Liver induced transgene tolerance with AAV vectors

Abstract

Immune tolerance is a vital component of immunity, as persistent activation of immune cells causes significant tissue damage and loss of tolerance leads to autoimmunity. Likewise, unwanted immune responses can occur in inherited disorders, such as hemophilia and Pompe disease, in which patients lack any expression of protein, during treatment with enzyme replacement therapy, or gene therapy. While the liver has long been known as being tolerogenic, it was only recently appreciated in the last decade that liver directed adeno-associated virus (AAV) gene therapy can induce systemic tolerance to a transgene. In this review, we look at the mechanisms behind liver induced tolerance, discuss different factors influencing successful tolerance induction with AAV, and applications where AAV mediated tolerance may be helpful.

Keywords: AAV; Gene therapy; Immune tolerance; Immunology.

Figure 1. Mechanisms involved in the induction of tolerance via AAV directed gene therapy

The induction of tolerance within the liver relies on the integrity of the tolerogenic environment of the liver. The maintenance of this tolerogenic environment, as well as the induction of systemic tolerance, is the result of a cellular orchestration within the liver. Tg=Transgene, Ag=Antigen, KC=Kupffer cell, HSC=Hepatic Stellate Cell, DC=Dendritic Cell, HC=Hepatocyte