Identifying and targeting novel IFN-I regulators in pDCs for Lupus therapy

Type I interferons (IFN-I) play a central role in the development and progression of systemic lupus erythematosus (SLE), a disease characterized by chronic inflammation and autoimmunity (when a patient’s immune system attacks their own cells and tissues). Elevated levels of IFN-I in the blood of SLE patients are linked to disease severity. Plasmacytoid dendritic cells (pDCs), which produce large amounts of IFN-I in response to self-nucleic acids, are key drivers of the disease. However, due to the difficulty in studying pDCs in the lab, progress in identifying regulators of their function has been limited. To address this, Dr. Chiale and her advisor, Dr. Zuniga, have built on a model developed in the Zuniga lab to identify compounds that modulate IFN-I production in pDCs.

Dr. Chiale aims to discover and characterize chemical compounds that can regulate IFN-I production in pDCs, with the potential to offer new therapeutic strategies for SLE. The first goal is to screen a large compound library to identify promising modulators of IFN-I production in pDCs. These compounds will then be validated in both pDC model cells and human pDCs. The second aim is to test the efficacy of these compounds in lupus-prone mouse models and in pDCs from people with SLE, assessing their impact on disease symptoms, immune responses, and IFN-I production. Additionally, Dr. Chiale’s work will explore drug-delivery strategies to enhance the therapeutic potential of compounds that could reduce the harmful effects of pDC-driven IFN-I production in SLE.

What this means for people with lupus:

Findings from Dr. Chiale’s study could lead to the development of prodrugs (medications that turn into their active form once they enter the body) that specifically target pDCs, offering a more precise and potentially less harmful approach compared to current therapies. By regulating the production of IFN-I in pDCs, this work may offer a way to break the cycle of immune over-activation in SLE, leading to improved disease management and better outcomes for people living with lupus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by widespread inflammation and multi-organ damage. A hallmark of SLE is the persistent activation of plasmacytoid dendritic cells (pDCs), leading to excessive type I interferon (IFN-I) production, which fuels immune dysregulation and tissue damage. While therapies targeting IFN-I pathways have shown promise, their efficacy is limited, and off-target effects remain a challenge. Therefore, identifying new approaches to regulate IFN production by pDCs is critical for developing safer and more effective therapies for lupus. This proposal aims to screen a library of diverse chemical compounds to identify novel regulators of IFN-I production by pDCs. Using the ReFRAME library, which includes FDA-approved drugs and preclinical candidates, we will perform high-throughput screening to pinpoint compounds with the capacity to modulate pDC IFN responses. Initial findings will be validated in both in vitro systems and ex vivo studies using pDCs isolated from lupus patient samples. By leveraging patient-derived cells, I aim to ensure the translational relevance of our findings. To evaluate the therapeutic potential of lead compounds, I will test their efficacy in preclinical lupus models. I will assess their impact on disease progression, including immune activation, IFN-I signatures, and tissue inflammation. Importantly, I will explore prodrug strategies to enhance compound specificity and reduce systemic toxicity by targeting pDCs selectively. This approach aims to improve the therapeutic index of candidate drugs while minimizing adverse effects. By integrating chemical screening with translational and in vivo studies, this project seeks to uncover new therapeutic targets and approaches for IFN modulation in lupus. The outcomes have the potential to advance our understanding of pDC-driven immune dysregulation and pave the way for innovative treatments that address key limitations of current therapies.