This expression of Fas-L in turn allows for the direct deletion of Teff cells through a Fas (CD95)/Fas-L manner, as Fas is constitutively expressed on Teff cells within the liver [85]. disease causing gene that is missing or deficient in individuals. Viruses are commonly used in the field of gene therapy for many reasons: 1) large quantity, 2) very easily manipulated, and 3) they have naturally evolved to deliver their genetic payload to target cells or cells. Within the field of gene therapy, adenovirus, adeno-associated disease, retrovirus, and lentivirus have enjoyed probably the most success. The choice of viral vector system is based on several factors: common versus localized transduction, long-term vs short-term transgene manifestation, packaging capacity, and immunogenicity. Of all the viral centered vector systems utilized for gene therapy, adeno-associated disease (AAV) has become probably one of the most popular today. AAV is definitely a parvovirus that contains a single stranded DNA genome of ~4.7kb. AAV is unable to replicate without a helper disease and is non-pathogenic in hosts, including humans. Recombinant AAV (rAAV) retains the inverted terminal repeats (ITRs) of the wild-type genome permitting rAAV to have a packaging capacity of up to 5kb. rAAV vectors have several important properties that make them well suited for gene therapy. They can infect non-dividing cells, vector genomes are minimally integrative and are managed episomally, come in a wide array of serotypes with a specific tropism for a certain tissue, and importantly, possess low immunogenicity [1C3]. However, there remains a risk for immune responses. ZM 306416 hydrochloride For example, when treating an inherited disorder in which there is no protein expression, the restorative protein can be seen as nonself and may result in a T and B cell mediated immune response [4]. It is widely approved that AAV ZM 306416 hydrochloride liver directed gene therapy can harness the tolerogenic nature of the liver and induce systemic immunological tolerance to transgene products [5C8]. ZM 306416 hydrochloride Tolerance is definitely defined as the failure of the body to mount an immune response to an antigen whether it be to self or a foreign protein. Regulatory T cells (Tregs) are known to play a crucial part in the induction and maintenance of tolerance. Tregs suppress immune reactions in the periphery through a number of mechanisms including direct and indirect suppression of antigen showing cells, B lymphocytes, and T effector cells (Fig. 1) [9C14]. By leveraging this unique ability to induce immune tolerance to ZM 306416 hydrochloride transgene products, it is possible to develop enduring treatments for a multitude of diseases (for a more total listing of diseases which have been treated using gene therapy see the article by Roncarolo, within this issue). Open in a separate window Number 1 Mechanisms involved in the induction of tolerance via AAV directed gene therapyThe 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 Multiple cells have been investigated for inducing transgene tolerance including hematopoietic stem cells, thymus, muscle mass, and liver (for a more total review observe [15]). This review will primarily focus on AAV gene transfer to the liver, the current understanding of specific cellular interactions between resident liver and immune cells, and mechanisms of tolerance induction. We will focus on key factors to consider for successful and durable tolerance induction and provide an overview of pre-clinical data assisting AAV mediated tolerance induction in several different disease models, as well as discuss potential limitations for translation into humans. Finally, we will discuss a novel software of AAV gene therapy, using transgene tolerance induction to treat an autoimmune disease. Immune tolerance and Tregs A deleterious immune response to an AAV delivered transgene is definitely a potential complication associated with long-term correction of disease. This response becomes more prominent in cases where the restorative gene Nrp1 ZM 306416 hydrochloride being delivered is completely absent, not just mutated [4]. In this case, the transgene.