0869: PD-1 inhibitor unleashes pathogenic CD8+ T cells and induce arthritis in collagen-primed mice

Background/Purpose:
Background/Purpose: Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events, including inflammatory arthritis (ICI-arthritis). The pathophysiology of ICI-arthritis, particularly the role of T cells, remains unclear due to the lack of preclinical murine models.



Methods: We immunized 8-12-week-old C57BL/6 mice with type II chicken collagen (CII) Two to three weeks later, we administered a PD-1 inhibitor and measured arthritis scores until the mice were euthanized. Inflamed joints (knees) and CII-draining lymph nodes (dLNs) were harvested for immunologic and histological analyses.

Methods: We immunized 8-12-week-old C57BL/6 mice with type II chicken collagen (CII) Two to three weeks later, we administered a PD-1 inhibitor and measured arthritis scores until the mice were euthanized. Inflamed joints (knees) and CII-draining lymph nodes (dLNs) were harvested for immunologic and histological analyses.

Results: Mice primed with CII but without PD-1 inhibitors (CII_No PD-1i) or mice that did not receive CII but were given PD-1 inhibitors (No CII_PD-1i) did not develop arthritis. In contrast, CII-primed mice began developing arthritis 4-5 days after the initiation of PD-1 inhibitors, recapitulating human PD-1i-induced arthritis. The severity of arthritis at euthanasia was comparable between mice with PD-1i arthritis and conventional collagen-induced arthritis (CIA) mice. Histological analysis of the knee joints showed inflammation and joint destruction in CII_PD-1i mice. The numbers of CD45⁺ immune cells were increased in the joint and draining lymph nodes (dLN) in CII_PD-1i mice compared to the CII_No PD-1i and No CII_PD-1i groups. Notably, CD8⁺ T cells were expanded in the inflamed joints and dLNs of CII_PD-1i mice. Furthermore, these CD8⁺ T cells produced inflammatory cytokines including IFNγ and TNFα in response to CII. Levels of pathogenic CII-specific antibodies in CII_PD-1i mice were lower than in CIA, suggesting that the pathogenesis of PD-1i arthritis differs from that of rheumatoid arthritis.

Conclusion: CII-primed mice developed de novo arthritis following PD-1 inhibition, suggesting that these mice can serve as a murine model of PD-1i arthritis. Of note IFNg⁺ TNFa⁺ CD8⁺ T cells are expanded in these mice, indicating that PD-1 inhibitor unleashes pathogenic CD8⁺ T cells in CII-primed mice.