Investigating immune cell changes post IL-4 and IL-13 blockade with the biological inhibitor Dupilumab

Supervisor: Prof Cindy Ma, Head, Human Immune Disorders Laboratory.

Allergic diseases such as atopic dermatitis are among the fastest growing chronic conditions in Australia. The cellular basis of allergic disease involves distinct but co-operating immune cell types: pathogenic T helper 2 (Th2) lymphocytes, which aberrantly produce excessive amounts of the cytokines interleukin (IL) IL-4, IL-5 and IL-13, and activated B cells that produce pro-allergenic IgE antibodies. Dupilumab, is a monoclonal antibody targeting the IL-4 receptor alpha chain (IL-4Ra). Since IL-4Ra is shared by receptor complexes for both IL-4 and IL-13, Dupilumab blocks the effects of both of these cytokines. Dupilumab has been licensed in most countries to treat severe atopic dermatitis in patients 12 years and above and was listed on the PBS in Australia on 1^st March 2021. Clinically, Dupilumab has resulted in life-changing events for patients who experience remission of severe atopic dermatitis. This is unequivocal proof that IL-4 and/or IL-13 play a central role in mediating atopic dermatitis. However, the mechanisms that contribute to these pathological processes still remain unclear and up to 40% of people do not respond to Dupilumab. The aim of this project is to determine the cellular and molecular differences in patients pre- and post-treatment with Dupilumab as well as in responders versus non-responders compared to healthy controls. This will provide insights into the pathways implicated in IL-4 and/or IL-13-mediated severe atopic dermatitis. These aims will be achieved by state-of-the-art techniques such as multiparameter flow cytometry, and bulk and single cell RNA-seq. The goal is to identify “immune cell signatures” which can be used as biomarkers of disease as well as indicators of efficacy post-treatment with Dupilumab.