Modulating immune responses to AAV by expanded polyclonal T-regs and capsid specific chimeric antigen receptor T-regulatory cells
Gruntman, Alisha M
Flotte, Terence R
Keeler, Allison M
UMass Chan AffiliationsHorae Gene Therapy Center
Microbiology and Physiological Systems
Document TypeJournal Article
KeywordsAAV gene therapy
CAR T regulatory cells
chimeric antigen receptor T-regulatory cells
immune responses to AAV
immune responses to capsid
immune responses to transgene
MetadataShow full item record
AbstractImmune responses to adeno-associated virus (AAV) capsids limit the therapeutic potential of AAV gene therapy. Herein, we model clinical immune responses by generating AAV capsid-specific chimeric antigen receptor (AAV-CAR) T cells. We then modulate immune responses to AAV capsid with AAV-CAR regulatory T cells (Tregs). AAV-CAR Tregs in vitro display phenotypical Treg surface marker expression, and functional suppression of effector T cell proliferation and cytotoxicity. In mouse models, AAV-CAR Tregs mediated continued transgene expression from an immunogenic capsid, despite antibody responses, produced immunosuppressive cytokines, and decreased tissue inflammation. AAV-CAR Tregs are also able to bystander suppress immune responses to immunogenic transgenes similarly mediating continued transgene expression, producing immunosuppressive cytokines, and reducing tissue infiltration. Taken together, AAV-CAR T cells and AAV-CAR Tregs are directed and powerful immunosuppressive tools to model and modulate immune responses to AAV capsids and transgenes in the local environment.
SourceArjomandnejad M, Sylvia K, Blackwood M, Nixon T, Tang Q, Muhuri M, Gruntman AM, Gao G, Flotte TR, Keeler AM. Modulating immune responses to AAV by expanded polyclonal T-regs and capsid specific chimeric antigen receptor T-regulatory cells. Mol Ther Methods Clin Dev. 2021 Oct 28;23:490-506. doi: 10.1016/j.omtm.2021.10.010. PMID: 34853797; PMCID: PMC8605179.
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/51667
RightsCopyright 2021 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).; Attribution-NonCommercial-NoDerivatives 4.0 International
The following license files are associated with this item:
- Creative Commons
Except where otherwise noted, this item's license is described as Copyright 2021 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).