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CMV Infection and Allograft Rejection :

CMV Infection and Allograft Rejection :. Are we missing the point?. Jeremy Chapman Westmead Hospital, Sydney. The simple Paradigm. CMV Infection. Acute Rejection. D+ R- OKT3/ATG HHV6/7. CMV Disease. HLA induction Adhesion mols Cytokines. Chronic Rejection. Chronic Something.

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CMV Infection and Allograft Rejection :

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  1. CMV Infection and Allograft Rejection : Are we missing the point? Jeremy Chapman Westmead Hospital, Sydney

  2. The simple Paradigm CMV Infection Acute Rejection D+ R- OKT3/ATG HHV6/7 CMV Disease HLA induction Adhesion mols Cytokines Chronic Rejection Chronic Something

  3. Evidence that the relationship with CMV may be more complex • Biology of CMV infection/disease • Effects of CMV prophylaxis • Relationships between CMV and rejection • Effects of Biopsy identified Cellular infiltrate • Mechanisms of damage Questions not answers

  4. Biology of CMV US3 US2,US11 TAP Proteosome CMV US6 Golgi Nucleus ER HLA E

  5. Detection of CMV after Liver Transplantation 100000 10000 Log viral load (copies/ml) 1000 100 Asymptomatic infection CMV disease Humar et al Transplantation 1999; 68:1305 -11

  6. Control of CMV Why isn’t the graft lost to CMV? T T SELF ALLO

  7. CMV Tetramers 5% CD8 positive Tetramer positive Singhal et al Transplantation 2000; 69: 2251-2259

  8. CMV Tetramers in BMT • Donor & Recip CMV + CMV CTL = 21% of CD8 T cells • Matched Unrelated Donors CMV C TL recovery delayed • CMV CTL by CMV reactivation, by pred • CMV CTL > 10x 106/l associated with protection from CMV Cwynarski et al Blood 2001: 97: 1232-40

  9. CMV - HHV6 STUDYOdds of getting Disease CMV + HHV6 HHV6 CMV D + R - OKT3/ATG ODDS RATIO

  10. Detecting CMV Histopathology Immunohistochemistry In-situ hybridisation IHC and ISH detected CMV in 70% of cases with negative histology.(1) ISH detected CMV in bile ducts of 10/10 liver transplants with VBDS. (2) 1. Am J Clin Path 1996;166:544-8 2. Hepatology 1997;Jan: 190-4

  11. Prevention of CMV disease after Transplantation:Effects on incidence of rejectionEvidence from clinical trials

  12. VALACICLOVIR *P<0.01

  13. Valacyclovir Prophylaxis reduces both CMV and Biopsy confirmed acute rejection Lowance et al New Engl J Med 1999; 340: 1462 - 70

  14. Transplant Coronary Artery Disease after CMV infection Grattan et al JAMA 1989; 261: 3561 - 66

  15. Prophylactic Ganciclovir prevents Transplant Coronary Artery Disease Valentine et al Circulation 1999; 100: 61-66

  16. Ganciclovir prophylaxis reduces incidence of CMV pneumonitis and chronic Obliterative Bronchiolitis Soghikian et al J Heart and Lung Transplant 1996; 15: 881-7

  17. Messages from Protocol Histology Determinants of long term damage to renal allografts Nankivell et al Transplantation 2001; 71: 515-523

  18. Westmead Study • consecutive renal Tx (n = 180) • study group (function @ 3 mo., n = 163) • protocol Tx. biopsy (n = 112) • blinded Banff (95) evaluation • adequate tissue (n = 102) analysis • No biopsy • anticoagulation • hyperacute rejection • PC - dilatation • pediatric kidney • medical • declined/unknown donor biopsy (n = 91)

  19. Westmead CMV data Acute Rej 58% 5yr GS 69% Acute Rej 45% 5yr GS 91% No CMV Prophylaxis

  20. 3-month histology 1. Acute changes • Banff “borderline” changes 49% • subclinical rejection 29% HLA mismatch & acute rejection (P < 0.05) 2. Chronic changes • Banff chronic nephropathy 24% DGF, donor microvascular & age, cold ischemia, vascular rejection (P < 0.05 - 0.01)

  21. Mean Banff scores (3 mo) * 1.5 1 * 0.5 0 NIL Cellular Vascular Effects of prior acute rejection Mean + SEM DGF excluded CI CT CV

  22. ci cv chronic nephropathy Effects of subclinical rejection on 12 month histology 2 12 month Banff scores * * 1.5 1 0.5 0 Nil Borderline Subclinical 3 month Banff grade

  23. Site of chronic 12-month damage 3 mo 12 mo r P i -> ci 0.36 0.05 t -> ct 0.32 0.05 v -> cv 0.66 0.001 compartment specific • chronic damage is localized to histological compartment of 3 month acute injury

  24. CMV Disease patients Protocol 3 month histology - acute qualifiers Patient g i t v outcome 1 0 3 3 0 >10years 2 0 2 2 0 >8years 3 0 2 2 0 Fail 7years non-compliance 4 0 1 1 1 >10years mean 0 1.1 1.1 .08

  25. CAN: multivariate predictors 95% CI KAT (10 min) CV (grade) Tubular Injury Late rejection Proteinuria Hypertension 1 10 100 ODDS RATIO

  26. Late rejection • 45% of graft failures • non-compliance (r=0.57, P < 0.001)

  27. Graft survival (%) Chronic interstitial fibrosis 100 ci 0 90 ci 1 80 70 ** ci 2 > 60 50 5 15 0 10 Years after transplantation

  28. 100 90 80 70 60 50 0 5 10 15 Graft survival (%) Chronic vascular changes cv 0 * cv 1 > Years after transplantation

  29. CI CV Tubular Injury interstitial lymph. Late rejection 95% CI Age (year) ODDS RATIO 10 100 Graft failure: Cox predictors 0.1 1

  30. What damages a transplant? EARLY LATE donor quality (cv) chronic CSA toxicity ischemia non-compliance ATN-DGF late rejection acute vascular recurrence of GN rejection proteinuria subclinical rejection (hypertension)

  31. CMV Control of Virus Activation Immune response Target Organ Damage Cytopathic effect CTL mediated effect T T T T T T CTL mediated rejection T T T

  32. Hypothesis: Host control of CMV infection by T cells is a normal process in latently infected individuals, that co-exists with other allograft pathology such as acute rejection and stable graft acceptance, but may have consequences for the graft. Failure of Host control mechanisms leads to viral disease, which may also have direct consequences for the graft

  33. Mechanisms of Graft Damage CMV Cytopathic effect Amount of GRAFT DAMAGE CTL vs CMV+Allo Allograft Rejection Spectrum of response

  34. Balance Mechanisms Anti-T cell Immunosuppression Anti-Viral Agents

  35. Mechanisms of Graft Damage ANTI-T CELL THERAPY CMV Cytopathic effect CTL vs CMV+Allo Allograft Rejection

  36. Mechanisms of Graft Damage ANTI-VIRAL THERAPY CMV Cytopathic effect CTL vs CMV+Allo Allograft Rejection

  37. Mechanisms of Graft Damagewhat can you see? CMV Cytopathic effect CTL vs CMV+Allo Cellular Allograft Rejection

  38. Hypothesis: Host control of CMV infection by T cells is a normal process in infected individuals, that both co-exists and interacts with other allograft pathology such as acute rejection and stable graft acceptance, but may have consequences for the graft. Failure of Host control mechanisms leads to viral disease, which may also have direct consequences for the graft

  39. Does it matter? • If CMV infection is controlled by T cells and damages the graft then anti-T cell therapy will increase the damage, while anti CMV therapy will reduce the damage • When a cellular infiltrate is due to T cells directed at Allo Ag then increased anti T cell therapy will be effective. But when the T cells are directed at CMV/Allo anti T cell therapy will lead to uncontrolled CMV

  40. Graft failure • CAN 75%, recurrent GN 15%, other 10% Features: CAN Nil P • late rejection 43% 3% 0.001 • non-compliance 30% 3% 0.001 • proteinuria 86% 24% 0.001 • hypertension 95% 76% NS • mean Ch. Banff 1.33 0.92 0.05

  41. Lowance et al New Engl J Med 1999; 340: 1462 - 70

  42. Westmead CMV - HHV6 STUDY DISEASE NO DISEASE OKT3/ATG NONE

  43. IV GANCICLOVIR VERSUS PLACEBO/CONTROLIN HEART TRANSPLANTATION

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