ST2/IL-33 signaling worsens immune-mediated hepatitis from drug haptens
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1
Johns Hopkins University, ACCM, Pediatrics, Pathology, United States
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2
Johns Hopkins University, ACCM, United States
Susceptible persons develop immune-mediated drug-induced liver disease (Im-DILI) following exposure to certain drugs. Antibodies in Im-DILI are detectable in other forms of hepatitis suggesting that animal models of Im-DILI may uncover innovative therapeutic options for Im-DILI and other forms of hepatitis. IL-33 is an IL-1 family member that drives Th2 cytokines, cells and injury in asthma (Verri et al., 2010), but protects in atherosclerosis and Con A hepatitis. In experimental anesthetic Im-DILI, IL-1β, IL-2, IL-6 and IL-13, were demonstrated, in addition to neutrophils, mast cells, eosinophils, NK and NKT cells (Njoku et al., 2005). Furthermore, hepatitis was successfully transferred to naive mice using CD4+T cells. We hypothesized that signaling via ST2/IL-33 worsens experimental Im-DILI. To test our hypothesis we immunized female BALB/c mice with our catalytic site epitope of CYP2E1 (JHDN-5) that was covalently altered by a trifluroacetyl hapten (TFA) on days 0 and 7 ± IL-33 blocking antibody. Three weeks later liver supernatants were tested for IL-6, TARC, IL-33 and ST2 by ELISA. Hematoxylin and eosin-stained slides were scored for inflammation. Sera were tested for TFA, S100 and CYP2E1 antibodies. We found significantly elevated IL-6, TARC and IL-33 in TFA-JHDN-5 – immunized mice; additionally, anti-IL-33 diminished inflammation scores from 2.8 ± 1.1 to 1.6 ± 0.6 but increased TFA, S100 and CYP2E1 antibodies (p<0.05, Mann-WhitneyU). We confirm that IL-33 worsens Im-DILI and suggest protective roles for antibodies. This preliminary study suggests that anti-IL-33 and other antibodies may offer therapeutic options to diminish Im-DILI and possibly other forms of hepatitis.
Acknowledgements
William F. Riehnhoff, MD Jr. Scholars Foundaiton
Keywords:
DILI,
IL-33,
ST2/ST2L,
Immune Regulation,
Autoantibodies
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Immune-mediated disease pathogenesis
Citation:
Njoku
D,
Goodman
SB,
Cho
J,
Kim
L and
Haham
M
(2013). ST2/IL-33 signaling worsens immune-mediated hepatitis from drug haptens.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.00877
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Received:
20 Jun 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Dr. Dolores Njoku, Johns Hopkins University, ACCM, Pediatrics, Pathology, Baltimore, United States, njoku@wustl.edu