PROJECT SUMMARY/ABSTRACT
PD-1 is a key immune checkpoint receptor that dampens T cell function. While extensive studies have
investigated how PD-1 modulates T cell effector function in cancer settings, how PD-1 regulates systemic
autoimmunity and humoral immunity remains poorly defined. Clinically, immune checkpoint inhibitors, including
anti-PD-1, induces inflammatory arthritis immune related adverse events (IA-irAE), but the underlying
mechanisms and the relationship between IA-irAE and classic rheumatic diseases are unexplored. Importantly,
no autoimmune animal models exist that permit direct analysis of clinically-used anti-PD-1 antibodies because
they do not interact with mouse PD-1. We utilize novel humanized PD-1 and PD-L1 mouse models to
investigate the mechanisms by which clinically-used anti-PD-1 and anti-PD-L1 biologics modulate humoral
immune response in a classic collagen induced arthritis model. Furthermore, through comparative analysis of
clinical data and immunological profiles between anti-PD-1 induced IA-irAE and rheumatoid arthritis, we
uncover remarkable similarity between IA-irAE and seronegative rheumatoid arthritis, a hitherto little
understood form of systemic autoimmunity. Our central hypothesis is that anti-PD-1 and anti-PD-L1 biologics
induces T cell-dominating and antibody-independent autoimmune toxicity, and impaired PD-1
signaling is a contributing factor to IA-irAE and seronegative rheumatoid arthritis (RA). To test this
hypothesis, we will (1) To determine the immunopathology and molecular mechanisms of clinically-used PD-1
and PD-L1 blockade mediated autoimmune diseases, and (2) To investigate how dysregulation of PD-1
signaling contributes to IA-irAE and seronegative RA in human subjects. Building on our clinical and basic
research expertise and innovations that integrate novel mouse models, innovative pharmacological
interventions and comparative patient cohort analysis, our research will address fundamental questions in PD-
1 signaling, humoral immunity, and systemic autoimmunity, with direct relevance to the improvement of clinical
practice and patients’ wellbeing. Additionally, our study will provide a valuable animal model as a research tool
for the field of irAE.
