간이식 면 면 면 면 면 면 면
주 동 진 연세대학교 의과대학 세브란스병원 이식외과
1. Introduction
2. Donor Specific Antibody in LT
3. ABO incompatible LT
Today….
Immune Tolerance
Remove or neutralize circulating anti-donor antibody
Graft liver endothelium, hepatocytes
T-cell
Recruitment of other immune cells Ab production Cell killing
What is DSA?
HLA Class I molecules 1) HLA-A,B,C gene products 2) All nucleated cell 3) CD8(+) T-cell - cytotoxic function - cellular immunity
HLA Class II molecules 1) HLA-D/DR gene products 2) B-cell, Activated T-cell, APC (macrophage, mococyte, Dendritic cell) 3) CD4(+) T-cell - helper/inducer function
Donor Specific Antibody (DSA)
Preformed antibody against donor HLA (Sensitization)
Pregnancy Transfusion
Previous transplantation
de novo DSA after liver transplantation (HLA mismatch)
How can we detect DSA?
(complement-dependent cytotoxicity) Donor
lymphocyte Recipient
serum Viable cells (negative)
complement
complement
Cell lysis (positive)
CDC Crossmatch
+
Controversial Issues
No difference!!
Controversial Issues
Independent Risk factor in Small size graft
Effects of DSA on graft outcomes
O’Leary JG, et al. Liver Transplantation 2013; 19(9): 973-980
DSA Persistency after Liver Transplantation
Rejection related with DSA (Class II)
O’Leary JG, et al. Liver Transplantation 2013; 19(9): 973-980
Patient Survival according to DSA
O’Leary JG, et al. Liver Transplantation 2013; 19(9): 973-980
O’Leary JG, Gebel HM, Ruiz R, et al. Class II alloantibody and mortality in simultaneous liver-kidney transplantation. Am J Transplant 2013;13(4):954-60
In Simultaneous Liver-Kidney transplantation, Class II DSA increase Liver rejection and Kidney AMR.
Biliary stricture related with DSA
Speranta Iacob, et al. Liver Int 2012; 32(8):1253-1261
Miyagawa-Hayashino A, et al. Liver Transpl 2012; 18:1333–1342.
DSA associated with idiopathic fibrosis
79 Pediatric LT 5-yr protocol Bx DSA (+) or (-)
Acute/Chronic rejection Biliary stricture Graft fibrosis
Poor Graft Survival
Old New
Preformed De Novo
Patient Survival according to de novo DSA
H. Kaneku, et al. De Novo Donor-specific HLA antibodies decrease patient and graft survival in liver transplantation . Am J Transplant 2013;13(6):1541-1548
O’Leary JG, et al. Am J Transplant 2011;11:1868-1876
Chronic rejection patients showed Higher MFI DSA Preformed
de novo
Class I
Class II
H. Kaneku, et al. De Novo Donor-specific HLA antibodies decrease patient and graft survival in liver transplantation . Am J Transplant 2013;13(6):1541-1548
De Novo DSA after Liver Transplantation
Preformed DSA (Retrospectively-designed)
Results (Graft survival rate)
Post-transplant year
P >0.05 DSA − (N=187) DSA + (N= 32)
Song SH, Joo DJ, et al. Ann Surg Treat Res 2015;88(2):100-105
Results (Graft survival rate)
Post-transplant year
P=0.294 No or single DSA (N=205) Multi DSA (N=14)
Song SH, Joo DJ, et al. Ann Surg Treat Res 2015;88(2):100-105
Graft survival rate according to %PRA B.
C.
A.
PRA class I PRA class II
Total (Sum of % PRA)
Song SH, Joo DJ, et al. Ann Surg Treat Res 2015;88(2):100-105
High PRA > 30% Poor graft survival
DSAs after Transplantation (Prospective design)
Graft outcomes during f/u
Patients (n=40) Acute rejection 4 (10%) Chronic rejection 1 (2.5%) GVHD 1 (2.5%) Primary non function 1 (2.5%) Biliary complication Stricture Leakage
9 (22.5%) 2 (5%)
Mortality 2 (5%)
Graft outcomes according to DSA (+/-----)
Pre-DSA – (36) Pre-DSA + (4) P-value
Acute rejection 3(8.3%) 1(25%) 0.355
Biliary Cx. 9(25%) 2(50%) 0.300
AR + Biliary Cx. 12(33%) 3(75%) 0.139
Post-DSA – (34) Post-DSA + (6) P-value
Acute rejection 2(6%) 2(33%) 0.100
Biliary Cx. 7(20%) 4(66%) 0.039
AR + Biliary Cx. 9(38%) 6(83%) 0.001
Preformed
After LT
0
5000
10000
15000
20000
25000
PreTx POD7d POD14d POD21d POD3m POD6m
MFI change of Class II DSA after LT
MFI Difference According to Rejection
0
2000
4000
6000
8000
10000
12000
PreTx 7 14 21 90 180
No Acute rejection (N=4)
Acute rejection (N=2)
MFI
Day
6000
Conclusion
Preformed DSAs no correlation with graft outcomes. de novo DSAs after transplantation associated with biliary complication. The higher MFI of DSA The more acute rejection.
How can we do?
MCS,median channel s hifts
Desensitization?
Induction?
1270 LT patients 33 patients given induction therapy ATG or OKT3 + Daclizumab
O’Leary JG, et al. Liver Transplantation 2013 (e-Pub ahead)
Induction >> No DSA
Bortezomib?
Velcade® 26S proteasome inhibitor Plasma cell depletion Indication: Multiple myeloma
Steroid resistance Abnormal C4d deposition Plasma cell infiltration Elevated DSA titers
ABO incompatible Liver Transplantation
Liver may be less susceptible than other organs to an antibody reaction.
1974, Starzl TE et al, Transplant Proc 1984, Iwatsuki S et al, Transplant Poc 1990, Gugenheim J et al, Lancet
Hepatic necrosis Intrahepatic biliary complication
N=3
N=10/13, 1yr
Hemagglutin levels < 1:16
Desensitization!
Pre-transplant Desensitization
Plasmapheresis / Exchange transfusion Splenectomy Rituximab PV infusion HA infusion
Both or Select one
Both or Select one
Preformed circulating Ab
Plasma exchange
Newly matured B-cell
Rituximab (anti-CD20)
Thank you for donating your attention!
Role of mTORi in Liver Transplantation
Milan criteria can be “ carefully extended” with SRL.
2491:12167
High dose Tacrolimus (>10ng/mL) increased Risk of HCC recurrence!
Slide Number 1Slide Number 2Slide Number 3Slide Number 4Slide Number 5Slide Number 6Slide Number 7Slide Number 8Slide Number 9Slide Number 10Slide Number 11Slide Number 12Slide Number 13Slide Number 14Slide Number 15Slide Number 16Slide Number 17Slide Number 18Slide Number 19Slide Number 20Slide Number 21Slide Number 22Slide Number 23Slide Number 24Slide Number 25Slide Number 26Slide Number 27Slide Number 28Slide Number 29Slide Number 30Slide Number 31Slide Number 32Slide Number 33Slide Number 34Slide Number 35Slide Number 36Slide Number 37Slide Number 38Slide Number 39Slide Number 40Slide Number 41Slide Number 42Slide Number 43Slide Number 44ABO incompatible �Liver TransplantationSlide Number 46Slide Number 47Slide Number 48Slide Number 49Slide Number 50Slide Number 51Slide Number 52Slide Number 53Role of mTORi �in Liver TransplantationSlide Number 55Slide Number 56Slide Number 57Slide Number 58Slide Number 59Slide Number 60Slide Number 61