Distinct immune responses to transgene products from rAAV1 and rAAV8 vectors

Abstract

Recently developed serotypes of recombinant adeno-associated virus (rAAV) vectors have significantly enhanced the use of rAAV vectors for gene therapy. However, host immune responses to the transgene products from different serotypes remain uncharacterized. In the present study, we evaluated the differential immune responses to the transgene products from rAAV1 and rAAV8 vectors. In non-obese diabetic (NOD) mice, which have a hypersensitive immunity, rAAV serotype 1 vector (rAAV1-hAAT) induced high levels of both humoral and cellular responses, while rAAV8-hAAT did not. In vitro studies showed that rAAV1, but not rAAV8 vector transduced dendritic cells (DCs) efficiently. In vivo studies indicated that vector transduction of DCs was essential for the immune responses; while the presence of a transgene product (or foreign gene product produced by host cells) was not immunogenic. Intriguingly, preimmunization with rAAV8-hAAT vector or with serum of hAAT transgenic NOD mouse induced immune tolerance to rAAV1-hAAT injection. These results demonstrate the immunogenic differences of rAAV1 and rAAV8 and imply tremendous potential for these vectors in different applications, where an immune response to transgene is to be either elicited or avoided. DC activation ͉ rAAV vectors

Longevity of rAAV vector and plasmid DNA in blood after intramuscular injection in nonhuman primates: implications for gene doping

“…For Mac4, autoimmune anemia may have been facilitated by transduction of dendritic cells by the rAAV1 vector, which has been shown to be efficient at transducing this cell type. 37 Manno et al 19 successfully transduced the human liver using a rAAV2-Factor IX vector. They observed the presence of the rAAV2 vector up to 20 weeks in human PBMCs, up to 14 weeks in serum and up to 4 weeks in urine, with their highest dose (2E12 vg kg À1 ), which is 8-80-fold higher than the doses administrated to the NHPs in this report.…”

Intradermal α1-antitrypsin therapy avoids fatal anaphylaxis, prevents type 1 diabetes and reverses hyperglycaemia in the NOD mouse model of the disease

“…ELISA for the detection of serum hAAT and BAFF levels and antibodies against hAAT Detection of hAAT and antihAAT antibodies in mouse serum was performed as previously described [17]. Purified hAAT was used as standard (Athens Research & Technology, Athens, GA, USA).…”

Direct and Retrograde Transduction of Nigral Neurons with AAV6, 8, and 9 and Intraneuronal Persistence of Viral Particles

“…Similarly, high titers of neutralizing antibodies reduced transgene expression in rats after striatal AAV injection (Sanftner et al, 2004). AAV binding to heparin has been postulated as a prerequisite for dendritic cell infection and development of persisting immunity (Vandenberghe et al, 2006;Lu and Song, 2009). We therefore focused our study on two non-heparin-binding serotypes, AAV8 (Gao et al, 2002) and AAV9 (Gao et al, 2004).…”