Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease

TLDR

Therapy for autoimmune diseases should eliminate pathogenic cells while sparing protective immunity, yet feasible strategies have been elusive. We engineered human T cells to express a chimeric autoantibody receptor (CAAR) comprising the PV autoantigen desmoglein‑3 fused to CD137‑CD3ζ signaling domains. In pemphigus vulgaris, Dsg3 CAAR‑T cells specifically kill anti‑Dsg3 B cells in vitro and persistently eliminate them in vivo, suggesting CAAR‑T cells as a universal strategy to target autoreactive B cells in antibody‑mediated autoimmune disease.

Abstract

Ideally, therapy for autoimmune diseases should eliminate pathogenic autoimmune cells while sparing protective immunity, but feasible strategies for such an approach have been elusive. Here, we show that in the antibody-mediated autoimmune disease pemphigus vulgaris (PV), autoantigen-based chimeric immunoreceptors can direct T cells to kill autoreactive B lymphocytes through the specificity of the B cell receptor (BCR). We engineered human T cells to express a chimeric autoantibody receptor (CAAR), consisting of the PV autoantigen, desmoglein (Dsg) 3, fused to CD137-CD3ζ signaling domains. Dsg3 CAAR-T cells exhibit specific cytotoxicity against cells expressing anti-Dsg3 BCRs in vitro and expand, persist, and specifically eliminate Dsg3-specific B cells in vivo. CAAR-T cells may provide an effective and universal strategy for specific targeting of autoreactive B cells in antibody-mediated autoimmune disease.