title: Characterization of pulmonary T cell response to helper-dependent adenoviral vectors following intranasal delivery.
abstract: In spite of the extensive research in the field of gene therapy, host immune responses continue to be the major barrier in translating basic research to clinical practice. Helper-dependent adenoviral (HD-Ad) vectors show great potential for pulmonary gene therapy, but the knowledge of pulmonary immune responses toward these vectors is very limited. In this study, we show that HD-Ad vectors are potent stimulators of dendritic cell (DC) maturation, thus leading to stimulation of T cell proliferation with approximately 6% of naive CD4(+) T cells from pulmonary mediastinal lymph node responding to HD-Ad-treated DCs. In contrast to the belief that HD-Ad vectors are unable to prime adaptive immune response, we show for the first time, through in vivo pulmonary studies in mice, that HD-Ad vectors can prime CD4(+) and CD8(+) T cell responses in the lung at high and substantially low doses. This indicates cross-presentation of HD-Ad-derived epitopes by DCs to prime CD8(+) T cell responses. To assess the basis of pulmonary T cell response against HD-Ad vectors, we examined the response of conventional DCs (cDCs) and plasmacytoid DCs (pDCs) in the lung. In response to HD-Ad delivery, there is induction of maturation in both cDC and pDC subsets, but it is the cDCs, not pDCs, that migrate rapidly to draining lymph nodes within the first 2 days after vector delivery to prime adaptive immune response against these vectors. These findings have implications for development of strategies to prevent adaptive immune responses against gene therapy vectors.
authors.affiliation: Physiology and Experimental Medicine Research Program, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Rahul
authors.initials: R
authors.lastname: Kushwah
authors.forename: Huibi
authors.initials: H
authors.lastname: Cao
authors.forename: Jim
authors.initials: J
authors.lastname: Hu
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000257:Adenoviridae Infections / Q000276:immunology / Q000821:virology; D000281:Administration, Intranasal; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000821:virology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000145:classification / Q000166:cytology / Q000276:immunology / Q000821:virology; D005822:Genetic Vectors / Q000008:administration & dosage*; D006378:Helper Viruses / Q000235:genetics / Q000276:immunology*; D007113:Immunity, Innate; D008168:Lung / Q000276:immunology* / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism