studies

528A AASLD ABSTRACTS HEPATOLOGY, October, 2015
The following authors have nothing to disclose: Guo-Xiang Yang, Takashi Tomiyama,
Ying Sun, Weici Zhang, Patrick S. Leung, Xiao-Song He, Sandeep S.
Dhaliwal, M. Eric Gershwin
640
Natural killer cells regulate T cell immunity in primary
biliary cirrhosis
Shinji Shimoda 1 , Minoru Nakamura 2 , M. Eric Gershwin 3 ; 1 Kyushu
University, Fukuoka, Japan; 2 Nagasaki University, Nagasaki,
Japan; 3 UC Davis, Davis, CA
BACKGROUND: Dissection of the multi-lineage response that
leads to biliary epithelial destruction is essential for future therapeutic
efforts. Indeed, a variety of work has already reflected
that there are autoreactive T and B cells that do target biliary
epithelial cells (BEC), but there is also an emerging set of data
that suggests innate immunity is critical not only for the initiation,
but also for a variety of interactions that alter the natural
history of cholangitis. Our previous work has demonstrated that
biliary cell cytotoxity is dependent on the initiation of innate
responses followed by chronic adaptive as well as bystander
mechanisms which are the interactions between natural killer
(NK) cells and BEC. OBJECTIVE: We have taken advantage
of our ability to isolate NK, BEC and endothelial cells from
explanted liver samples, and studied the interactions between
NK cells and BEC and focused on the mechanisms that activated
autoreactive T cells in the presence or absence of antigen
presenting cells (APC) and their dependence on IFN-g as
well as expression of BEC HLA class I and class II molecules.
Explanted liver and spleen from a total of 7 patients included
2 with PBC and 5 with hepatitis C virus infection were used.
There were no significant differences in the results derived from
the liver mononuclear cells or the BEC population from either
PBC or hepatitis C and ultimately all data were combined. This
is consistent with our thesis that the BEC is an innocent victim
as well as the established data that PBC reoccurs following
transplantation. RESULTS: At a high NK/BEC ratio, NK cells
attack autologous BEC in either a PBC-specific nor auto antigen-specific
manner, and as glutathiolation does not occur in
apoptotic BEC, autoantigen PDC-E2 that exists in the mitochondrial
membrane is not degenerated by caspases in PBC, PDC-
E2 from lysed BEC activate autoreactive CD4 positive T cells
in the presence of APC. In contrast, at a low NK/BEC ratio,
BEC were not lysed whereas IFN-g production was induced
from NK cells, which in turn induced expression of HLA class
I and II molecules on BEC and protected them from lysis upon
exposure to autoreactive NK cells. In addition, IFN-g secretion
from NK cells after exposure to autologous BEC enabled autoreactive
CD4 positive T cells to lyse BEC in the presence of
PDC-E2 antigen. CONCLUSION: Our data suggest that NK cell
mediated innate immune responses are critical for the breach
of tolerance at the initial stage of PBC, but also maintained the
cytotoxic effect of autoantigen-specific T cells, which are critical
for disease progression.
Disclosures:
The following authors have nothing to disclose: Shinji Shimoda, Minoru
Nakamura, M. Eric Gershwin
641
Combination Anti-Retroviral Therapy Provides Reduction
in Human Betaretrovirus Load and Durable Biochemical
Responses in Patients with Primary Biliary Cirrhosis
Ellina Lytvyak, Aldo J. Montano-Loza, Lynora Saxinger, Andrew
Mason; University of Alberta, Edmonton, AB, Canada
Purpose/Background: A human betaretrovirus has been characterized
in primary biliary cirrhosis (PBC). Reverse transcriptase
inhibitors lamivudine and zidovudine have shown limited
efficacy. Whereas combination lopinavir/ritonavir (LPRr) and
tenofovir/emticitabine (TDF/FTC) has been reported to be
efficacious in normalizing liver tests (Lancet 2011). Methods:
PBC patients unresponsive to UDCA were randomized into
a crossover study with daily TDF/FTC 300/200mg and LPRr
800/200mg versus placebo for 6 months; followed by an
open label study for a total of 24 months. HBRV DNA was
assessed in PBMC using digital droplet PCR. Results: (A) In the
6 month RCT, a significant reduction in Alk Phos was observed
in patients on TDF/FTC and LPRr (p