# Inhibitory Receptors and  Autoimmune Arthritis

> **NIH NIH R01** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2020 · $334,400

## Abstract

Rheumatoid arthritis (RA) is an inflammatory disorder characterized by autoimmunity.
We propose a novel method for suppressing inflammation by upregulating and activating
natural inhibitory receptors called leukocyte associated immunoglobulin-like receptors
(LAIR). One of these, LAIR-1 (also called CD305) acts as a negative regulator of
immune cell receptor signaling, suggesting that activating LAIR-1 receptors may lead to
diminished autoimmune activity and less severe disease in patients with RA. We have
further demonstrated that culture with vitamin D increases LAIR-1 on CD4+ T cells. The
discovery of a new secosteroidogenic pathway initiated by P450scc that produces
vitamin D3 hydroxyderivatives has opened new options in treatment for RA. We predict
that upregulating Lair-1 by using new vitamin D3 hydroxyderivatives could lead to
attenuation of the severity of arthritis using safer therapies than are currently available.
We propose a set of experiments using murine models of autoimmune arthritis. Our
central hypothesis is that inflammation can be downregulated by stimulation of
the inhibitory receptor LAIR-1 and that vitamin D and its analogs enhance this
suppression by upregulating LAIR-1. We also believe that the noncalcemic
20(OH)D3 will be as effective and less toxic than the classical form of vitamin D3
[1,25(OH)2D3]. To understand the mechanisms by which inhibitory receptors attenuate
inflammation we propose the following specific aims: Specific Aim 1: To test the
hypothesis that activation of the LAIR-1 inhibitory receptor leads to suppression of T cell
cytokine production and that the inhibition is enhanced by vitamin D or the noncalcemic
20(OH)D3 analog. Specific Aim 2. Determine whether activation of LAIR-1 will
attenuate autoimmune arthritis and whether vitamin D or 20(OH)D3 enhances this effect
using two mouse models of arthritis: collagen-induced arthritis (CIA) and the IL-1
receptor antagonist deficiency IL-1Rn-/- spontaneous arthritis model (SAD). Specific
Aim 3. To test the hypothesis that upregulation of LAIR-1 leads to suppression of T cell
signaling by repressing the canonical T cell pathway and altering T cell cytokine
production and that vitamin D or 20(OH)D3 will enhance this effect. Successful
completion of these experiments will elucidate the mechanisms whereby treatment with
new Vit D analogs leads to upregulation of the inhibitory receptor LAIR-1, ultimately
inducing suppression of cytokine secretion and prevention of arthritis.

## Key facts

- **NIH application ID:** 9729528
- **Project number:** 5R01AR069010-04
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** AE-KYUNG YI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $334,400
- **Award type:** 5
- **Project period:** 2016-05-13 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9729528

## Citation

> US National Institutes of Health, RePORTER application 9729528, Inhibitory Receptors and  Autoimmune Arthritis (5R01AR069010-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9729528. Licensed CC0.

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