Gene replacement therapies, like organ and cell transplantation are likely to introduce neo-antigens that elicit rejection via humoral and/or effector T cell immune responses. Nonetheless, thanks to an ever growing body of pre-clinical studies it is now well accepted that gene transfer protocols can be specifically designed and optimized for induction of antigen-specific immune tolerance. One approach is to specifically express a gene in a tissue with a tolerogenic microenvironment such as the liver or thymus. Another strategy is to transfer a particular gene into hematopoietic stem cells or immunological precursor cells thus educating the immune system to recognize the therapeutic protein as "self". In addition, expression of the therapeutic protein in pro-tolerogenic antigen presenting cells such as immature dendritic cells and B cells has proven to be promising. All three approaches have successfully prevented unwanted immune responses in pre-clinical studies aimed at the treatment of inherited protein deficiencies, e.g. lysosomal storage disorders and hemophilia, and of type I diabetes and multiple sclerosis. In this review we focus on current gene transfer protocols that induce tolerance, including gene delivery vehicles and target tissues, and discuss successes and obstacles in different disease models.
Keywords: Autoimmune disease; Treg; gene therapy; gene transfer; genetic disease; immune response; tolerance; vector.