Immune response to controlled release of immunomodulating peptides in a murine experimental autoimmune encephalomyelitis (EAE) model

Abstract

The effects of controlled release on immune response to an immunomodulating peptide were evaluated in a murine experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). The peptide, Ac-PLP-BPI-NH 2-2 (Ac-HSLGKWLGHPDKF-(AcpGAcpGAcp) 2-ITDGEATDSG-NH 2; Ac = acetyl, Acp = є aminocaproic acid) was designed to suppress T-cell activation in response to PLP 139–151, an antigenic peptide in MS. Poly-lactide-co-glycolide (PLGA) microparticles containing Ac-PLP-BPI-NH 2-2 (8 ± 4 µm, 1.4 ± 0.2% (w/w)) were prepared by a powder-in oil-in water emulsion-solvent evaporation method, sterilized and administered subcutaneously (s.c.) to SJL/J (H-2 s) mice in which EAE had been induced by immunization with PLP 139–151. Treatment groups received Ac-PLP-BPI-NH 2-2: (i) in solution by repeated i.v. or s.c. injection, (ii) in solution co-administered with blank PLGA microparticles, (iii) in solution co-administered with Ac-PLP-BPI-NH 2-2 loaded microparticles, and (iv) as Ac-PLP-BPI-NH 2-2 loaded microparticles. Administration of Ac-PLP-BPI-NH 2-2 as an s.c. solution produced clinical scores and maintenance of body weight comparable to i.v. solution, but with reduced overall survival, presumably due to anaphylaxis. Administration as s.c. microparticles provided a somewhat less effective reduction in symptoms but with no toxicity during treatment. Thus, the results suggest that s.c. administration of Ac-PLP-BPI-NH 2-2 microparticles can provide pharmacological efficacy and reduction in dosing frequency without increased toxicity.