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Secreted PD-L1 alleviates inflammatory arthritis in mice through local and systemic AAV gene therapy
Wenjun Li1,2, Junjiang Sun1, Susi Feng1
1Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Introduction:
Rheumatoid 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.
Method:
In 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.
Result:
After 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.
Conclusion:
In 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.
Insights
Gene therapy using adeno-associated virus vectors delivering soluble PD-L1 (sPD-L1) effectively treats rheumatoid arthritis (RA) in mice. This approach reduces joint inflammation and systemic immune responses, showing promise for RA treatment.
Area of Science:
- Immunology
- Gene Therapy
- Rheumatology
Background:
- Rheumatoid arthritis (RA) is a systemic autoimmune disease impacting joints and multiple organs, with current treatments having limitations.
- Programmed death-ligand 1 (PD-L1) is crucial in immune regulation and implicated in autoimmune disease pathogenesis.
Purpose of the Study:
- To investigate the efficacy of adeno-associated virus (AAV)-mediated delivery of soluble PD-L1 (sPD-L1) for treating rheumatoid arthritis.
- To compare the therapeutic effects of intra-articular and systemic delivery of AAV-sPD-L1 in a collagen-induced arthritis (CIA) mouse model.
Main Methods:
- Intra-articular and systemic administration of AAV vectors encoding sPD-L1 (AAV6/shPD-L1 and AAV8/shPD-L1) in CIA mice.
- Evaluation of joint inflammation, paw swelling, immunoglobulin levels, anti-collagen antibodies, pro-inflammatory cytokines, and T cell apoptosis.
Main Results:
- Intra-articular AAV6/shPD-L1 showed improved potency compared to wild-type PD-L1 at lower doses.
- Systemic AAV8/shPD-L1 administration significantly reduced joint inflammation, paw swelling, and systemic immune responses, including immunoglobulin and pro-inflammatory cytokine levels.
- Increased T cell apoptosis was observed in treated mice, suggesting modulation of immune cell activity.
Conclusions:
- AAV-mediated delivery of sPD-L1 demonstrates significant therapeutic potential for rheumatoid arthritis.
- Both local and systemic delivery of AAV/sPD-L1 offer benefits, with systemic delivery showing promise in blocking inflammatory arthritis development and inhibiting systemic immune responses.
