# Mechanistically based therapeutic strategies in murine primary biliary cholangitis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2021 · $404,589

## Abstract

Summary
The treatment of primary biliary cholangitis (PBC) has lagged behind other autoimmune diseases. We propose
to challenge this void with our multidisciplinary team with expertise in metabolomics, immunology, molecular
biology and pathology. We submit that our use of ARE–/– mice are a powerful new model as mice recapitulate
human PBC with female predominance, AMAs, portal inflammation, increased total bile acids, itching, fibrosis
and elevated female expression of type I interferon (IFN), required for TLR7 mediated function. We will first
propose an entirely new approach to treat autoimmunity, in which depletion of pathogenic immune cells in
combination with gut microbiome metabolite therapy restores tolerance. Autoimmune liver diseases are ideal for
such therapies because the liver is situated upstream from the colon. Indeed, if pathogenic cell removal, followed
by tolerogenic diets work in PBC (our Aim 1), it should lead to trials in other autoimmune diseases. Th1 or Th17
cell removal is a radical new approach, and it is important to complement this with understanding of individual
Th1 or Th17/Tfh/germinal centre pathway molecules, to understand whether Th1 or Th17 biology underpins
PBC. We will address pathway involvement by downregulating effector function by modulating TLR7 and altering
germinal center function (Aim 2) and/or directly addressing IFN receptor signaling (Aim 3). These goals are
based on our data, and unique resources that directly target the mechanisms of autoimmune cholangitis. Our
group has a wealth of published/unpublished data including extensive experience in modulating autoimmunity
by diet and metabolites. Hence our three goals are firstly to eliminate pathogenic cells through antibody depletion
of Th1 (CXCR3 mAb), or Th17 and Tfh (CCR6 mAb), followed by immune restoration/regulation with beneficial
bacterial metabolites that boost Tregs and promote tolerance. This step involves use of HAMS (high amylose
maize starch) diets that produce very large amounts of gut butyrate or acetate. This approach has worked
spectacularly well in our hands for diabetes in the NOD mouse. Our second goal is to modulate TLR7, critical for
GC formation, and prevent disease in female ARE–/– mice; TLR7 is highly expressed in female ARE–/– mice.
These data may lead to future opportunities using small molecules that target TLR7 signaling. In our third and
final aim we propose that inhibition of type I IFN receptor signaling will be therapeutic. We know that deletion of
the type I IFN receptor in ARE–/– mice reduces disease severity. Thus, we will block the IFN receptor with a mAb
and JAK/STAT signaling with a JAK inhibitor. Collectively we submit that this proposal is innovative, likely to lead
to better therapeutic approaches, and has importance not only in PBC but generically in other autoimmune
diseases.

## Key facts

- **NIH application ID:** 10102244
- **Project number:** 5R01DK123262-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** MERRILL E GERSHWIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $404,589
- **Award type:** 5
- **Project period:** 2020-02-10 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10102244

## Citation

> US National Institutes of Health, RePORTER application 10102244, Mechanistically based therapeutic strategies in murine primary biliary cholangitis (5R01DK123262-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10102244. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*