Local gene therapy with CTLA4-immunoglobulin fusion protein in experimental allergic encephalomyelitis

It has been reported previously that the induction phase of experimental al lergic encephalomyelitis (EAE) is highly sensitive to systemic blockade of stimulation via MHC class II molecules and co-stimulation via the CD28:CD80 /CD86 pathways. In contrast, the effector phases of EAE were relatively una ffected by similar treatments using MHC class II antigen (Ag)-specific mAb and cytotoxic T lymphocyte antigen (CTLA)4-Ig fusion proteins in some studi es. This has been attributed to different sensitivities of effector cell fu nction or the poor penetrance of inhibitory proteins into the central nervo us system (CNS). To examine this question further, MHC class II Ag-specific mAb and CTLA4-Ig were delivered directly into the CNS following EAE induct ion, and both were found to inhibit disease. While it was found that system ic administration of mouse CTLA4-Ig could also inhibit the progression of e ffector immune responses when administered shortly before or during clinica l disease, these were significantly more active when delivered directly int o the CNS, which probably involved an action on both CD28 ligands, CD80 and CD86. Although mouse CTLA4-human Ig was therapeutically less efficient tha n mouse CTLA4-mouse Ig protein, probably due to the enhanced immunogenicity and lower functional activity, gene delivery of CTLA4-human fg into the CN S using a non-replicating adenoviral vector was more effective than a singl e injection of CTLA4-human Ig protein. Gene delivery significantly ameliora ted the development of EAE, without necessarily inhibiting unrelated periph eral immune responsiveness. Local gene delivery of CTLA4-Ig may thus be an important target for immunotherapy of human autoimmune conditions such as m ultiple sclerosis.