# Mechanism of autoimmune hepatitis development  in a novel mouse model

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $380,281

## Abstract

SUMMARY. Autoimmune hepatitis (AIH) is an inflammatory liver disease of unknown etiology. The
inflammatory response is thought to be orchestrated by CD4+ T lymphocytes recognizing liver self-
antigens. The identification of susceptibility HLA-DRB1 (*0401 and *0301) alleles within the human
leukocyte antigen (HLA) region suggested that faulty antigen presentation by these alleles and ensuing T
cell activation may play a role in the pathogenesis of AIH. We recently generated a mouse model,
Traf6TEC, displaying impaired antigen presentation in the thymus due to depletion of medullary thymic
epithelial cells (mTECs). Expression of tissue restricted antigens (TRAs) by mTECs and presentation of
these self-antigens to developing thymocytes leads to elimination of autoreactive T cells and suppression
of autoimmunity. Conditional depletion of mTECs in Traf6TEC mice associated with spontaneous
development of autoimmune hepatitis (AIH) that recapitulated the known histopathological and
immunological hallmarks of human AIH. More recently we found that antibiotic treatment reduced AIH
histopathology in Traf6TEC mice implicating the gut microbiota in AIH development. We also found
increased production of regulatory T cells and T cells expressing the gut-homing receptors 47 and CCR9
in the gut and liver of Traf6TEC mice accompanied by increased expression of endothelial-cell adhesion
molecules and chemokines in the liver. These results establish a connection between the gut microbiota
and development of AIH in this mouse model and additionally recapitulate similar evidence observed in the
clinical setting of other liver autoimmune diseases. Based on our results to date, we propose the following
hypothesis: mTEC depletion leads to production of autoreactive T cells that home to the liver and initiate
inflammation through aberrant recognition of liver self-antigens. Changes in the microbiota of knockout
animals lead to increased production of mucosal T cells that circulate to the liver and exacerbate AIH. To
examine this hypothesis we will: 1) Determine the contributions of autoreactive T cells vs. the gut
microbiota in AIH development/maintenance and identify liver self-antigens targeted by autoreactive T
cells; 2) Elucidate the mechanism of gut-mediated induction and/or exacerbation of AIH; and 3) Define the
microbiota profile of Traf6TEC and how it differs from normal microbiota and identify a signature/bacterial
species that associate with AIH pathology. Elucidation of the mechanisms that regulate of AIH
development may lead to much-needed novel therapeutic strategies to better manage and perhaps treat
this disease. These experiments may also define a common mechanism underling the development of
other liver autoimmune diseases irrespective of their ultimate cellular targets.

## Key facts

- **NIH application ID:** 9962898
- **Project number:** 5R01DK107992-05
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** KONSTANTINA ALEXANDROPOULOS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $380,281
- **Award type:** 5
- **Project period:** 2016-07-20 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962898

## Citation

> US National Institutes of Health, RePORTER application 9962898, Mechanism of autoimmune hepatitis development  in a novel mouse model (5R01DK107992-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9962898. Licensed CC0.

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