Administration of Chemically-Modified Poly(lactide-co-glycolide) Nanoparticles to Engineer the Immune Response for Tolerance Induction

Administration of Chemically-Modified Poly(lactide-co-glycolide) Nanoparticles to Engineer the Immune Response for Tolerance Induction;Biomedical Engineering;Chemical Engineering;Engineering;Chemical Engineering

Kuo, RobertWen, Fei ;

University of Michigan

关键词: Administration of Chemically-Modified Poly(lactide-co-glycolide) Nanoparticles to Engineer the Immune Response for Tolerance Induction;    Biomedical Engineering;    Chemical Engineering;    Engineering;    Chemical Engineering;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/137024/robrtkuo_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Autoimmune diseases are the result of a severe immune response targeted against native tissues. Current strategies in the clinic to treat autoimmunity involve administering immunosuppressant medications which suppress broad components of the immune system. While effective for managing symptoms, reduced immune competency leads to harmful side effects such as increased risk for infection. Therefore, developing more targeted approaches to induce immune tolerance in the treatment of autoimmunity are highly desirable. One approach to induce antigen-specific tolerance has been to administer antigen coupled to poly(lactide-co-glycolide) (PLG) nanoparticles. These nanoparticles have been effective in treating models of autoimmunity, allergy, and transplant rejection, however the mechanism of action is poorly understood. Herein contains investigations of downstream cellular and molecular events following nanoparticle internalization by antigen-presenting cells (APCs). Increasing the amount of both administered nanoparticles and coupled antigen led to higher levels of antigen presentation on the APC surface. Co-stimulatory analysis of APCs with detectable MHC-restricted antigen revealed a significant reduction of positive co-stimulatory molecules (CD86, CD80, and CD40) as nanoparticle concentration was increased. These trends in co-stimulatory expression were not observed in APCs administered increasing amounts of soluble antigen, suggesting the critical role of antigen coupling to nanoparticles. Cell signaling activity of APCs treated with either antigen-coupled nanoparticles (PLG-OVA) or antigen-coupled splenocytes (SP-OVA) were compared to identify tolerance mechanisms resulting from different antigen delivery vehicles. Network analysis revealed NF-KB had an integral role within macrophages to connect signaling among several different transcription factors while NF-KB was less critical to integrate signaling across dendritic cell networks.Macrophages treated PLG-OVA or SP-OVA before co-culture with activated T cells did not dramatically affect T cell response. Dendritic cells treated SP-OVA compared to PLG-OVA were more effective to attenuate not only IL-2Rα expression but also other indicators of T cell activity. Inhibiting NF-KB signaling in macrophages treated with SP-OVA led to reduced T cell expression of IL-2Rα, suggesting a potential role for targeting NF-KB activity to improve tolerance induction.Nanoparticles encapsulating small interfering RNA (siRNA) were investigated to inhibit autoimmune signaling pathways. A feasibility study was conducted focusing on CCR2, a chemokine receptor correlated with worse prognoses in models of multiple sclerosis. An siRNA mixture targeting CCR2 expression (siCCR2) was complexed to polyethylenimine prior to PLG encapsulation. Complexed and encapsulated siCCR2 were evaluated by measuring CCR2 levels and cell migratory potential. Encapsulated siCCR2 were also examined by administering 1.0 mg in a mouse model of multiple sclerosis on Days 7, 9, and 11 following disease induction. Mean clinical scores were significantly reduced compared to administering either encapsulated non-specific siRNA complexes or buffered solution. These findings suggest encapsulated siRNA complexes may have clinical applications for the treatment of multiple sclerosis and other autoimmune diseases. This work identified several mechanisms, including IL-10 production, T cell apoptosis, and reduced T cell proliferation affected by antigen-coupled nanoparticle treatment. Intracellular signaling activity of treated APCs revealed a central role of NF-KB to mediate macrophage signaling. Macrophages treated with SP-OVA and an NF-KB inhibitor prior to co-culture with activated T cells resulted in attenuated T cell activity. More targeted approaches to inhibit molecules of interest were explored using PLG nanoparticles encapsulating siRNA. Initial studies focused on CCR2, whose expression during autoimmunity is correlated with worsening prognosis. Encapsulated CCR2-targeting siRNA had good feasibility for reducing both in vitro and in vivo inflammatory responses.