TY - JOUR
T1 - Modulation of the liver immune microenvironment by the adeno-associated virus serotype 8 gene therapy vector
AU - Carestia, Agostina
AU - Kim, Seok-Joo
AU - Horling, Franziska
AU - Rottensteiner, Hanspeter
AU - Lubich, Christian
AU - Reipert, Birgit M
AU - Crowe, Brian A
AU - Jenne, Craig N
N1 - © 2020 The Author(s).
PY - 2021/3/12
Y1 - 2021/3/12
N2 - Adeno-associated viruses (AAVs) are emerging as one of the vehicles of choice for gene therapy. However, the potential immunogenicity of these vectors is a major limitation of their use, leading to the necessity of a better understanding of how viral vectors engage the innate immune system. In this study, we demonstrate the immune response mediated by an AAV vector in a mouse model. Mice were infected intravenously with 4 × 1012 copies (cp)/kg of AAV8, and the ensuing immune response was analyzed using intravital microscopy during a period of weeks. Administration of AAV8 resulted in the infection of hepatocytes, and this infection led to a moderate, but significant, activation of the immune system in the liver. This host immune response involved platelet aggregation, neutrophil extracellular trap (NET) formation, and the recruitment of monocytes, B cells, and T cells. The resident liver macrophage population, Kupffer cells, was necessary to initiate this immune response, as its depletion abrogated platelet aggregation and NET formation and delayed the recruitment of immune cells. Moreover, the death of liver cells produced by this AAV was moderate and failed to result in a robust, sustained inflammatory response. Altogether, these data suggest that AAV8 is a suitable vector for gene therapy approaches.
AB - Adeno-associated viruses (AAVs) are emerging as one of the vehicles of choice for gene therapy. However, the potential immunogenicity of these vectors is a major limitation of their use, leading to the necessity of a better understanding of how viral vectors engage the innate immune system. In this study, we demonstrate the immune response mediated by an AAV vector in a mouse model. Mice were infected intravenously with 4 × 1012 copies (cp)/kg of AAV8, and the ensuing immune response was analyzed using intravital microscopy during a period of weeks. Administration of AAV8 resulted in the infection of hepatocytes, and this infection led to a moderate, but significant, activation of the immune system in the liver. This host immune response involved platelet aggregation, neutrophil extracellular trap (NET) formation, and the recruitment of monocytes, B cells, and T cells. The resident liver macrophage population, Kupffer cells, was necessary to initiate this immune response, as its depletion abrogated platelet aggregation and NET formation and delayed the recruitment of immune cells. Moreover, the death of liver cells produced by this AAV was moderate and failed to result in a robust, sustained inflammatory response. Altogether, these data suggest that AAV8 is a suitable vector for gene therapy approaches.
KW - Adeno-associated virus-8
KW - gene therapy
KW - immune response
KW - inflammation
KW - intravital imaging
KW - liver
UR - http://www.scopus.com/inward/record.url?scp=85097900411&partnerID=8YFLogxK
U2 - 10.1016/j.omtm.2020.10.023
DO - 10.1016/j.omtm.2020.10.023
M3 - Article
C2 - 33376758
SN - 2329-0501
VL - 20
SP - 95—108
JO - Molecular Therapy Methods and Clinical Development
JF - Molecular Therapy Methods and Clinical Development
ER -