Role of Vector in Activation of T Cell Subsets in Immune Responses against the Secreted Transgene Product Factor IX
| Autor: | K. John Pasi, Mark L. McCleland, Valder R. Arruda, Elina Armstrong, Roland W. Herzog, Katherine A. High, Dariusz W. Kowalczyk, Hildegund C. J. Ertl, J. Nathan Hagstrom, Paul A. Fields |
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| Rok vydání: | 2000 |
| Předmět: |
T cell
Genetic Vectors Antigen presentation Fluorescent Antibody Technique Biology medicine.disease_cause Hemophilia B Adenoviridae Factor IX Mice Th2 Cells Immune system T-Lymphocyte Subsets Drug Discovery Genetics medicine Animals Cytotoxic T cell Transgenes Molecular Biology Adeno-associated virus B cell Pharmacology Gene Transfer Techniques Th1 Cells Adoptive Transfer Mice Inbred C57BL medicine.anatomical_structure Immunoglobulin G Helper virus Immunology biology.protein Cytokines Molecular Medicine Antibody T-Lymphocytes Cytotoxic |
| Zdroj: | Molecular Therapy. 1:225-235 |
| ISSN: | 1525-0016 |
| DOI: | 10.1006/mthe.2000.0032 |
| Popis: | Defining immune responses against the secreted transgene product in a gene therapy setting is critical for treatment of genetic diseases such as hemophilia B (coagulation factor IX deficiency). We have previously shown that intramuscular administration of an adeno-associated viral (AAV) vector results in stable expression of therapeutic levels of factor IX (F.IX) and may be associated with humoral immune responses against F.IX. This study demonstrates that intramuscular injection of an AAV vector expressing F.IX fails to activate F.IX-specific cytotoxic T lymphocytes (CTLs) in hemostatically normal or in hemophilia B mice, so that there is an absence of cellular immune responses against F.IX. However, transgene-derived F.IX can cause B cell responses characterized by production of T helper cell-dependent antibodies (predominantly IgG1, but also IgG2 subclasses) resulting from activation of CD4+ T helper cells primarily of the Th2 subset. In contrast, administration of an adenoviral vector efficiently activated F.IX-specific CTLs and T helper cells of both Th1 and Th2 subsets, leading to inflammation and destruction of transduced muscle tissue and activation of B cells as well. Therefore, vector sequences fundamentally influence T cell responses against transgene-encoded F.IX. In conclusion, activation of the immune system in AAV-mediated gene transfer is restricted to pathways mediated by F.IX antigen presentation through MHC class II determinants resulting in T and B cell responses that are more comparable to responses in the setting of protein infusion rather than of viral infection/gene transfer. |
| Databáze: | OpenAIRE |
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