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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!

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