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Humoral theory

Humoral theory. Am. J. Transpl 2003 3:665. Antibodies cause hyperacute rejection. 1969 Immediate failure Kidney recipients. with antibodies, pos XM . 24/30. Patel, Terasaki, N Engl J Med 280:735, 1969 . 2. Primary Graft Failure. 132. 123. 123. 119. 119. 117. 100. 104. 18.

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Humoral theory

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  1. Humoral theory Am. J. Transpl 2003 3:665

  2. Antibodies cause hyperacute rejection

  3. 1969Immediate failureKidney recipients with antibodies, pos XM 24/30 Patel, Terasaki, N Engl J Med 280:735, 1969

  4. 2 Primary Graft Failure 132 123 123 119 119 117 100 104 18 94 75 81 72 80 76 1 38 0 Percent Cause of death Hyperacute Rejection 1 17 13 11 11 10 10 12 10 8 1 1 1 3 1 1 2 0 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02

  5. Hyperacute Rejection 0.5 0.4 9 23 0.3 Percent of Hyperacute 27 0.2 36 76 0.1 43 0 <10 10-80 >80 1 2 >2 % PRA Transplant No.

  6. Primary Non-function 3 164 70 2 256 345 Percent of Primary Nonfunction 1145 706 1 0 <10 10-80 >80 1 2 >2 % PRA Transplant No.

  7. Graft Failure in 1 month 13 12 301 11 622 1283 10 9 8 1550 7 Percent of Graft Failure 6341 3744 6 5 4 3 2 1 0 <10 10-80 >80 1 2 >2 Transplant No. % PRA

  8. Antibodies cause acute rejection

  9. C4d- (N =42) 100 90 80 70 60 50 40 30 20 10 0 90% C4d+ (N =43) 57% Graft Survival (%) Biopsies within first month 0 1 2 3 4 5 6 7 8 9 10 11 12 Months Posttransplant Feucht, Albert, et al. Kidney Intern 43:1333-38, 1993

  10. 100 75 C4d- (N =101) Cumulative Survival (%) 50 C4d+ (N =117) P= 0.0001 25 0 0 4 8 12 16 Years Posttransplant Lederer, et al. Kidney International 59:334-341, 2001

  11. C4d publications Feucht, Schneeberger, et al. Kidney Int 1993: 43:1333. Feucht, Opelz. Kidney Int 1996: 50:1464. Behr, Feucht, et al. J Heart Lung Transplant 1999; 18:904. Lederer, Kluth-Pepper, et al. Kidney Int 2001; 59:334.

  12. Collins, Schneeberger, et al. J Am Soc Nephrol 1999; 10:2208. Crespo, Pascual, et al. Transplantation 2001; 71:652. Mauiyyedi, Pelle, et al. J Am Soc Nephrol 2001; 12:574. Mauiyyedi, Colvin. Curr Opin Nephrol Hypertens 2002; 11:609. Mauiyyedi, Crespo, et al. J Am Soc Nephrol 2002; 13:779.

  13. Regele, Watschinger, et al. Nephrol Dial Transplant 2001; 16:2058. Bohmig, Exner, et al. J Am Soc Nephrol 2002; 13:1091. Bohmig, Exner, et al. Curr Opin Urol 2002; 12:95. Watschinger, Pascual. J Am Soc Nephrol 2002; 13:2420. Nickeleit, Zeiler, et al. J Am Soc Nephrol 2002; 13:242.

  14. HLA antibodies cause chronic rejection

  15. Review: Anti-HLA antibodies post transplant in solid organ transplantation McKenna, Takemoto, Terasaki Transplantation 69:319, 2000 American J Transplantation, June, 2003

  16. El Fettouh, Cook, et al. Urology 2000; 56:369. Tambur AR, Bray et al.Transplant 2000; 70:1055 Muller-Steinhardt, Fricke, et al. Clin Transplant 2000; 14:85. Kerman, Katz, et al. Transplant Proc 2001; 33:402. Worthington, Martin, et al. Transpl Proc 2001; 33:475.

  17. T Piazza, Poggi, et al. Transplantation 2001; 71:1106. Piazza, Borrelli, et al. Transpl Int 2000; 13:s439. Pelletier, Adams, et al. Am J Transplant 2002; 2:134. Palmer, Davis, et al. Transplantation 2002; 74:799. Lau, Palmer, et al. Ann Thorac Surg 2000; 69:1520.

  18. After failure or removal of graft 1969, Morris N=24 54% 1981, Iwaki N=25 72% 1987, Park N=122 82% 1995, Harmer N=100 95%

  19. After failure or removal of graft 1969, Morris N=24 54% 1981, Iwaki N=25 72% 1987, Park N=122 82% 1995, Harmer N=100 95%

  20. After failure or removal of graft 1969, Morris N=24 54% 1981, Iwaki N=25 72% 1987, Park N=122 82% 1995, Harmer N=100 95%

  21. After failure or removal of graft 1969, Morris N=24 54% 1981, Iwaki N=25 72% 1987, Park N=122 82% 1995, Harmer N=100 95%

  22. After failure or removal of graft ELISA AHG 96% 24 Rosenberg,N = 254 11 AHG 96.4% 16 28 Lazda N = 445 AHG 2001, El Awar 152 96% N=825 at 5 centers 33 El-Awar,Terasaki et al, Transpl Proc 34:2531, 2002

  23. 0 <6M 1yr 2 3 4 5 6 7 8yr 5 Time to antibody 8 Time to failure 12 6 4 2 11 Lee,Terasaki, Transpl 74:1192, 2002

  24. Years Posttransplant 0 2 4 6 8 10 12 14 16 Class II Time to antibody Time to failure Worthington, et al. Transplantation 2003, 75:1034

  25. Years Posttransplant 0 2 4 6 8 10 12 14 16 Class I Time to antibody Time to failure I Worthington, et al. Transplantation 2003, 75:1034

  26. Chronic Rejection Chronic Rejection Renal allograft - Post transplant

  27. To prove the role of HLA antibodies in a prospective trial,One year ago 2,551 patients with functioning transplants were tested for HLA antibodies

  28. 36 International transplant centers, patients tested in 2002 60 KIDNEY LIVER 40 HEART LUNG % HLA antibody Post-transplant 20 115 41 43 41 21 17 167 104 63 47 12 61 52 0 628 100 50 26

  29. Combination Drug No pre-tx antibody 40 20 * % HLA antibody Post-transplant 0.34 0.073 <0.0001 0 CsA, MMF FK, Aza CsA, Aza FK, MMF N 233 67 533 536

  30. Date of transplant in 2,551 patients 92 93 94 95 96 97 98 99 2000 01 02 03 1 yr wait period Antibody No antibody

  31. Kidney Transplants

  32. Deaths in a total 2551 patients followed one year 567 with antibody 1.9% died 1 year later, 32 died 1.1% died 1,984 without antibody P=0.08

  33. Graft failure in a total 2551 patients followed one year 567 with antibody 5.6% fail 1 year later, 72 fail 2.0% fail 1,984 without antibody P=0.000003

  34. Graft failure in patients without pre-transplant antibody 1,725 total 256 with antibody 6.6% fail 1 year later, 45 fail 1.9% fail 1,469 without antibody P=0.00001

  35. The tests were done by PRA (panel reactive antibodies), but are Donor Specific antibodies found?

  36. Single antigen flow cytometry beads Produced by isolating antigens from recombinant lines, and adhering to beads #11 Pei, Lee et al Transpl 2003 75:43

  37. Single antigen beads #29 B38 B57 B7 B52 B27 B8 B65 Cont B55 A1 A2 A3 A69 A66 A29 A30 Cont A26

  38. Antibodies in patients AFTER rejection Pei, Lee et al Transpl 2003 75:43 Serum Single Antigen A-Allele Typings ID 1 2 11 23 24 26 29 30 31 33 34 66 68 69 3 1 2 3 4 5 XX 6 XX XX X XX X XX X XX 7 XX XX XX 8 XX XX 9 10 XX XX XX

  39. Antibodies in patients AFTER rejection Pei, Lee et al Transpl 2003 75:43 Serum Single Antigen A-Allele Typings ID 1 2 11 23 24 26 29 30 31 33 34 66 68 69 3 1 2 3 4 5 XX 6 XX XX X XX X XX X XX 7 XX XX XX 8 XX XX 9 10 XX XX XX

  40. Recip Mism Berlin, Schonemann Serum Single Antigen A-Allele Typings 25 ID 1 2 3 11 23 24 26 29 30 31 33 66 68 69 11 12 13 14 15 16 17 18 19 20

  41. NDSA C4d C4d DSA DSA NDSA NDSA C4d C4d DSA DSA DSA

  42. HLA antibodies were found to predict chronic rejection in a prospective trial. They should therefore be useful in increasing or decreasing immunosuppression

  43. Humoral Theory of Transplantation • Am. J. Transpl 2003 3:665 • HLA antibodies cause: • Hyperacute rejection • Damage by early non function • Acute rejection • Chronic rejection

  44. Humoral Theory of Transplantation • Am. J. Transpl 2003 3:665 • HLA antibodies cause: • Hyperacute rejection • Damage by early non function • Acute rejection • Chronic rejection

  45. Humoral Theory of Transplantation • Am. J. Transpl 2003 3:665 • HLA antibodies cause: • Hyperacute rejection • Acute rejection

  46. Humoral Theory of Transplantation • Am. J. Transpl 2003 3:665 • HLA antibodies cause: • Hyperacute rejection • Acute rejection Chronic rejection

  47. Jan 31 to Feb 1, 2004 Los Angeles, Century Plaza Hotel HLAtransplantationconference.org

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