A dynamic approach for treating autoimmune disease.

Abstract

Abstract Cell-based immunotherapies have the potential to reverse autoimmune disease by inducing or restoring immune-tolerance. Extensive preclinical studies have demonstrated that regulatory T cell (Tregs) play a key role in both induction and maintenance of tolerance. Several strategies aimed at harvesting and expanding autologous Tregs and then re-infusing them into patients have been investigated. Unfortunately, development of a large scale in vitro method has not been achieved, especially for human cells. On the other hand, a clinically relevant in vivo approach for inducing Ag-specific tolerance has successfully been demonstrated using ectopic expression of an antigen in the liver. Here, we have developed a long-lasting immunotherapy that induces functionally suppressive, Ag-specific Tregs in the murine model of multiple sclerosis using a liver directed adeno-associated virus (AAV) vector expressing myelin oligodendrocyte glycoprotein (MOG). Modulation of EAE disease in C57BL/6 is typically limited to a single immunodominant epitope. By engineering the AAV vector to express full-length protein (MOG1-247), we have created an immunotherapy that is capable of dynamically inducing Ag-specific tolerance against multiple immunogenic epitopes (e.g MOG35-55, MOG119-132). Mice received a single peripheral injection of AAV.MOG vector, or control. EAE was induced between 2 weeks and 8 months later using various MOG epitopes emulsified in adjuvant. Within 14-days, control mice developed significant neurological deficits, whereas none of the treated mice exhibited any symptoms. This work completely abrogates the deficiencies associated with ex vivo expanded Tregs providing a new paradigm for treating autoimmune diseases.