Induction of immunological tolerance to adenoviral vectors by using a novel dendritic cell-based strategy
| Autor: | Rongqi Duan, Rahul Kushwah, Shaf Keshavjee, Li Zhang, Jordan R. Oliver, Jim Hu |
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| Rok vydání: | 2012 |
| Předmět: |
Transgene
T cell Genetic enhancement Adenoviridae Infections Immunology Genetic Vectors Biology Microbiology Immune tolerance Adenoviridae Mice Immune system Virology medicine Immune Tolerance Animals Humans Vector (molecular biology) Lung Cells Cultured Homeodomain Proteins Mice Knockout Dendritic cell Dendritic Cells Genetic Therapy Acquired immune system Interleukin-10 Mice Inbred C57BL medicine.anatomical_structure Insect Science Models Animal Immunologic Techniques Pathogenesis and Immunity |
| Zdroj: | Journal of virology. 86(7) |
| ISSN: | 1098-5514 |
| Popis: | The success of helper-dependent adenoviral (HD-Ad) vector-mediated lung gene therapy is hampered by the host immune response, which limits pulmonary transgene expression following multiple rounds of vector readminstration. Here, we show that HD-Ad-mediated pulmonary gene expression is sustained even upon three rounds of readministration to immunodeficient mice, highlighting the need to suppress the adaptive immune response for sustained gene expression following vector readministration. Therefore, we devised a dendritic cell (DC)-based strategy for induction of immunological tolerance toward HD-Ad vectors. DCs derived in the presence of interleukin-10 (IL-10) are refractory to HD-Ad-induced maturation and instead facilitate generation of IL-10-producing Tr1 regulatory T cells which suppress HD-Ad-induced T cell proliferation. Delivery of HD-Ad-pulsed, IL-10-modified DCs to mice induces long-lasting immunological tolerance to HD-Ad vectors, whereby pulmonary DC maturation, the T cell response, and antibody response to HD-Ad vectors are suppressed even after three rounds of pulmonary HD-Ad readministration. Moreover, sustained transgene expression is also observed in the lungs of mice immunized with HD-Ad-pulsed, IL-10-modified DCs even after three rounds of pulmonary HD-Ad delivery. Taken together, these studies identify the use of DCs generated in the presence of IL-10 as a novel strategy to induce long-lasting immune tolerance to HD-Ad vectors. |
| Databáze: | OpenAIRE |
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