Chimeric Antigen Receptor (CAR) regulatory T cells effectively suppress autoimmune uveitis in presence of antigen

We evaluated the therapeutic efficacy of chimeric antigen receptor T regulatory (CAR Treg) cells to reduce ocular inflammation in a mouse model of experimental autoimmune uveitis (EAU). Engineered CAR Tregs that recognize adeno-associated virus (AAV) as antigen were delivered systemically to EAU mice along with intraocular injection of AAV. EAU disease severity and inflammation were reduced in mice that received an intraocular AAV injection, but not in those without the AAV antigen. CAR Tregs outperformed endogenous T cells, indicating that their efficacy requires the antigen specificity of the engineered CAR. CAR Tregs delivered systemically were found in the eyes as well as peripheral immune system sites. Additionally, increased numbers of endogenous Foxp3 + cells were found in the eyes of AAV + CAR Treg mice, indicating that CAR Tregs trained the host immune system to target eye inflammation. Adoptive transfer of T cells from treated donor EAU-recovered mice reduced EAU severity in recipient mice, suggesting the induction of bystander suppression and infectious tolerance by the CAR Tregs. Delivering anti-inflammatory gene alpha-1 antitrypsin (AAT) in AAV to the eye with co-treatment of CAR Tregs also improved disease severity. This work advances CAR Tregs as an appealing single or dual therapeutic approach for uveitis and other inflammatory autoimmune diseases.