Graduate Student Virginia Commonwealth Univ. Sch. of Med., United States
Disclosure(s):
Araba Abaidoo-Myles, MPhil: No financial relationships to disclose
Introduction/Rationale: Atopic Dermatitis (AD) remains one of the most chronic inflammatory skin diseases and is strongly associated with other atopic diseases like asthma. Though Th2 response is known to be the main humoral response in AD, follicular helper T (Tfh) cells have been recently identified as key mediators in AD pathogenesis. AD presents with increased serum IgE levels and associated cytokines, IL4 and IL13. Our lab has shown that upon stimulating Dendritic cells with Altenaria alternata (a fungal allergen) in an allergic asthma model, there was an increase in the glutamine metabolic pathway. Upon inhibiting the glutamine metabolic pathway, we observed a reduction in downstream Tfh2 polarization and reduced IgE production. We therefore hypothesized that Telegnastat (CB-839), a glutaminase I inhibitor would decrease Tfh2 responses in AD.
Methods: Auricles of C57BL/6 mice were treated with MC903 and house dust mite for a period of 15 days. Ear thickness was measured throughout the model. Mice received topical treatment with CB-839 after day six. Mice were euthanized on day 15; organs were harvested and processed for flow cytometry, sectioning, RNA isolation and bulk RNA sequencing.
Results: Topical treatment with CB-839 inhibited AD in treated mice with a reduction in IgE+ and IgG1+ Plasma cells as well as Tfh2 cells, while an increase in T follicular regulatory cells was observed. AD associated genes such as GATA3 and CARD11 were observed to be decreased in CB-839 treated mice. Bulk RNA sequencing analysis also showed that with treatment, there was an increase in genes involved in wound healing, immune regulation and tissue development.
Conclusion: Overall, topical treatment of AD with the GLS-1 inhibitor, CB-839 in mice is associated with a decrease in the hallmarks of AD.
