Suppression of Murine Lupus by CD4 + and CD8 + T Regulatory Cells Induced by T-Cell Targeted Nanoparticles Loaded with IL-2 and TGF-β.

OBJECTIVE: To develop a nanoparticle platform that can expand both CD4+ and CD8+ T regulatory cells (Tregs) in vivo for the suppression of autoimmune responses in systemic lupus erythematosus (SLE).

METHODS: Poly(lactic-co-glycolic) acid (PLGA) nanoparticles (NPs) encapsulating IL-2 and TGF-β were coated with anti-CD2/CD4 antibodies and administered to mice with lupus-like disease induced by the transfer of DBA/2 T cells into (C57BL/6 x DBA/2)F1 (BDF1) mice. Peripheral frequency of Tregs was monitored ex vivo by flow cytometry. Disease progression was assessed by measuring serum anti-dsDNA antibodies by ELISA. Kidney disease was evaluated as proteinuria and by renal histopathology.

RESULTS: Anti-CD2/4 antibody-coated, but not non-coated NPs encapsulating IL-2 and TGF-β, induced CD4+ and CD8+ Foxp3+ Tregs in vitro. In vivo studies in non-lupus mice determined the optimal dosing regimen of NPs for expansion of CD4+ and CD8+ Tregs that was then tested in BDF1 lupus mice. The administration of anti-CD2/4 antibody-coated NPs encapsulating IL-2 and TGF-β resulted in the expansion of CD4+ and CD8+ Tregs, a marked suppression of anti-DNA antibody production, and reduced renal disease.

CONCLUSION: This study shows for the first time that T cell-targeted PLGA NPs encapsulating IL-2 and TGF-β can expand both CD4+ and CD8+ Tregs in vivo and suppress murine lupus. This approach that enables the expansion of Tregs in vivo and inhibits pathogenic immune responses in SLE could represent a potential new therapeutic modality in autoimmune conditions characterized by impaired Tregs function associated with IL-2 deficiency. This article is protected by copyright. All rights reserved.