Local gene therapy with CTLA4-immunoglobulin fusion protein in experimental allergic encephalomyelitis.
Croxford JL., O'Neill JK., Ali RR., Browne K., Byrnes AP., Dallman MJ., Wood MJ., Fedlmann M., Baker D.
It has been reported previously that the induction phase of experimental allergic 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 unaffected by similar treatments using MHC class II antigen (Ag)-specific mAb and cytotoxic T lymphocyte antigen (CTLA)4-Ig fusion proteins in some studies. This has been attributed to different sensitivities of effector cell function or the poor penetrance of inhibitory proteins into the central nervous system (CNS). To examine this question further, MHC class II Ag-specific mAb and CTLA4-Ig were delivered directly into the CNS following EAE induction, and both were found to inhibit disease. While it was found that systemic administration of mouse CTLA4-Ig could also inhibit the progression of effector immune responses when administered shortly before or during clinical disease, these were significantly more active when delivered directly into the CNS, which probably involved an action on both CD28 ligands, CD80 and CD86. Although mouse CTLA4-human Ig was therapeutically less efficient than mouse CTLA4-mouse Ig protein, probably due to the enhanced immunogenicity and lower functional activity, gene delivery of CTLA4-human Ig into the CNS using a non-replicating adenoviral vector was more effective than a single injection of CTLA4-human Ig protein. Gene delivery significantly ameliorated the development of EAE, without necessarily inhibiting unrelated peripheral immune responsiveness. Local gene delivery of CTLA4-Ig may thus be an important target for immunotherapy of human autoimmune conditions such as multiple sclerosis.