Developing Novel Tools for Precision Targeting of Pro-Autoimmune Th17 Cells

Autoimmune diseases, affecting over 23 million Americans, occur when the immune system attacks the body's own tissues. Traditional treatments often involve non-selective immunosuppressants, leading to severe side effects. Recent advancements in biologics, such as IL-23 monoclonal antibodies, have improved treatment selectivity by targeting pathogenic cells like IL-17 producing Th17 cells. However, these therapies can increase infection susceptibility due to the dual role of IL-23-dependent Th17 cells in autoimmunity and infection control. Although pro-autoimmune and anti-infection Th17 cells were previously perceived as indistinguishable, the FDA- approved drug clofazimine (CLF) was identified as the first pro-autoimmune Th17-selective inhibitor without affecting anti-infection Th17 cells. However, CLF has adverse effects compromising patient compliance. One strategy is to continue screening small molecule compounds or FDA-approved drugs, while another approach involves designing and synthesizing inhibitors based on the specific targets of CLF in pro-autoimmune Th17 cells. Thus, the objective of this proposal is to establish a high-throughput drug screening pipeline to identify selective inhibitors of pro-autoimmune Th17 cells and to generate reagents for determining the cellular targets of CLF. The rationale is that creating a high-throughput screening system and facilitating CLF target identification will accelerate the discovery of small molecule inhibitors that selectively target pro-autoimmune Th17 cells while sparing anti-infection Th17 cells. This approach will address the urgent need for treatments with better efficacy and safety profiles for autoimmune disease patients. Aim 1 focuses on establishing a high-throughput drug screening pipeline by generating and validating a novel reporter mouse model. Aim 2 involves generating biotinylated CLF to identify its molecular targets in pro-autoimmune Th17 cells, enabling the pull-down of CLF- interacting proteins for identification by mass spectrometry. The significance of this study lies in its potential to discover highly selective inhibitors for pro-autoimmune Th17 cells, thereby reducing the adverse effects associated with current treatments for autoimmune diseases. The innovation of this project includes the development of a novel high-throughput screening pipeline and the creation of biotinylated CLF for precise target identification. These advancements could revolutionize the therapeutic landscape for autoimmune diseases, offering more effective and safer treatment options. Project Number: 1R03AI190780-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Zhiheng He | Institution: UNIVERSITY OF SOUTHERN CALIFORNIA, Los Angeles, CA | Award Amount: $166,000 | Activity Code: R03 | Study Section: Mechanisms of Autoimmunity Study Section[MAI] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R03AI19078001