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Characterization of Pulmonary T Cell Response to Helper-Dependent Adenoviral Vectors following Intranasal Delivery¹

Rahul Kushwah^*,, Huibi Cao^* and Jim Hu^2,*,

^* Physiology and Experimental Medicine Research Program, Hospital for Sick Children and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

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 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by Operating Grants from the Canadian Institutes of Health Research, the Canadian Cystic Fibrosis Foundation, and the Foundation Fighting Blindness-Canada (to J.H.). J.H. was a Canadian Cystic Fibrosis Foundation Scholar and recipient of the Canadian Cystic Fibrosis Foundation Zellers Senior Scientist Award, and holds a Premier’s Research Excellence Award of Ontario, Canada. R.K. is a recipient of Restracomp Studentship Award from the Hospital for Sick Children.

² Address correspondence and reprint requests to Dr. Jim Hu, Physiology and Experimental Medicine Research Program, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. E-mail address: jhu{at}sickkids.on.ca

³ Abbreviations used in this paper: HD-Ad, helper-dependent adenoviral; DC, dendritic cell; cDC, conventional DC; pDC, plasmacytoid DC; AAV, adeno-associated virus; MLN, mediastinal lymph node; BMDC, bone marrow-derived dendritic cell; BALF, bronchoalveolar lavage fluid; MOI, multiplicity of infection.