Suppression of Murine Lupus by CD CD 4+ and CD CD 8+ Treg Cells Induced by T Cell–Targeted Nanoparticles Loaded With Interleukin‐2 and Transforming Growth Factor β

摘要

Objective To develop a nanoparticle ( NP ) platform that can expand both CD 4+ and CD 8+ Treg cells in vivo for the suppression of autoimmune responses in systemic lupus erythematosus ( SLE ). Methods Poly(lactic‐co‐glycolic acid) ( PLGA ) NP s encapsulating interleukin‐2 ( IL ‐2) and transforming growth factor β ( TGF β) were coated with anti‐ CD 2/ CD 4 antibodies and administered to mice with lupus‐like disease induced by the transfer of DBA /2 T cells into (C57 BL /6 × DBA /2)F 1 ( BDF 1) mice. The peripheral frequency of Treg cells was monitored ex vivo by flow cytometry. Disease progression was assessed by measuring serum anti–double‐stranded DNA antibody levels by enzyme‐linked immunosorbent assay. Kidney disease was defined as the presence of proteinuria or renal histopathologic features. Results Anti‐ CD 2/ CD 4 antibody–coated, but not noncoated, NP s encapsulating IL ‐2 and TGF β induced CD 4+ and CD 8+ FoxP3+ Treg cells in vitro. The optimal dosing regimen of NP s for expansion of CD 4+ and CD 8+ Treg cells was determined in in vivo studies in mice without lupus and then tested in BDF 1 mice with lupus. The administration of anti‐ CD 2/ CD 4 antibody–coated NP s encapsulating IL ‐2 and TGF β resulted in the expansion of CD 4+ and CD 8+ Treg cells, 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 NP s encapsulating IL ‐2 and TGF β can expand both CD 4+ and CD 8+ Treg cells in vivo and suppress murine lupus. This approach, which enables the expansion of Treg cells in vivo and inhibits pathogenic immune responses in SLE , could represent a potential new therapeutic modality in autoimmune conditions characterized by impaired Treg cell function associated with IL ‐2 deficiency.