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DNA immunization 을 이용한 결핵감염에 대한 방어면역을 효과적으로 유도하는 방법에 관한 연구

DNA immunization 을 이용한 결핵감염에 대한 방어면역을 효과적으로 유도하는 방법에 관한 연구
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Identification of antigens that provide protective immunity via prophylactic and therapeutic vaccination against Mycobacterium tuberculosis (MTB) infection is critical for the development of subunit vaccines for tuberculosis (TB). In the first part of this study, a head-to-head comparison of seven well-known MTB antigens delivered by DNA vaccine and evaluation of their respective immunogenicities and protective efficacies in pre- and post-exposure mouse models were performed. All TB antigens were designed as a chimeric fusion with Flt3-L to enhance antigen-specific T cell immunity upon vaccination. Prophylactic vaccination with the Flt3L (F)-Mtb32 DNA vaccine elicited significant protection in both the lungs and spleen against MTB challenge, comparable to the BCG vaccine. F-Ag85A and F-Mtb32 DNA vaccines, in combination with ii chemotherapy, reduced bacterial burden to undetectable levels in the lungs of all mice infected with MTB. These data collectively indicate that the F-Mtb32 DNA vaccine confers the most efficient protective immunity that suppresses bacterial growth in the active or latent status of MTB. Although a potent protective and therapeutic TB antigen, Mtb32, were drived, search of an efficient adjuvant for DNA vaccines is crucial to overcome weak immunogenicity of DNA vaccine in larger animal model, and eventually human. Using an aerosol MTB infection mouse model, we analyzed how concurrent treatment of nonlytic Fc-fused IL-7 DNA (IL-7-nFc) and Flt3-ligand fused Mtb32 (F-Mtb32) DNA improved the immunogenicity of DNA vaccines. Mice were subject to conventional chemotherapy for 6 weeks starting at 4 weeks after aerosol infection of MTB. Once chemotherapy began, DNA immunizations were administered 5 times at 2 week intervals. Coadministration of IL-7-nFc and FMtb32 DNA during chemotherapy synergistically enhanced the effectiveness of Mtb32-specific T cell responses and was sustainable for up to one year after the last immunization as assessed by IFN-γ ELISPOT assay. Furthermore, after dexamethasone treatment, TB reactivation was significantly reduced in mice receiving both IL-7-nFc and F-Mtb32 DNA compared to control mice or mice administered with F-Mtb32 DNA alone. Additionally, mice treated with IL-7-nFc and F-Mtb32 together exhibited improved lung pathology and reduced pulmonary inflammation values relative to saline injected mice or F-Mtb32 DNA only treated iii mice. Intracellular cytokine staining demonstrated that the protective effects of the combinatory IL-7-nFc and F-Mtb32 DNA therapy was associated with enhanced Mtb32-specific IFN-γ secreting CD4+ T cell and CD8+ T cell responses stimulated using cytotoxic T lymphocyte epitope peptide in the lungs and spleens of mice. These data suggest that IL-7-nFc functions as a novel adjuvant by significantly enhancing TB DNA vaccine-induced T cell immunity and may facilitate future therapeutic TB DNA vaccine use in clinics.
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