2015 Banff meeting Liver summary October 9, 2015, Vancouver, B.C. Canada. Presented by Dr. Christopher Bellamy.

1. Banff 2015 – Liver
Agenda and Background
A.J. Demetris
Thomas Starzl Transplant Institute
Dept. of Pathology
Division of Transplantation
University of Pittsburgh Medical Center
Pittsburgh, PA

2. Goals of Meeting
• Discuss role of antibodies in OLTx:
– effector and ? other functions
• Discuss what is needed to establish a
diagnosis of antibody-mediated rejection
(AMR) in OLTx:
– Acute (or active) AMR
– Chronic AMR
• Agree on criteria and make
recommendations to the field.

3. EOSINOPHIL AND NK CELLS
IN ADCC AND LIVER INJURY
Luis G. Hidalgo, Ph.D., D(ABHI)
University of Alberta Hospitals –
Histocompatibility Laboratory
Dept. of Lab. Med. and Pathology
Alberta Transplant Applied Genomics Centre

4. 4
*
IFN-g/
TNF
Endothelium
ADCC?
NK cell
Monocyte
C’ R’s C’ products FcR’s
Proinflammatory
cytokines,
Lytic enzymes, ROS’s
IMMUNE EFFECTORS IN ABMR

5. Mononuclear phagocyte system
in liver transplantation
Chris Bellamy

6. Liver Allograft Pathology After
Effective Anti-HCV Therapies -
Changes and Challenges
Professor G.W. McCaughan
A/W Morrow Professor of Gastroenterology and Hepatology
ANLTU
University of Sydney
Centenary Institute
Royal Prince Alfred Hospital
Sydney, Australia

7. • Interferon free DAA AVT will largely reduce HCV
infection in the liver allograft but may only
prevent liver transplant in a minority
• However post transplant a small number of cases
will require astute liver biopsy and histological
assessment These include
– AVT resistance cases ( G3 at the moment)
– DILI
– Allograft rejection ( a decrease in Calcineurin inhibitor
levels)
– Immune hepatitis /Immune activation syndrome

8. Liver C4d TMA Study
Desley Neil
Birmingham, UK

9. Participating Centers
• USA
– UPMC
– Childrens hosp of
Pittsburgh
– Mayo
– Mt Sinai
– Kansas
– UCLA
– Mass General
– Baylor
– Medical College of
Wisconsin
– UWHC
– John Hopkins
– Emory
• Canada
– Alberta
• UK
• Birmingham
• Cambridge
• Edinburgh
• Kings
• Leeds
• France
• Paul Brousse
Paris
• Turkey
• Instanbul
• Ege
• Denmark
• Copenhagen
• Norway
• Oslo
• Switzerland
• Basel
• Belgium
• Leuven
• Italy
• Palermo
• Brazil
• Sao Paulo
• Japan
• Kyoto
• Kobe
• Australia
• Sydney
• Brisbane

10. TMA
30
TMA
10
TMA
39

11. CONCLUSIONS
• Portal veins and capillaries are most sensitive
target structures
– Sinusoids least sensitive and difficult to detect
– Ignore stromal staining (portal and central) in
perihilar areas/large portal tracts
• Variability in C4d staining between centres
– best performing method made available

12. Pathophysiologic Mechanisms of (Late) Liver
Allograft Injury/Fibrosis
Stefan Hübscher,
Institute of Immunology & Immunotherapy, University of Birmingham
Department of Cellular Pathology, Queen Elizabeth Hospital, Birmingham

13. Late Centrilobular/Perisinusoidal Fibrosis in Paediatric Liver Allografts
Further Evidence for Antibody- Mediated Mechanisms
(Miyagawa-Hayashino 2012 , Yamada 2012 ,Tomita 2013, Ohe 2014)
• Bridging fibrosis/cirrhosis in protocol biopsies > 5 years post transplant associated
with donor-specific antibodies - mainly class II (Miyagawa-Hayashino 2012, Ohe 2014)
• Pericentral/pericellular fibrosis in protocol biopsies > 1year post-transplant
associated with C4d deposits in portal vessels and hepatic veins (Yamada2012) and
with ABO-incompatibility (Tomita 2013)
• Mild inflammatory changes (portal and/or centrilobular) also present in 60-87%
biopsies showing centrilobular /perisinusoidal fibrosis (Miyagawa-Hayashino 2012,
Yamada 2012)
• Antibody-mediated mechanisms may lead to late
fibrosis with or without inflammation
• Importance of recognising fibrosis in different
regions (portal, sinusoidal, centrilobular)

14. De novo Donor-Specific Antibodies
in Liver Transplantation:
Clinical and Histopathological manifestations
Dr Arnaud DEL BELLO
Department of Nephrology and Organ Transplantation
CHU Toulouse Rangueil
France

15. Incidence of aAMR in de novo liver
transplantation
Del Bello et al, Transplant Int 2015
0
5
10
15
20
25
30
D0
n=152
M1
n=152
M3
n=149
M6
n=144
M12
n=129
M24
n=93
M36
n=70
M48
n=41
Percentageofpatientswithanti-HLA
dnDSAs
Time post liver transplantation (months)
dnDSAs (anti-class I +/- II)
anti-class I dnDSAs
anti-class II dnDSAs
152 LTR:
Follow-up 34 [1.5-77] months
14 % dnDSA+ at last Follow-up
Acute rejections: 52% (dnDSA+) vs.
21% (DSA-), p= 0.005
9 cases of aAMR
(incidence at LFU 5.1%)

16. dnDSA & acute AMR:
graft dysfunction with
1. dnDSA in serum
2. H & E staining
3. C4d positive
4. Exclusion of other causes

17. Long-Term Follow-up and Weaning Immunosuppression in
Pediatric Recipients:
Factors Influencing the Graft
Sandy Feng, MD, PhD
University of California San Francisco
2015 Joint Banff – CST Scientific Meeting
October 7, 2015
Vancouver, BC

18. Observations
• Stable, long-term pediatric liver transplant recipients with
normal liver tests can harbor significant histopathology.
• High MFI Class II DSA is a strong risk factor for interface
hepatitis (± fibrosis) and a modest risk factor for fibrosis.
• Spontaneously / operationally tolerant pediatric liver
transplant recipients do not exhibit progressive allograft
histopathology.
• (High MFI) Class II DSA, present either at baseline or
developing during withdrawal, is not prohibitive of
spontaneous / operational tolerance.

19. Chronic antibody-mediated
rejection: perspectives and issues
Jacqueline O’Leary
Baylor University Medical center
Texas

20. Arnaud Del
Bello
Adults
6 – 220
mo.
Indication ↑Fibrosis, NOS
24% of patients with de novo DSA developed acute AMR:
lymphocytic portal inflammation, lymphocytic cholangitis, PV C4d+,
endotheliitis
Sandy Feng Pediatric
> 4 years
Protocol Deceased donor and Class II DSA predicted assignment to patients
with interface activity with/out fibrosis whereas only recipient age
predicted assignment patients with fibrosis, alone.
Jackie O’Leary Adult
> 5 yrs
Protocol ↑ portal inflammation and interface activity
↑ lobular/perivenular inflammation and typical TCMR
↑ portal venopathy, portal “collagenization” and portal/periportal
and sinusoidal fibrosis
DSA strongly correlated with portal capillary and portal stromal
C4d (IPEX)
Histologic changes with chronic DSA

21. Consensus discussion
• Acute AMR
– compatible histology, diffuse C4d portal
microvascular positivity, serum DSA+
– grading of component features
• i-(immune) score: C4d immunopositivity
• h-(histopathology) score
• Probable chronic AMR
– compatible histology, C4d +, recent DSA +,
exclusion of other potential causes

22. i-(immune)-score (FFPE*):
0. No C4d deposition in portal microvasculature
1. Minimal (<10% portal tracts) C4d deposition in
portal microvascular endothelia
2. Moderate (10-50% portal tracts) C4d deposition
in portal microvascular endothelia – usually
without extension into periportal sinusoids
3. Diffuse (>50% portal tracts) C4d deposition in
the portal microvascular endothelia - often
with extension into inlet venules or periportal
sinusoids

23. h-(histopathology) score
• portal microvascular endothelial cell enlargement (portal veins,
capillaries, inlet venules) involving a majority of portal tracts with
sparse microvasculitis (images provided)
• monocytic , eosinophilic or neutrophilic micro-
vasculitis/capillaritis, with prominent portal and/or sinusoidal
microvascular endothelial cell enlargement involving a majority of
portal tracts or sinusoids, with some portal edema, portal
capillary and inlet venule dilatation. Fibrin deposition and RBC
sludging is more common and prominent in ABO-incompatible
allografts.
• As above, with at least focal microvascular disruption with fibrin
deposition, and extravasation of red blood cells into the portal
stroma and/or space of Disse (subsinusoidal space). The latter
findings are more prominent in ABO-incompatible allografts.

24. Probable chronic AMR
(all 4 criteria required):
1) Histopathological pattern of injury consistent with
chronic AMR: both required:
a. Otherwise unexplained and at least mild mononuclear
portal inflammation with interface hepatitis and/or
lymphocytic perivenulitis.
b. At least moderate sinusoidal and/or perivenular fibrosis
2) Recent circulating HLA DSA in serum samples
(for example, measured within 3 months of biopsy)
3) At least focal C4d positivity (>10% portal tracts).
4) Reasonable exclusion of other insults that might cause
a similar pattern of injury (see text).