studies

1242A AASLD ABSTRACTS HEPATOLOGY, October, 2015
2123
Liver Plasmacytoid Dendritic Cells Expressing miR-181
prolong graft survival by increasing T Regulatory cells
and Decreasing B cells as Revealed by Mass Cytometry
(CyTOF
Audrey H. Lau 1 , Matthew J. Vitalone 2 , Xiumei Qu 2 , Todd Shawler 2 ,
Olivia M. Martinez 2 , Carlos O. Esquivel 2 , Sheri M. Krams 2 ; 1 Pediatrics,
Division of Gastroenterology, Hepatology, and Nutrition,
Stanford/LPCH, San Francisco, CA; 2 Surgery, Stanford University,
Stanford, CA
Liver allografts are well tolerated and other solid organ
allografts, when transplanted concurrently with livers, show
improved outcomes. However, the mechanisms underlying
“hepatic tolerance” have yet to be elucidated. Previous data
show that hepatic dendritic cells (DC) have diminished antigen
presentation and immune stimulatory function compared
with DC in lymphoid tissue. Immature plasmacytoid (p)DC have
been shown to induce graft prolongation and we have previously
shown miR-181a1b1 is increased in pDC as compared
to conventional DC. Wild-type (WT) BALB/c mice were transplanted
with allogeneic (C57BL/6) vascularized heterotopic
heart grafts. Animals received either no treatment (n=3) or were
injected i.v. with 0.5×10 6 hepatic pDC (n=5) or miR-181a1b1 -/-
(KO) pDC (n=3) at day (D)−7 from transplant. Recipients with
no treatment rejected their allograft by D7 while recipients pretreated
with hepatic pDC had significantly prolonged allograft
survival to D15-21 (p1.5
yrs) Opn -/- mice, which displayed significant hepatomegaly
and splenomegaly compared to their age-matched WT littermates.
Morphological features consisted of small aggregates
of cells with intensely basophilic nuclei and clusters of immature
and mature myeloid cells located in the sinusoids and in
the portal areas. Accumulation of HSCs occurred also in the
spleen but to a much lesser extent in the kidney and in the lung.
Furthermore, Opn -/- mice showed premature exit of immature
hematopoietic cells from the bone marrow to the spleen and
to the liver, increased cellularity of lineage-negative cells and
elevated hepatic GCSF, CXCL1, MCSF, MIP1α, RANTES and
TNFα as well as serum MCSF and CXCL1 compared to WT
littermates. Opn -/- mice also presented numerous iron deposits
in the periportal zone of the liver, in the bone marrow and in
the spleen but they were minimal in the lung and were absent
in the heart and in the kidney, suggesting dysregulation of iron
metabolism in the absence of Opn compared to WT littermates.
CONCLUSION: These results suggest a critical role for OPN in
HSC homeostasis by regulation of bone marrow homing and
modulation of cytokine levels involved in their development.
Disclosures:
The following authors have nothing to disclose: Fernando Magdaleno, Xiadong
Ge, Holger Fey, Costica Aloman, M. Isabel Fiel, Natalia Nieto
2125
IL-17A plays a pivotal role in LPS/GalN-induced fulminant
hepatic injury in mice.
Hiroshi Kono, Shinji Furuya, Chao Sun, Hideki Fujii; First Department
of Surgry, University of Yamanashi, Chuo, Japan
Background Lipopolysaccharide/D-Galactosamine (LPS/Gal-
N)-induced hepatic injury is an experimental model of fulminant
hepatic failure in which tumor necrosis factor-a (TNF-a) plays
a pivotal role. Moreover, it was reported from our laboratory
that interleukin (IL)-17A enhanced production of TNF-a by the
Kupffer cell. Objective The purpose of this study was to determine
the role of IL-17A in LPS/GalN-induced hepatic injury
in mice. Methods LPS/GalN was injected into three mouse
models: wild-type (WT) mice, IL-17A knockout (KO) mice, or
IL-17A knockout mice treated with recombinant mouse (rm)
IL-17A homodimer (KO + rmIL-17A). Survival was assessed
for 24 hours after LPS/GalN injection, and histopathologic
findings were evaluated at various time points after LPS/GalN
injection for neutrophil and apoptosis markers. After LPS/GalN
injection, expression of the inflammatory mediators TNF-a, IL-6,
monocyte chemotactic protein (MCP)-1, IL-17A, high mobil-