# The Retinoid Tamibarotene Aggravates Skin Inflammation in a Model of Bullous Pemphigoid-like Epidermolysis Bullosa Acquisita

## TL;DR

Tamibarotene, a drug used for leukemia, worsens skin inflammation in a mouse model of a blistering autoimmune skin disease.

## Contribution

This study is the first to show that tamibarotene aggravates pemphigoid-like skin disease by reducing regulatory T cell recruitment.

## Key findings

- Tamibarotene increased skin inflammation in mice by 1.6-fold compared to controls.
- The drug reduced regulatory T cell recruitment to the skin, impairing inflammation control.
- Tamibarotene prolonged neutrophil responsiveness to immune complexes, potentially worsening disease.

## Abstract

Tamibarotene (AM80) is an agonist of retinoic acid receptor alpha. It is licensed in Japan for the treatment of acute promyelocytic leukemia. Results from preclinical models suggest that tamibarotene might also be effective in the treatment of diverse autoimmune diseases. The effect of tamibarotene on autoimmune diseases of the skin, however, has not been explored. We therefore examined the effect of tamibarotene on disease in the antibody-transfer mouse model of bullous pemphigoid (BP)-like epidermolysis bullosa acquisita (EBA), a prototypical example for pemphigoid diseases. Pemphigoid diseases are a group of autoimmune blistering skin diseases driven by autoantibodies and the recruitment and activity of granulocytes in the dermis. In sharp contrast to its effect in models of other autoimmune diseases, tamibarotene aggravated EBA pronouncedly. At the peak of disease, skin inflammation in tamibarotene-treated mice involved, on average, 1.6-fold more of the total body surface compared to vehicle-treated mice. Tamibarotene markedly reduced the recruitment of regulatory T cells (Tregs) into the dermis. This blunted the counterregulatory mechanisms that normally curb skin inflammation in this model. The effect aligns with previous reports describing tamibarotene-mediated downregulation of skin-homing receptors on Tregs. In addition, tamibarotene prolonged the responsiveness of aging neutrophils to immune complexes in vitro, providing another mechanism that may exacerbate EBA. Collectively, our results suggest that tamibarotene may elicit detrimental effects in patients with EBA by abolishing the recruitment of Tregs into skin. This warrants great caution when using tamibarotene in patients with EBA and possibly other pemphigoid diseases.