Transplant tolerance: progress and challenges Giuseppe Remuzzi - PowerPoint PPT Presentation

Transplant tolerance: progress and challenges Giuseppe Remuzzi Cagliari, 30 aprile 2011 1

Transplant of kidneys from one dog to another 2 Brigham Hospital, Boston

� Nothing is more ridiculous than saying that all this could have been done with computers or with tissue cultures. That � s like saying you can live without breathing or without having blood. It � s absolutely the most anti-intellectual thinking that ever existed � Joseph Murray, Nobel Prize Lecture, 1990 3

� Joe � s the only guy who ever won a Nobel Prize for pursuing a hobby � Francis Moore 4

23 Dicembre 1954, ore: 8.00 Ospedale Peter Bent Brigham di Boston 5

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Edith Helm and her sister Wanda Foster 8

GRAFT SURVIVAL AFTER RENAL TRANSPLANTATION IN THE PERIOD 1989-2005 Analysis of UNOS data on patients with functioning kidney 1 year post transplant 18 1995 20 9 10 Deceased donor 30 Projected median half-life 0 No rejection Rejection* 20 * within 1 year post-Tx (years) 9 10 13 0 89 91 93 95 97 99 2001 2003 2005 years of transplant Hariharan et al., N Eng J Med , 2000 USRDS, Am J Kidney Dis , 2009 9 9

THE PROMISE OF NOVEL IMMUNOSUPPRESSIVE AGENTS Basiliximab CAMPATH-1H Belatacept (chimeric monoclonal (humanized anti-CD52 (IgG/CTLA4 fusion antibody against IL-2 R) antibody - T and B cells protein selective depletion) blocker of T cell activation) Daclizumab Everolimus (humanized monoclonal (m-TOR T cell antibody against IL-2 R) proliferation inhibitor) Kidney Tx Kidney Tx Kidney Tx Heart Tx Kidney Tx (Nashan et al., (Vincenti et al., (Calne et al., (Eisen et al., (Vincenti et al., Lancet) N Engl J Med) Lancet) N Engl J Med) N Engl J Med) 2005 1997 2003 1998 10 10 10

RISK OF DEVELOPING A TUMOR IN TRANSPLANT RECIPIENTS 100 Tx patients with tumor (%) 80 60 40 20 0 0 10 20 30 40 Survival post-Tx (years) 11 11 11

New drugs are not necessarily better drugs 12 12 12

Cumulative probability 0.2 Patient death HR: 0.96 (95%CI � 0.28 to 3.31), p=0.95 0.1 Mycophenolate mofetil Azathioprine 0,62 euro 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Cumulative probability 0.2 Death-censored graft loss HR: 0.89 (95%CI � 0.32 to 2.46), p=0.83 Mycophenolate 0.1 mofetil 15,12 euro Azathioprine Daily cost dose 0 72 0 6 12 18 24 30 36 42 48 54 60 66 Months after transplantation Remuzzi et al., J Am Soc Nephrol, 2007 13

THE TARGET: TRANSPLANTATION TOLERANCE One of the major questions remaining in clinical transplantation is whether it will be possible to induce states of true tolerance with little or no long-term drug therapy � ideally one would like to alter the host � s initial contact with the graft to promote a state of donor-specific unresponsiveness Carpenter, N Engl J Med, 1993 14 14

Transplants in Rats Made Without Usual Drugs By LAWRENCE K. ALTMAN Kidney graft survival > 70 days 15 15

i.t. injection Time to Tx Kidney graft survival (leukocytes x 10 8 ) (days) (days) 1.8 14 > 350 7.0 7 > 100 Knechtle et al., Transplantation, 1997 16 16 16

RARE EXAMPLES OF SPONTANEOUS CLINICAL TRANSPLANTATION TOLERANCE AFTER IMMUNOSUPPRESSANT DISCONTINUATION 12 of 42 longest surviving liver recipients Years post-Tx Years off immunosuppressive drugs 17 15 23 13 16 13 22 10 18 7 19 4 24 3 17 2 14 2 13 2 26 1 14 1 Patients who are immunosuppression-independent show donor cell chimerism, i.e. persisting donor hematopoietic cells migrated from the transplanted organ into the host peripheral blood and bone marrow 17 17

IN KIDNEY TRANSPLANT RECIPIENTS GIVEN DONOR BONE MARROW INFUSIONS LONG-TERM GRAFT SURVIVAL IS IMPROVED - Immunosuppressive therapy: OKT3, Tacrolimus, MMF, steroid - Donor BMC infusion at day 4 and/or day 11 post-Tx - Follow-up: 2.9 to 6.3 years (mean: 4.7 years) 100 DBMC (n = 63) 90 p = 0.039 (death censored) % graft survival Control (n = 219) 80 70 60 50 0 12 24 36 48 60 72 18 Months post-Tx Ciancio et al., Transplantation, 2001

A CLINICALLY APPLICABLE ANIMAL MODEL TO DISSECT MECHANISMS OF ORGAN TRANSPLANTION TOLERANCE BN bone marrow or leukocyte infusion BN kidney (70-200 x 10 6 ) transplant CsA (10 mg/kg/day, i.m.) 15 20 0 Lewis rat Days after cell infusion recipient Noris et al., J Am Soc Nephrol, 2001 19 19

Lewis rat PBMC and kidney allograft Brown Norway recipient BM cells Groups Donor cell infused Kidney graft survival (x 10 6 ) (days) CsA alone / 7, 7, 8, 9, 10, 10 BN- PBMC + CsA 70 16,17,25, 27,30,33,33,58,>70, >70>70,>70,>70,>70,>70,>70,>70 BN- BM + CsA 70 6,8,10,14,17,17,17,17,20,>60, >60,>60,>60 BN-PBMC + CsA 200 >70,>70,>70,>70 Noris et al., J Am Soc Nephrol, 2001 20 20

INTRATHYMIC MICROCHIMERISM DETERMINES THE OUTCOME OF TOLERAZING PROTOCOLS TARGETED AT SOLID ORGAN TRANSPLANTATION Kidney graft + PBL or BM Brown Norway Lewis rat Tolerance Rejection 100 100 MHCII + % rats with microchimerism % rats with microchimerism 80 80 60 60 40 40 20 20 0 0 Thymus Liver Spleen Blood Thymus Liver Spleen Blood Noris et al., J Am Soc Nephrol, 2001 21

100 80 Controls % graft survival 60 40 MHC II + cells depletion 20 0 0 20 40 60 Time post-transplant (days) Noris et al., J Am Soc Nephrol, 2001 22

Graft survival (days) Control 19, 55, >70, >70, >70, >70 Thymectomy * 5, 8, 15, 17, 17 * on the day of the kidney transplant Noris et al., J Am Soc Nephrol, 2001 23

How near are we to reaching the point where transplant tolerance will become a clinical reality? 24 24

CHIMERISM AND TOLERANCE AFTER RENAL AND BONE MARROW TRANSPLANTATION 5 subjects with ESRD: Alport � s syndrome (2), MPGN, PKD (2) Bone marrow (day 0) and kidney from one-haplotype-mismatched, living-related donors Preparative regimen Cyclophosphamide 60 mg/kg Thymic irradiation 700 cGy Anti-CD2 mAb 0.1 mg/kg CsA 5 mg/kg i.v. 375 mg/m 2 BSA Rituximab Post-Tx immunosuppression CsA 8-12 mg/d orally Prednisone 2 mg/kg Follow-up after discontinuation of immunosuppression: 5 - 7 years 25 25 Kawai et al., N Engl J Med, 2008 25

LONG-TERM FOLLOW-UP (September 2010) Patient n ° Original disease Discontinuation Kidney survival immunosuppressive (years) therapy (years) Alport � 1 s syndrome 6.6 7.3 2 MPGN type 1 6.1 7.2 * 10 days # 3 PKD NO Alport � 4 s syndrome 4.9 5.5 5 PKD 3.8 4.6 * Relapse of MPGN # In 2004 underwent a second kidney Tx (stable renal function on conventional immunosuppressive therapy since then 26

LONG-TERM FOLLOW-UP Patient n ° Discontinuation T cell Donor specific immunosuppressive unresponsiveness antibodies therapy (years) Yes No 1 6.6 No Yes 2 6.1 Yes N/A 3 NO early humoral rejection Yes* 4.9 Yes 4 late persistent Yes* 3.8 Yes 5 late persistent * co-development of autoantibodies Porcheray, Am J Transpl, 2009 27

Unusually high incidence of acute humoral rejection despite the combined conditioned regimen of thymic irradiation, cyclophosphamide, anti- CD2 mAb, cyclosporine and rituximab Risk of infections and aplasia and ultimately death outweigh the potential benefit of tolerance 28 28 28

, Clinical update: immunosuppression minimisation 29

BASILIXIMAB COMBINED TO LOW-DOSE RATG IN HIGH RISK KIDNEY TRANSPLANT RECIPIENTS Kidney Tx Standard RATG (2 mg/kg/day) 0 1 2 3 4 5 6 7 Days post Tx Randomization Low-dose RATG (0.5 mg/kg/day) Basiliximab (20 mg) Basiliximab (20 mg) 0 1 2 3 4 5 6 7 Days post Tx Maintenance therapy with CsA, ST, MMF 1 episode of biopsy-proven acute rejection on low-dose RATG plus basiliximab, and 2 on standard-dose RATG Less side effects* with the combined low-dose RATG and basiliximab * fever, elukopenia, anemia, CMV reactivation 30 Ruggenenti et al., C J Am Soc Nephrol, 2006

, Kidney Tx Low SRL Low CsA + low dose AZA or low MMF Bas - L-RATG* 3-5 mg/kg/day 75 mg/day 750 mgx2/day 20 mg - 0.5 mg/kg/die MP MP MP 0 d1 d2 Time post Tx - No acute humoral rejection * for 6 days - Acute cellular graft rejection: 20% 3

The first 4 renal transplant recipients randomized to low SRL/MMF maintenance immunosuppressive regimen developed acute allograft rejection 32 32

Kidney Tx Low SRL ? Low CsA + low dose AZA or low MMF 3-5 mg/kg/day 75 mg/day 750 mgx2/day Bas - L-RATG 20 mg 0.5 mg/kg MP MP MP 0 d1 d2 Time post Tx 33

Regulatory Effector T Regulatory Effector T cells cells cells cells REJECTION TOLERANCE Salama, Remuzzi, Harmon et al., J Clin Invest, 2001 34

DONOR-SPECIFIC T REGULATORY CELLS PLAY A ROLE IN TOLERANCE INDUCED BY PBMC INFUSION IN RATS Kidney Blood donor Tx leukocytes Isolation of graft Isolation of Collection of infiltrating lymph nodes thymus lymphocytes BN rat donor LW rat recipient CsA days - 10 0 5 30 60 Graft survival prolongation: 47 % of total transplanted rats Tolerance: 53 % Cavinato et al., Kidney Int , 2007 35 35

INDUCTION EARLY POST-Tx MAINTENANCE graft A N A A R R ? A R R R Foxp3 + CD4 + CD25 + BN rat donor CsA days - 10 0 5 30 60 Cavinato et al., Kidney Int , 2007 36 36