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
This file is in Adobe Acrobat (PDF) format. If you have not installed and configured the Adobe Acrobat Reader on your system.
Having trouble reading a PDF?
PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.
Having trouble saving a PDF?
Many versions of the free Acrobat Reader do not allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users: Right-click on the Download link and choose the option that says something like "Save Link As...". Mac users should hold the mouse button down on the link to get these same options.
Having trouble printing a PDF?
- Try printing one page at a time or to a newer printer.
- Try saving the file to disk before printing rather than opening it "on the fly." This requires that you configure your browser to "Save" rather than "Launch Application" for the file type "application/pdf", and can usually be done in the "Helper Applications" options.
- Make sure you are using the latest version of Adobe's Acrobat Reader.
