Donor specific antibodies are associated with higher inflammatory activity, more fibrosis and higher expression of rejection associated transcripts in human liver allografts with subclinical rejection

ORAL PRESENTATIONS Methods: Between February 2014 and June 2015, 142 patients listed for decompensated cirrhosis without HCC were treated with DAA. Delisted patients were prospectively followed up until October, 31st 2016, with regular visits, liver function tests and abdominal ultrasounds. Results: Thirty-four of 142 (23.9%) patients were delisted due to clinical improvement. Median (IQR) follow up from start of therapy was 111 weeks (98–125) while median follow up from delisting was 58 weeks (22–80). Median MELD and Child-Pugh score at start of DAA therapy were 14 (IQR: 11–15) and 9 (IQR: 8–10) respectively. The same scores improved over time and were 9.5 (IQR: 8–11) and 6 (IQR5–6) 78 weeks afterwards (Figure 1). To date all 34 delisted patients are alive and 2 (5.8%) were relisted for clinical redecompensation. Their MELD score at relisting were 16 and 15. Another patient with difficult to treat ascites is under evaluation for TIPS or relisting. Overall, 3 patients (3/34 = 8.8%) did not show a durable clinical improvement after DAAs. No patient had to be relisted for occurrence of HCC. Of the other 108 patients, 8 were inactivated due to clinical improvement after DAA but not delisted. Reasons for not delisting were: incomplete reversal of signs of decompensation (5 patients), viral relapse requiring retreatment (1 patient) occurrence of HCC (1 patient), suspicion of HCC (1 patient). Conclusions: After a median follow up of 58 weeks from delisting, the outcome of delisted patients is favourable since only 3 patients (8.8%) had to be relisted or considered for relisting and no patient developed HCC to date. Longer follow up are needed to confirm these preliminary positive outcomes. PS-064 Donor specific antibodies are associated with higher inflammatory activity, more fibrosis and higher expression of rejection associated transcripts in human liver allografts with subclinical rejection A. Höfer1,2, M. Verboom3, M. Hallensleben3, B. Hartleben4, D. Jonigk4, J. Schlue4, F. Lehner5, S. Hübscher6, M.P. Manns1, E. Jaeckel1,2, R. Taubert1,2. 1Gastroenterology, Hepatology and Endocrinology; 2 Integrated Research and Treatment Center Transplantation (IFB-Tx); 3 Transfusion Medicine; 4Pathology; 5Visceral- and Transplant Surgery, Hannover Medical School, Hannover, Germany; 6Cellular Pathology, University Hospitals Birmingham, National Health Service Foundation Trust, Birmingham, United Kingdom E-mail: [email protected] Background and Aims: Subclinical rejection (SCR) is a common finding in protocol biopsies after liver transplantation and has a good medium-term prognosis even if left untreated. We recently found hints for an intrahepatic regulation of cytotoxic T cells by regulatory T cells (Treg) in SCR. However, the role of donor-specific antibodies (DSA) has not been investigated in detail in this setting. Methods: We included all hepatitis C negative patients from our protocol biopsy program. Biopsy proven rejection with liver enzymes (ALT, AST, AP) >2 × upper limit of normal (ULN) was defined as acute cellular rejection (ACR), and with liver enzymes ≤2 × ULN as SCR. No histological rejection (NHR) was defined as RAI < 2, and normal liver enzymes. RT-PCR was performed on tissue obtained from 90 liver biopsies using published panels with 90 genes for rejection, endothelial cell activation, operational tolerance, T cell exhaustion and immune regulation markers. DSAwere detected with bead assays. Results: On the transcriptional level SCR biopsies were more related to NHR than to ACR biopsies in a cluster analysis of RT-PCR results ( p < 0.05 and q < 0.08). It is interesting that the levels of GARP, a marker for activated Treg, but not of FOXP3, the Treg lineage marker, were higher in grafts with SCR compared ACR. DSAs were found in paired blood samples from 22/88 (25.0%) patients with biopsies showing SCR, 4/42 (9.5%) with NHR and 18/85 (21.2%) with ACR, while the overall DSA rate was 21.8% (75/343). The DSA+ SCR biopsies had significantly higher scores for the RAI, interface hepatitis and central perivenulitis as well as more portal and S40

perisinusoidal fibrosis compared to DSA- SCR biopsies. Additionally the expression of mostly rejection and endothelial activation associated transcripts was higher in DSA+ SCR biopsies. No DSA+ liver biopsy showed positive C4d staining with our local protocol. Nonetheless, 8/88 (9.1%) of SCR biopsies fulfilled the 2016 Banff criteria for possible chronic antibody mediated rejection (AMR). The gene expression analysis of these possible AMR biopsies is currently ongoing. Conclusions: SCR is transcriptionally more related to biopsies without rejection. This is in line with the good clinical prognosis of untreated SCR. However, the appearance of DSA seems to identify SCR biopsies with more inflammation and fibrosis. The combination of SCR in biopsies with DSA positivity might therefore identify patients with more pronounced graft inflammation, which might require a change in immunosuppression. PS-065 Changes in brain integrity underlying cognitive and functional recovery following liver transplantation plateaus after six months V. Ahluwalia1, J. Wade1, J.L. Steinberg1, M. White1, A. Fagan1, D. Ganapathy1, F.G. Moeller1, J.S. Bajaj1. 1Virginia Commonwealth University, Richmond, United States E-mail: [email protected] Background and Aims: Cognitive improvement after liver transplant (LT) is variable and is often found within 6 months. The linkage between evolving cognitive changes and brain integrity after 6 months post-LT is unclear. The aim was to define the temporal course of cognitive, quality of life and multi-modal brain MRI [Functional MRI (fMRI), MR spectroscopy (MRS) diffusion tensor imaging (DTI)] up to one year post-LT. Methods: Cirrhotic pts listed for LT underwent evaluation of quality of life (Sickness Impact Profile, SIP), cognitive function (PHES) and brain MRI pre-transplant, 6-month and 1-year post-LT. Brain MRI: fMRI: Patients performed inhibitory control test (ICT); correct inhibition to lures (CIL) contrasts were created. Voxel-wise group paired comparisons were done between timepoints. MRS: Brain MRS [(glutamine + glutamate (Glx), myoinositol (mI), Choline (Cho)] were performed in the posterior gray matter (PGM) to assess ammoniaassociated changes. DTI: DTI studies white matter integrity. For DTI analysis, Fractional Anisotropy (FA), Mean Diffusivity (MD), Longitudinal Diffusivity (LD) were studied; MD/LD increase indicate axonal recovery. The analyses of cognition, SIP and brain multi-modal MRI parameters were performed between pre-LT, 6 months and 1-year post-LT.

Journal of Hepatology 2017 vol. 66 | S33–S62