Abstract
Chronic graft-versus-host disease (cGVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic transplantation. cGVHD pathophysiology involves cooperation between T follicular helper cells (TFHs) and germinal center B cells (GCBs), allo- and autoantibody depositions in cGVHD tissues, and fibrosis. We evaluated human CD19–directed chimeric antigen receptor (CAR19) T cell therapy in a clinically relevant murine cGVHD model with bronchiolitis obliterans syndrome (BOS). Although CD8+ CAR19 T cells effectively reduced peripheral B cell and GCB frequencies, pulmonary function was unimproved. In contrast, a single infusion of CAR19 CD4+ regulatory T cells (Tregs) mitigated ongoing pulmonary disease and modulated germinal centers (GCs) associated with reduced TFH frequencies compared with control Tregs but without measurable B cell depletion. Compared with EGFR Treg infusion, mice receiving CAR19 Tregs exhibited enhanced suppression of B cell activation and preserved splenic architecture, and CAR19 Treg infusion provided greater opportunities for interaction with CD19+ B cells at the B cell follicle boundary zones. Taken together with the absence of detectable B cell cytolysis, these findings were most consistent with GC suppression rather than B cell depletion as the dominant mechanism. Overall, our findings suggest that CAR19 Tregs represent a promising and safe cGVHD/BOS therapeutic strategy, offering immunosuppressive benefits and improved disease outcomes that may be more limited with CD8+ CAR19 T cell treatment.
Authors
Sujeong Jin, Michael C. Zaiken, Cameron McDonald-Hyman, Christina R. Hartigan, Sara Bolivar-Wagers, Jemma H. Larson, Yiyun Peng, Sophia Hani, Megan Riddle, Asim Saha, Angela Panoskaltsis-Mortari, Eun Ko, Yujie Zhao, Rocio Amaro Marquez, Pooja Shree Marri Baskar, Cindy R. Eide, William J. Murphy, Keli L. Hippen, Geoffrey R. Hill, Jakub Tolar, Peter T. Sage, Christopher A. Pennell, Leslie S. Kean, Bruce R. Blazar
Figure 4
CAR19 Treg cytolytic activity is uninhibited by cGVHD/BOS serum and requires cell-cell contact.
