Intra-articular delivery of AAV vectors encoding PD-L1 attenuates joint inflammation and tissue damage in a mouse model of rheumatoid arthritis

• Published in: Frontiers in immunology Vol. 14; p. 1116084
• Main Authors: Li, Wenjun, Sun, Junjiang, Feng, Susi Liu, Wang, Feng, Miao, Michael Z, Wu, Eveline Y, Wallet, Shannon, Loeser, Richard, Li, Chengwen
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 03.03.2023
• Subjects: AAV (Adeno-associated virus); Animals; Arthritis, Experimental; Arthritis, Rheumatoid - therapy; B7-H1 Antigen - genetics; B7-H1 Antigen - metabolism; Collagen Type II - genetics; Cytokines - metabolism; Disease Models, Animal; Gene Therapy; Humans; Immunology; Inflammation; Inflammation - therapy; Mice; PD-L1; rheu matoid arthritis; Tissue Distribution; PD-L1; Inflammation; AAV (Adeno-associated virus); rheu matoid arthritis; Gene Therapy
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2023.1116084

Rheumatoid arthritis (RA) is the most common form of autoimmune inflammatory arthritis. Intra-articular gene delivery to block proinflammatory cytokines has been studied in pre-clinical models and human clinical trials. It has been demonstrated that the level of programmed death-ligand 1 (PD-L1) is associated with rheumatoid arthritis (RA). This study examined the therapeutic role of PD-L1 by intra-articular delivery via adeno-associated virus (AAV) vectors in the mouse collagen-induced arthritis (CIA) model. Mice were intra-articularly injected with AAV5 vectors encoding human PD-L1 on day 0 and immunized with bovine type II collagen to induce CIA simultaneously. On day 49 post AAV administration, joints were collected for histo-pathological and cytokine analysis. Additionally, the systemic impacts of intra-articular injection of AAV5/PD-L1 vectors were also studied. To study the therapeutic effect of PD-L1, AAV5/PD-L1 vectors were administered into the joints of RA mice on day 21. After administration of AAV5/PD-L1 vectors, strong PD-L1 expression was detected in AAV transduced joints. Joints treated with PD-L1 at the time of arthritis induction exhibited significantly less swelling and improved histopathological scores when compared to untreated joints. Additionally, the infiltration of T cells and macrophages was decreased in joints of CIA mice that received AAV5/PD-L1 vectors (P<0.05). The levels of pro-inflammatory cytokines, including IL-1, IL-6, IL-17 and TNFα, were lower in AAV5/PD-L1 treated than untreated joints (P<0.05). Furthermore, the administration of AAV5/PD-L1 vectors into the joints of CIA mice did not impact serum cytokine levels and the antibody titers to type II collagen. Biodistribution of AAV vectors after intra-articular injection showed undetectable AAV genomes in other tissues except for a low level in the liver. Similar to the results of AAV5/PD-L1 vector administration on day 0, decreased joint swelling and lower histopathological damage were observed in joints treated with AAV5/PD-L1 vectors on day 21. The results from this study demonstrate that local AAV mediated PD-L1 gene delivery into the joints is able to prevent the development and block the progression of arthritis in CIA mice without impacting systemic immune responses. This study provides a novel strategy to effectively treat inflammatory joint diseases using local AAV gene therapy by interference with immune checkpoint pathways.