Induction of immunological tolerance to transgene products

Gene transfer holds the possibility of correcting difficult or impossible to treat disorders, ranging from inherited monogenic diseases to graft rejection in transplant surgery. However, one barrier to success in gene therapy is the immune response to the protein encoded by the transgene. Because the transgene product is often missing in the patient, they will have developed lymphocytes capable of generating an immune response to the therapeutic protein, thereby rendering treatment ineffective. Thus, finding a way to induce tolerance to the gene product is the focus of a considerable amount of research. This research often relies heavily on delivery of the transgene to anatomical sites of the body that are naturally immune privileged or potentially immune suppressive, such as the liver, central nervous system, eyes, and hematopoietic cells. The benefits of tolerance induction by gene transfer are not limited for using gene therapy as a protein replacement strategy but can be extended to any situation where an immune response is unfavorable, such as autoimmune disease. This chapter focuses on the different strategies used to induce tolerance to transgene products along with the practical applications and limitations of those strategies based on the physiology of each anatomical site targeted.