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Clinical Differences Between Anti-HLA and Anti-ABO Antibodies In Renal Transplantation The 7th Banff Conference on

Clinical Differences Between Anti-HLA and Anti-ABO Antibodies In Renal Transplantation The 7th Banff Conference on Allograft Pathology Millie Samaniego, MD Johns Hopkins School of Medicine. Controversies In Transplant Immunology. Humoral theory of graft rejection

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Clinical Differences Between Anti-HLA and Anti-ABO Antibodies In Renal Transplantation The 7th Banff Conference on

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  1. Clinical Differences Between Anti-HLA and Anti-ABO Antibodies In Renal Transplantation The 7th Banff Conference on Allograft Pathology Millie Samaniego, MD Johns Hopkins School of Medicine

  2. Controversies In Transplant Immunology • Humoral theory of graft rejection • Cellular theory of graft rejection Sir Peter Medawar (1915-1987)

  3. MH Sayeh and LA Turka. N Engl J Med 1998; 338(25):1813-21

  4. Waiting Time (days) 2500 2000 >79 1500 1000 20-79 500 <20 0 PRA REMAINING BARRIERS TO RENAL TRANSPLANTATION Nearly 30% of the 52,000 patients on the kidney waiting list are sensitized due to previous transplant, blood transfusion, or pregnancy.

  5. HLA-A20201 with bound peptide MHC MOLECULES 1-chain 2-chain 2m 3-chain

  6. REMAINING BARRIERS TO RENAL TRANSPLANTATION There is a 35% chance that any 2 individuals will be ABO incompatible: • 1/3 of potential live donors are excluded immediately due to ABO incompatibility.

  7. ABO GROUP ANTIGENS

  8. Source: OPTN/SRTR DATA as of August 1, 2001

  9. LAG BETWEEN CLINICAL AND BENCH RESEARCH • Characterization of the ‘humoral” response to transplantation antigens: • Targets of antibody response: • HLA versus Non-HLA antigens (ABO, polymorphic tissue antigens, endothelial cell antigens) • Animal models • Which is/are the effector (s) of injury: Antibody or the Complement System? • Poor understanding of the role of the B-cell in rejection: • APC, Effector, co-stimulator?

  10. Immunomodulation and Accommodation in Kidneys Transplanted Across Donor Specific HLA Antibodies and ABO Incompatibility MD Samaniego, AA Zachary, KE King, L Racusen, M Haas, RA Montgomery  Johns Hopkins University

  11. INCLUSION CRITERIA AND END-POINTS • PRE-EMPTIVE PROTOCOL: • Positive Donor specific X-match before Tx. • Identification of donor-specific anti-HLA Ab pre-Tx. • End-point: Negative Donor specific X-match before Tx. • RESCUE PROTOCOL: • Histologic and immunofluorescent features of humoral rejection. • Identification of donor-specific anti-HLA Ab post-Tx. • End-point: Biopsy-proven resolution of rejection Elimination of donor-specific anti-HLA Ab

  12. PP/CMV-IVIg Protocol • Plasmapheresis: • Delivered via COBE Spectra cell separator. • Removal of 1 plasma volume, replaced with albumin or FFP. • Given QOD until endpoint: • Pre-emptive group = Neg cytotoxic donor-specific X-match • Rescue = Elimination of DSA

  13. PP/CMV-IVIg Protocol • CMV Hyperimmune globulin: • Infusion followed each plasmapheresis • Each patient received 100 mg/kg/dose

  14. Rescue Group: Methylprednisolone pulse (500 mg/d x 3 days) Steroid taper FK506 – trough 10-15 ng/ml MMF – 2g/d Pre-Emptive Group: At 1st PP/CMV-IVIg session FK506 – trough 10-15 ng/ml MMF – 2g/d At time of Transplant Daclizumab x 5 doses Methylprednisolone pulse (500 mg/d x 3 days) Steroid taper PP/CMV-IVIg Protocol Immunosuppression:

  15. PATIENT CHARACTERISTICS ALLOGRAFT PERFORMANCE # of Patients MEDIAN AGE (RANGE) 46 45 (20-69) Acute Rejection (+) AHG at the time of Tx 28/46 10/46 Previous Transplants 21 ANTIBODY-MEDIATED REJECTION Median time to rejection 20/46 9 days PRE-TRANSPLANT PP/CMV-Ig TREATMENTS () 4.7 MEAN CURRENT SERUM Cr (mg/dl) 1.3 + 0.7 POST-TRANSPLANT PP/CMV-Ig TREATMENTS () 2.3 (4.3 for Rx) MEDIAN FOLLOW-UP TIME 14 mos (1 – 60) CLINICAL OUTCOMES: PRE-EMPTIVE PP/CMV-Ig THERAPY FOR A POSITIVE CROSSMATCH * 6 graft losses: 1 noncompliance; 1 pt death due to sepsis; 1 pt death due to biopsy complication; 1 recurrent disease; 2 AMRx

  16. PATIENT CHARACTERISTICS ALLOGRAFT PERFORMANCE # of Patients AGE (RANGE) 33 49 (13-67) AMR IN DAYS POST-TX DAYS (RANGE) 9 (2-750) LIVE / CADAVERIC DONOR 11 / 24 SCr AT TIME OF AMR (mg/dl±SD) 6.0 + 3.4 DSA Identified Class I/Class II 26 15/11 MEAN F/U TIME (Mos) 28.8 MEDIAN # PP/CMV-IG TREATMENTS 6.5 (2-50) MEAN CURRENT SCr (mg/dl±SD) 1.9 + 1.0 CLINICAL OUTCOMES:AMRx RESCUE USING PP/CMV-Ig * 8 graft losses: 2 recurrent Dz, 2 chronic rejection, 2 death with normal renal Fx, 1 surgical complication, 1 with recalcitrant AMRx

  17. Risk Factors

  18. Impact on HLA-Specific Antibodies • Of the 49 patients: • 3 graft losses: 2 to rejection, 1 to Bx-related incident • 1 patient died with functioning graft, 3 years post-Tx • 1 year graft survival ~91%

  19. 4 ABO incompatible 3 DSA+ 1 week earlier ELISA vs C4d Staining

  20. CONCLUSIONS-1 • Anti-HLA Antibodies: • Donor specific unresponsiveness • Anti-HLA DSA remains undetectable in all patients treated pre-emptively with PP/IVIG for a (+) Xmatch and in 28 of 33 patients in the rescue protocol • 3rd party anti-HLA Ab often returns

  21. ABOI-TRANSPLANT PROTOCOL End-point: Isoagglutinin titer  1:16 by AHG • Plasmapheresis • CMV-IVIg 100 mg/Kg after plasmapheresis • Pre-Tx splenectomy • Immunosuppression: • Daclizumab x 5 doses • Methylprednisolone pulse (500 mg/d x 3 days) • Steroid taper • FK506 – trough 10-15 ng/ml • MMF – 2g/d

  22. Characteristics of ABOI Kidney Transplant Recipients

  23. ABO Incompatible Transplants With Rituximab in lieu of Splenectomy

  24. Blood Group Antigen Expression on ABOI Transplanted Kidneys Pre-Tx Post-Tx 1 Week 1 Month H&E Anti-A1 No decrease in blood group antigen staining has been observed in any sections examined thus far, suggesting that decreased antigen expression on the donor kidney does not explain accommodation.

  25. CONCLUSIONS-2 • ABO Isoagglutinins:Accommodation • Isoagglutinin titers rebound after cessation of PP/IVIG but this does not appear to have consequences for the graft • C4d+ staining is not indicative of rejection unless other features are present

  26. SPEAKER OBJECTIVES • To recognize that antibody responses to HLA and ABO molecules are qualitatively different • To recognize that early graft acceptance in patients with preformed HLA usually requires elimination of DSA • To recognize that in ABOI transplants low levels on ABO isoagglutinins may facilitate engraftment • A regimen of plasmapheresis, IVIg and anti-B cells monoclonal antibodies enables renal transplantation across a DSA or ABO incompatibility barrier

  27. INKT PROGRAM Bob Montgomery Andrea Zachary Matt Cooper Karen King Renal Pathology Lorraine Racusen Mark Haas Baldwin Laboratory Wink Baldwin Barbara Wasowska RIST Investigators Yolanda Becker Nina Tolkoff-Rubin Mark Pescovitz Gonzalo Gonzalez-Stawinski ACKNOWLEDGEMENTS

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