Secreted PD-L1 alleviates inflammatory arthritis in mice through local and systemic AAV gene therapy
IntroductionRheumatoid arthritis (RA) primarily affects the joints but can also affect multiple organs and profoundly impacts patients’ ability to carry out daily activities, mental health, and life expectancy. Current treatments for RA are limited in terms of duration, efficacy, and adverse effects...
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Frontiers Media S.A.
2025-02-01
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| author | Wenjun Li Wenjun Li Junjiang Sun Susi Feng Ariana La Rosa Panli Zhang Eveline Y. Wu Richard Loeser Chengwen Li Chengwen Li Chengwen Li |
| author_facet | Wenjun Li Wenjun Li Junjiang Sun Susi Feng Ariana La Rosa Panli Zhang Eveline Y. Wu Richard Loeser Chengwen Li Chengwen Li Chengwen Li |
| author_sort | Wenjun Li |
| collection | DOAJ |
| description | IntroductionRheumatoid arthritis (RA) primarily affects the joints but can also affect multiple organs and profoundly impacts patients’ ability to carry out daily activities, mental health, and life expectancy. Current treatments for RA are limited in terms of duration, efficacy, and adverse effects. PD-L1 is a checkpoint protein that plays important roles in immune regulation and has been implicated in the initiation and progression of multiple autoimmune diseases.MethodIn a previous study, we demonstrated that intra-articular injection with adeno-associated virus (AAV) vectors encoding wild type PD-L1 improved local inflammation in the joint in the collagen-induced arthritis (CIA) mouse model of RA. To further improve efficacy, we explored AAV-mediated delivery of the soluble PD-L1 (sPD-L1) to CIA mice.ResultAfter intra-articular injection of AAV6 vectors expressing the optimal isoform of sPD-L1 (shPD-L1), more potency was observed when compared to wild type PD-L1, with a lower dose of AAV6/shPD-L1 needed for arthritis improvement. To study the therapeutic effect of systemic expression of sPD-L1, we administered AAV8/shPD-L1 gene therapy in CIA mice via retro-orbital injection and found significant improvements in joint inflammation and paw swelling, exhibiting similar phenotypes to that in naïve mice. The levels of total immunoglobulin and anti-collagen specific antibodies were lower in AAV8/shPD-L1 treated CIA mice than those in controls. The levels of pro-inflammatory cytokines in blood were also significantly decreased in shPD-L1 treated mice. Additionally, T cell apoptosis rates in the spleen showed a 2-fold increase in treated mice. Finally, we investigated the therapeutic effect of AAV/shPD-L1 via intramuscular injection. After injection of AAV6/shPD-L1, decreased paw swelling, reduced joint inflammation, and lower levels of pro-inflammatory cytokines in blood were achieved. The therapeutic effect of shPD-L1 was dose dependent via intramuscular treatment with AAV vectors.ConclusionIn conclusion, the findings in this study suggest that intra-articular injection of AAV vectors encoding sPD-L1 results in greater therapeutic benefit on arthritis, and systemic AAV/sPD-L1 is able to block the development of inflammatory arthritis with inhibition of the systemic immune response, underlining the potential of gene therapy with systemic delivery of shPD-L1 via AAV vectors in RA. |
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| institution | Kabale University |
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| language | English |
| publishDate | 2025-02-01 |
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| spelling | doaj-art-d7d29ce944b3417e880d229339ed92ea2025-02-03T05:12:01ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-02-011610.3389/fimmu.2025.15278581527858Secreted PD-L1 alleviates inflammatory arthritis in mice through local and systemic AAV gene therapyWenjun Li0Wenjun Li1Junjiang Sun2Susi Feng3Ariana La Rosa4Panli Zhang5Eveline Y. Wu6Richard Loeser7Chengwen Li8Chengwen Li9Chengwen Li10Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesDivision of Oral and Craniofacial Biomedicine, University of North Carolina Adams School of Dentistry, Chapel Hill, NC, United StatesGene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesGene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesGene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesGene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesDepartment of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesDivision of Rheumatology, Allergy, and Immunology, University of North Carolina, Chapel Hill, NC, United StatesGene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesDepartment of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesCarolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, NC, United StatesIntroductionRheumatoid arthritis (RA) primarily affects the joints but can also affect multiple organs and profoundly impacts patients’ ability to carry out daily activities, mental health, and life expectancy. Current treatments for RA are limited in terms of duration, efficacy, and adverse effects. PD-L1 is a checkpoint protein that plays important roles in immune regulation and has been implicated in the initiation and progression of multiple autoimmune diseases.MethodIn a previous study, we demonstrated that intra-articular injection with adeno-associated virus (AAV) vectors encoding wild type PD-L1 improved local inflammation in the joint in the collagen-induced arthritis (CIA) mouse model of RA. To further improve efficacy, we explored AAV-mediated delivery of the soluble PD-L1 (sPD-L1) to CIA mice.ResultAfter intra-articular injection of AAV6 vectors expressing the optimal isoform of sPD-L1 (shPD-L1), more potency was observed when compared to wild type PD-L1, with a lower dose of AAV6/shPD-L1 needed for arthritis improvement. To study the therapeutic effect of systemic expression of sPD-L1, we administered AAV8/shPD-L1 gene therapy in CIA mice via retro-orbital injection and found significant improvements in joint inflammation and paw swelling, exhibiting similar phenotypes to that in naïve mice. The levels of total immunoglobulin and anti-collagen specific antibodies were lower in AAV8/shPD-L1 treated CIA mice than those in controls. The levels of pro-inflammatory cytokines in blood were also significantly decreased in shPD-L1 treated mice. Additionally, T cell apoptosis rates in the spleen showed a 2-fold increase in treated mice. Finally, we investigated the therapeutic effect of AAV/shPD-L1 via intramuscular injection. After injection of AAV6/shPD-L1, decreased paw swelling, reduced joint inflammation, and lower levels of pro-inflammatory cytokines in blood were achieved. The therapeutic effect of shPD-L1 was dose dependent via intramuscular treatment with AAV vectors.ConclusionIn conclusion, the findings in this study suggest that intra-articular injection of AAV vectors encoding sPD-L1 results in greater therapeutic benefit on arthritis, and systemic AAV/sPD-L1 is able to block the development of inflammatory arthritis with inhibition of the systemic immune response, underlining the potential of gene therapy with systemic delivery of shPD-L1 via AAV vectors in RA.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1527858/fullAAVRAintra-articularsystemicsoluble |
| spellingShingle | Wenjun Li Wenjun Li Junjiang Sun Susi Feng Ariana La Rosa Panli Zhang Eveline Y. Wu Richard Loeser Chengwen Li Chengwen Li Chengwen Li Secreted PD-L1 alleviates inflammatory arthritis in mice through local and systemic AAV gene therapy Frontiers in Immunology AAV RA intra-articular systemic soluble |
| title | Secreted PD-L1 alleviates inflammatory arthritis in mice through local and systemic AAV gene therapy |
| title_full | Secreted PD-L1 alleviates inflammatory arthritis in mice through local and systemic AAV gene therapy |
| title_fullStr | Secreted PD-L1 alleviates inflammatory arthritis in mice through local and systemic AAV gene therapy |
| title_full_unstemmed | Secreted PD-L1 alleviates inflammatory arthritis in mice through local and systemic AAV gene therapy |
| title_short | Secreted PD-L1 alleviates inflammatory arthritis in mice through local and systemic AAV gene therapy |
| title_sort | secreted pd l1 alleviates inflammatory arthritis in mice through local and systemic aav gene therapy |
| topic | AAV RA intra-articular systemic soluble |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1527858/full |
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