I • 89 class II • 7 MICA • Allo Antibodies Adsorbed to r-HLA Single Antigen cell lines and eluted • Monoclonal Antibodies El-Awar, N. 2013

  11. Partial List of 110 Class I Epitope p: ns

  12. Partial List of 110 Class I Epitope p: ns

  13. Kidney Graft Survival Amino acid position 163 MM vs. Match Primary DD TX - UNOS (1995-2012)

  14. Kidney Graft Survival Eplet at position 163 MM vs. Match Primary DD TX - UNOS (1995-2012)

  15. Kidney Graft Survival MM vs. Match at 5 most & least Immunogenic positions Primary DD TX - UNOS (1995-2012)

  16. Kidney Graft Survival 0 AA/pos MM, 0 Eplet MM, 0 AB MM vs. 1+ MM Primary LD TX 0 DR MM - UNOS (1995-2012)

  17. Effect of Amino Acid Mismatch in UNOS Dataset 10-Year Kidney Graft Survival Primary DD TX - UNOS (1995-2010) 64 most common antigen, converted to allele 44,918 3 position-aa table with distance<27A Sasaki N, El-Awar N, Idica A. Effect of Amino Acid Mismatch in UNOS Dataset. Clin Transpl. 2011:299-309.

  18. Effect of Amino Acid Mismatch in UNOS Dataset 10-Year Kidney Graft Survival Primary DD TX - UNOS (1995-2010) 64 most common antigen, converted to allele 44,918 3 position-aa table with distance<27A Sasaki N, El-Awar N, Idica A. Effect of Amino Acid Mismatch in UNOS Dataset. Clin Transpl. 2011:299-309.

  19. Effect of Amino Acid Mismatch in UNOS Dataset 10-Year Kidney Graft Survival Primary DD TX - UNOS (1995-2010) 64 most common antigen, converted to allele 44,918 3 position-aa table with distance<27A Sasaki N, El-Awar N, Idica A. Effect of Amino Acid Mismatch in UNOS Dataset. Clin Transpl. 2011:299-309.

  20. Effect of Amino Acid Mismatch in UNOS Dataset 10-Year Kidney Graft Survival Primary DD TX - UNOS (1995-2010) 64 most common antigen, converted to allele 44,918 3 position-aa table with distance<27A Sasaki N, El-Awar N, Idica A. Effect of Amino Acid Mismatch in UNOS Dataset. Clin Transpl. 2011:299-309.

  21. Effect of Amino Acid Mismatch in UNOS Dataset 10-Year Kidney Graft Survival Primary DD TX - UNOS (1995-2010) 64 most common antigen, converted to allele 44,918 3 position-aa table with distance<27A Sasaki N, El-Awar N, Idica A. Effect of Amino Acid Mismatch in UNOS Dataset. Clin Transpl. 2011:299-309.

  22. Effect of Amino Acid Mismatch in UNOS Dataset 10-Year Kidney Graft Survival Primary DD TX - UNOS (1995-2010) 64 most common antigen, converted to allele 44,918 3 position-aa table with distance<27A Sasaki N, El-Awar N, Idica A. Effect of Amino Acid Mismatch in UNOS Dataset. Clin Transpl. 2011:299-309.

  23. Effect of Amino Acid Mismatch in UNOS Dataset 10-Year Kidney Graft Survival Primary DD TX - UNOS (1995-2010) 64 most common antigen, converted to allele 44,918 3 position-aa table with distance<27A Sasaki N, El-Awar N, Idica A. Effect of Amino Acid Mismatch in UNOS Dataset. Clin Transpl. 2011:299-309.

  24. Effect of Amino Acid Mismatch in UNOS Dataset 10-Year Kidney Graft Survival Primary DD TX - UNOS (1995-2010) 64 most common antigen, converted to allele 44,918 3 position-aa table with distance<27A Sasaki N, El-Awar N, Idica A. Effect of Amino Acid Mismatch in UNOS Dataset. Clin Transpl. 2011:299-309.

  25. Effect of Amino Acid Mismatch in UNOS Dataset 10-Year Kidney Graft Survival Primary DD TX - UNOS (1995-2010) We were going to run mismatch analyses for each of all 44,918 theoretical 3-position epitopes BUT we realized that the answers are the same among all these theoretical epitopes which share the same specificity. 44,918 theoretical epitopes were grouped by their specificities into 3,703 BM epitopes. Graft Survival analyses were run on mismatched cases for each of 3,703 BM epitopes, in Primary DD tx first, then in Primary LD tx and concordance checked. Sasaki N, El-Awar N, Idica A. Effect of Amino Acid Mismatch in UNOS Dataset. Clin Transpl. 2011:299-309.

  26. Partial List of 1620 A23+A24 Epitopes, all treated as one BM epitope Nearly 45,000 3-position/aa epitopes are reduced to 3703 BM epitopes by grouping epitopes of the same specificities together. Sasaki N, El-Awar N, Idica A. Effect of Amino Acid Mismatch in UNOS Dataset. Clin Transpl. 2011:299-309.

  27. Partial List of 1611 A*8001 Epitopes, all treated as one BM epitope Nearly 45,000 3-position/aa epitopes are reduced to 3703 BM epitopes by grouping epitopes of the same specificities together. Sasaki N, El-Awar N, Idica A. Effect of Amino Acid Mismatch in UNOS Dataset. Clin Transpl. 2011:299-309.

  28. 10-Year Kidney Graft Survival Mismatch by each of 3703 BM epitopes Primary LD TX vs Primary DD TX - UNOS (1995-2010) Totally discordant result on the same epitope between LD and DD TX. The majority of the dots fall in the center circle except those few with very low number of cases(marked in pink) Sasaki N, El-Awar N, Idica A. Effect of Amino Acid Mismatch in UNOS Dataset. Clin Transpl. 2011:299-309.

  29. 10-Year Kidney Graft Survival Mismatch by each of 3703 BM epitopes Primary LD TX vs Primary DD TX - UNOS (1995-2010) Mismatch on some BM epitopes gave comparatively high 10-yr graft survival for both LD population in 90’s and 70’s in DD population. Sasaki N, El-Awar N, Idica A. Effect of Amino Acid Mismatch in UNOS Dataset. Clin Transpl. 2011:299-309.

  30. 10-Year Kidney Graft Survival Mismatch by each of 3703 BM epitopes Primary LD TX vs Primary DD TX - UNOS (1995-2010) And some low’s Sasaki N, El-Awar N, Idica A. Effect of Amino Acid Mismatch in UNOS Dataset. Clin Transpl. 2011:299-309.

  31. 10-Year Kidney Graft Survival Mismatch by each of 3703 BM epitopes Primary LD TX vs Primary DD TX - UNOS (1995-2010) A23/A24 BM epitope 1759, NEP003, and 1600+ other epitopes including some Eplet 74% LD and 67% DD Sasaki N, El-Awar N, Idica A. Effect of Amino Acid Mismatch in UNOS Dataset. Clin Transpl. 2011:299-309.

  32. 10-Year Kidney Graft Survival Mismatch by each of 3703 BM epitopes Primary LD TX vs Primary DD TX - UNOS (1995-2010) A23/A24 BM epitope 1759, NEP003, and 1600+ other epitopes including some Eplet 74% LD and 67% DD 1. Low N. Sasaki N, El-Awar N, Idica A. Effect of Amino Acid Mismatch in UNOS Dataset. Clin Transpl. 2011:299-309.

  33. 10-Year Kidney Graft Survival Mismatch by each of 3703 BM epitopes Primary LD TX vs Primary DD TX - UNOS (1995-2010) A23/A24 BM epitope 1759, NEP003, and 1600+ other epitopes including some Eplet 74% LD and 67% DD • Low N. • Concordance among multiple population. Sasaki N, El-Awar N, Idica A. Effect of Amino Acid Mismatch in UNOS Dataset. Clin Transpl. 2011:299-309.

  34. 10-Year Kidney Graft Survival Mismatch by each of 3703 BM epitopes Primary LD TX vs Primary DD TX - UNOS (1995-2010) A23/A24 BM epitope 1759, NEP003, and 1600+ other epitopes including some Eplet 74% LD and 67% DD • Low N. • Concordance among multiple population. • Data Translation Effect. Sasaki N, El-Awar N, Idica A. Effect of Amino Acid Mismatch in UNOS Dataset. Clin Transpl. 2011:299-309.

  35. Data translation on Epitope MM analysis Recip. HLA Antigen Recip. HLA Allele Recip. HLA Epitope Mismatched HLA Epitope Donor HLA Antigen Donor HLA Allele Donor HLA Epitope (1) Antigen to Allele translation, at most frequent basis.

  36. Data translation on Epitope MM analysis Recip. HLA Antigen Recip. HLA Allele Recip. HLA Epitope Mismatched HLA Epitope Donor HLA Antigen Donor HLA Allele Donor HLA Epitope (1) Antigen to Allele translation, at most frequent basis. (2) Allele to selected Epitope translation, 1000’s of others left out.

  37. Data translation on Epitope DSA analysis Donor HLA Antigen Donor HLA Allele Donor HLA Epitope (1) (2) Antibody Result by Epitope DSA (4) Recip Epitope reduction, eliminating all epitopes selected(2) for Recip. (3) Allele to selected Epitope translation, 1000’s of others left out. Antibody Result by Initial List of Epitope Antibody Result by Allele (5) Non-Donor Specific Epitope reduction translation, eliminating all epitopes not selected (2) for Donor. Antibody Result by Non-Self Trimmed List of Epitope

  38. Data translation on Epitope DSA analysis Donor HLA Antigen Donor HLA Allele Donor HLA Epitope (1) (2) Antibody Result by Epitope DSA (4) Recip Epitope reduction, eliminating all epitopes selected(2) for Recip. (3) Allele to selected Epitope translation, 1000’s of others left out. Antibody Result by Initial List of Epitope Antibody Result by Allele (5) Non-Donor Specific Epitope reduction translation, eliminating all epitopes not selected (2) for Donor. Antibody Result by Non-Self Trimmed List of Epitope

  39. Data translation on Epitope DSA analysis Donor HLA Antigen Donor HLA Allele Donor HLA Epitope (1) (2) Antibody Result by Epitope DSA (4) Recip Epitope reduction, eliminating all epitopes selected(2) for Recip. (3) Allele to selected Epitope translation, 1000’s of others left out. Antibody Result by Initial List of Epitope Antibody Result by Allele (5) Non-Donor Specific Epitope reduction translation, eliminating all epitopes not selected (2) for Donor. Antibody Result by Non-Self Trimmed List of Epitope

  40. Data translation on Epitope DSA analysis Donor HLA Antigen Donor HLA Allele Donor HLA Epitope (1) (2) Antibody Result by Epitope DSA (4) Recip Epitope reduction, eliminating all epitopes selected(2) for Recip. (3) Allele to selected Epitope translation, 1000’s of others left out. Antibody Result by Initial List of Epitope Antibody Result by Allele (5) Non-Donor Specific Epitope reduction translation, eliminating all epitopes not selected (2) for Donor. Antibody Result by Non-Self Trimmed List of Epitope

  41. Data translation on Epitope DSA analysis Donor HLA Antigen Donor HLA Allele Donor HLA Epitope (1) (2) Antibody Result by Epitope DSA (4) Recip Epitope reduction, eliminating all epitopes selected(2) for Recip. (3) Allele to selected Epitope translation, 1000’s of others left out. Antibody Result by Initial List of Epitope Antibody Result by Allele (5) Non-Donor Specific Epitope reduction translation, eliminating all epitopes not selected (2) for Donor. Antibody Result by Non-Self Trimmed List of Epitope

  42. Data translation on Epitope DSA analysis Donor HLA Antigen Donor HLA Allele Donor HLA Epitope (1) (2) Antibody Result by Epitope DSA? Really? (4) Recip Epitope reduction, eliminating all epitopes selected(2) for Recip. (3) Allele to selected Epitope translation, 1000’s of others left out. Antibody Result by Initial List of Epitope Antibody Result by Allele (5) Non-Donor Specific Epitope reduction translation, eliminating all epitopes not selected (2) for Donor. Antibody Result by Non-Self Trimmed List of Epitope

  43. Quick example • Donor mismatch is A23,A24 and we select A*2301 and A*2402 by frequency • Single Antigen test is positive on A*2301 and A*2402. • we assigned 3 DSA epitopes 003(A23+A24),202(A23) and 203(A24)

  44. Quick example • Donor mismatch is A23,A24 and we select A*2301 and A*2402 by frequency • Single Antigen test is positive on A*2301 and A*2402. • we assigned 3 DSA epitopes 003(A23+A24),202(A23) and 203(A24) • Is the list of DSA epitope complete?

  45. Quick example • Donor mismatch is A23,A24 and we select A*2301 and A*2402 by frequency • Single Antigen test is positive on A*2301 and A*2402. • we assigned 3 DSA epitopes 003(A23+A24),202(A23) and 203(A24) • Is the list of DSA epitope complete? • Are these really DSA?

  46. Quick example • Donor mismatch is A23,A24 and we select A*2301 and A*2402 by frequency • Single Antigen test is positive on A*2301 and A*2402. • we assigned 3 DSA epitopes 003(A23+A24),202(A23) and 203(A24) • Is the list of DSA epitope complete? • Are these really DSA? • Do we know how many antibodies we have in this example?

  47. Summary • Epitope matching may be effective in small series of patients, but when it is put to the test in large databases, it does not work. • It does not work in Opelz registry nor does it work in the UNOS registry. No data has been presented showing that it works using large databases. • Present Epitope analyses go through many data translation steps, the study results derived from these epitope information may not be attributable to the epitope characteristics themselves.

  48. Conclusion • In conclusion, although epitope matching is a good idea, no data has been presented to demonstrate the epitope matching actually works in a large scale database. • Furthermore, under the present data and testing constraints, it is not possible to analyze for the effect of antibodies against any specific epitope. • We therefore think that it is too premature to use epitope matching in any ways that affect the patients.

  49. Thank You

  50. Thank You

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