A bioartificial liver device secreting interleukin-1 receptor antagonist for the treatment of hepatic failure in rats.
BACKGROUND
Liver transplantation is the treatment of choice for many patients with fulminant hepatic failure (FHF). A major limitation of this treatment is the lack of available donors. An optimally functioning bio-artificial liver (BAL) device has the potential to provide critical hepatic support to patients with FHF. In this study, we examined the efficacy of combining interleukin-1 (IL-1) receptor blockade with the synthetic function of hepatocytes in a BAL device for the treatment of FHF.


METHODS
We injected an adenoviral vector encoding human IL-1 receptor antagonist (AdIL-1Ra) into the liver of D-galactosamine (GalN) intoxicated rats via the portal vein. We also transfected primary rat hepatocytes and reversibly immortalized human hepatocytes (TTNT cells) with AdIL-1Ra, and incorporated these transfected hepatocytes into our flat-plate BAL device and evaluated their efficacy in our GalN-induced FHF rat model after 10 h of extracorporeal perfusion.


RESULTS
Rats injected with AdIL-1Ra showed significant reductions in the plasma levels of hepatic enzymes. Primary rat hepatocytes transfected with AdIL-1Ra secreted IL-1Ra without losing their original synthetic function. Incorporating these cells into the BAL device and testing in a GalN-induced FHF rat model resulted in significant reductions in plasma IL-6 levels and significantly improved animal survival. Incorporating the AdIL-1Ra transfected TTNT cells in the BAL device and testing in the GalN-induced FHF rat model resulted in significantly reduced plasma IL-6 levels, and a trend toward improved survival was seen.


CONCLUSIONS
Hepatocytes producing IL-1Ra are a promising cell source for BAL devices in the treatment of GalN-induced FHF.
Shinoda
Masahiro
M
Center for Engineering in Medicine and Department of Surgery, Massachusetts General Hospital, Shriners Hospitals for Children, and Harvard Medical School, Boston, Massachusetts 02114, USA.
Tilles
Arno W
AW
Kobayashi
Naoya
N
Wakabayashi
Go
G
Takayanagi
Atsushi
A
Totsugawa
Toshinori
T
Harada
Hirohisa
H
Obara
Hideaki
H
Suganuma
Kazuhiro
K
Berthiaume
François
F
Shimazu
Motohide
M
Shimizu
Nobuyoshi
N
Tanaka
Noriaki
N
Kitajima
Masaki
M
Tompkins
Ronald G
RG
Toner
Mehmet
M
Yarmush
Martin L
ML
D000256:Adenoviridae / Q000235:genetics; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002461:Cell Line, Transformed; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005112:Extracorporeal Circulation; D005260:Female; D005688:Galactosamine / Q000633:toxicity; D015316:Genetic Therapy / Q000379:methods*; D022781:Hepatocytes / Q000166:cytology / Q000637:transplantation*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics* / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood; D008099:Liver / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000473:pathology / Q000628:therapy*; D019164:Liver, Artificial; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D015996:Survival Rate; D014162:Transfection; D020298:U937 Cells
D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; D005688:Galactosamine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase