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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. - PowerPoint PPT Presentation
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Jeremy Chapman
Westmead Hospital, Sydney
CMV Infection and Allograft Rejection :
Are we missing the point?
The simple Paradigm
CMV Infection
D+ R-
OKT3/ATG
HHV6/7
Chronic Rejection
Acute Rejection
CMV Disease
HLA induction
Adhesion mols
Cytokines
Chronic Something
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
Biology of CMV
ER Golgi
TAPProteosome
Nucleus
CMV
US2,US11
US6
US3
HLA E
100000
10000
1000
100
CMV disease Asymptomatic infection
Log
vir
al lo
ad (
cop
ies/
ml)
Humar et al Transplantation 1999; 68:1305 -11
Detection of CMV after Liver Transplantation
Control of CMV
SELF ALLO
Why isn’t the
graft lost to CMV?
CMV TetramersC
D8
pos
itiv
e
Tetramer positive
5%
Singhal et al Transplantation 2000; 69: 2251-2259
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
CMV - HHV6 STUDYOdds of getting Disease
0
5
0 10 20 30 40 50 60 70 80 90 100
ODDS RATIO
CMV + HHV6
HHV6
CMV
D + R -
OKT3/ATG
Detecting CMVHistopathology
Immunohistochemistry
In-situ hybridisation
IHC and ISH detected CMV in 70% of cases with negative histology.(1)
1. Am J Clin Path 1996;166:544-8
2. Hepatology 1997;Jan: 190-4
ISH detected CMV in bile ducts of 10/10 liver transplants with VBDS. (2)
Prevention of CMV disease after Transplantation:
Effects on incidence of rejectionEvidence from clinical trials
R+ (n=408)% D+/R- (n=208)%
VACV Placebo VACV Placebo
CMV disease 90days
0 6* 3 45*
CMV disease 6months
1 6* 16 45*
Acute rejection 6months
30 36 26 52*
HSV 8 34* 9 24*
1Lowance D, N Engl J Med (1999) 340(19):1462-70
VALACICLOVIR
*P<0.01
Lowance et al New Engl J Med 1999; 340: 1462 - 70
Valacyclovir Prophylaxis reduces both CMV and Biopsy confirmed acute rejection
Grattan et al JAMA 1989; 261: 3561 - 66
Transplant Coronary Artery Disease after CMV infection
Valentine et al Circulation 1999; 100: 61-66
Prophylactic Ganciclovir prevents Transplant Coronary Artery Disease
Soghikian et al J Heart and Lung Transplant 1996; 15: 881-7
Ganciclovir prophylaxis reduces incidence of CMV pneumonitis and chronic Obliterative Bronchiolitis
Messages from Protocol Histology
Determinants of long term damage to renal allografts
Nankivell et al Transplantation 2001; 71: 515-523
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
donor biopsy(n = 91)
No biopsy •anticoagulation•hyperacute rejection•PC - dilatation•pediatric kidney•medical•declined/unknown
Westmead CMV data
No CM V DISEASE71
CM V DISEASE6
CM V R POS77
CM V ?1
CM V DISEASE8
CM V D POS16
CM V D NEG11
CM V R NEG27
All105
Acute Rej 45%
5yr GS 91%
Acute Rej 58%
5yr GS 69%
No CMV Prophylaxis
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)
Effects of prior acute rejection
CVCTCI
0
0.5
1
1.5
NIL Cellular Vascular
*
*
Mean Banff scores (3 mo)Mean + SEM
DGF excluded
Effects of subclinical rejection on 12 month histology
12 month Banff scores
0
0.5
1
1.5
2
Nil Borderline Subclinical
3 month Banff grade
chronic nephropathy
cv
ci * *
3 mo 12 mo r P
i -> ci 0.36 0.05t -> ct 0.32 0.05v -> cv 0.66 0.001
compartment specific• chronic damage is localized to histological
compartment of 3 month acute injury
Site of chronic 12-month damage
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
CAN: multivariate predictors
Proteinuria
Late rejection
Tubular Injury
CV (grade)
KAT (10 min)
Hypertension
1 10 100ODDS RATIO
95% CI
Late rejection
0
0.05
0.1
0.15
0.2
Cumulative hazard
0 5 10 15
Years after transplantation
Late rejection
No late rejection
***Late rejection
No late rejection
0
0.25
0.5
0.75
1
Survival (%)
0 5 10 15
Year after transplantation
• 45% of graft failures
• non-compliance (r=0.57, P < 0.001)
50
60
70
80
90
100
0 5 10 15
Years after transplantation
Graft survival (%)
** ci 2 >
ci 1
ci 0
Chronic interstitial fibrosis
Chronic vascular changesGraft survival (%)
50
60
70
80
90
100
0 5 10 15
Years after transplantation
* cv 1 >
cv 0
Graft failure: Cox predictors
10.1
interstitial lymph.
Late rejection
Tubular Injury
10 100
CI
CV
Age (year) ODDS RATIO
95% CI
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)
CMV
Target Organ
Damage
Activation
Immune response
Cytopathic effect
CTL mediated effect
Control of Virus
CTL mediated rejectionT
T
T T
T
TT
T T
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
Mechanisms of Graft Damage
CMV Cytopathic effect
CTL vs CMV+Allo
Allograft RejectionAm
oun
t of
GR
AF
T D
AM
AG
E
Spectrum of response
Balance Mechanisms
Anti-T cell Immunosuppression
Anti-Viral Agents
Mechanisms of Graft Damage
CMV Cytopathic effect
CTL vs CMV+Allo
Allograft Rejection
ANTI-T CELL THERAPY
Mechanisms of Graft Damage
CMV Cytopathic effect
CTL vs CMV+Allo
Allograft Rejection
ANTI-VIRAL THERAPY
Mechanisms of Graft Damagewhat can you see?
CMV Cytopathic effect
CTL vs CMV+Allo
Cellular Allograft Rejection
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
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
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
Lowance et al New Engl J Med 1999; 340: 1462 - 70
Westmead CMV - HHV6 STUDY
CMV &HHV6
CMV HHV6 NONE CMV &HHV
CMV HHV6 NONE
SEVERE 1 0 0 0
MOD/MILD
8 1 3 0
TOTAL 9 1 3 0 0 5 0 4
SEVERE 0 0 0 0
MOD/MILD
2 0 0 0
TOTAL 2 0 0 0 0 0 1 5
OKT3/ATG
NONE
DISEASE
NO DISEASE
IV GANCICLOVIR VERSUS PLACEBO/CONTROL
IN HEART TRANSPLANTATION
R+ (%) D+/R-(% Regimen
n Control Active Control Active
149 46 9* 29 35 Placebo vs IV GCV/10mg/d (d 1–14) – 6 mg/dfor 5 d/wk (d 16–28) 1
56 25 25 71 11* Placebo vs IV GCV 5mg/1xd x 6wk++2wk ifrejection2
*P<0.05; +ATG induction1Merigan TC, N Engl J Med (1992) 326(18):1182–6; 2MacDonald PS, J Heart LungTransplant (1995) 14(1)32–8