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- Lemiale, Franck, et al.
(författare)
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Enhanced mucosal immunoglobulin A response of intranasal adenoviral vector human immunodeficiency virus vaccine and localization in the central nervous system.
- 2003
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Ingår i: Journal of Virology. - 0022-538X. ; 77:18, s. 10078-87
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Tidskriftsartikel (refereegranskat)abstract
- Replication-defective adenovirus (ADV) vectors represent a promising potential platform for the development of a vaccine for AIDS. Although this vector is typically administered intramuscularly, it would be desirable to induce mucosal immunity by delivery through alternative routes. In this study, the immune response and biodistribution of ADV vectors delivered by different routes were evaluated. ADV vectors expressing human immunodeficiency virus type 1 (HIV-1) Gag, Pol, and Env were delivered intramuscularly or intranasally into mice. Intranasal immunization induced greater HIV-specific immunoglobulin A (IgA) responses in mucosal secretions and sera than in animals with intramuscular injection, which showed stronger systemic cellular and IgG responses. Administration of the vaccine through an intranasal route failed to overcome prior ADV immunity. Animals exposed to ADV prior to vaccination displayed substantially reduced cellular and humoral immune responses to HIV antigens in both groups, though the reduction was greater in animals immunized intranasally. This inhibition was partially overcome by priming with a DNA expression vector expressing HIV-1 Gag, Pol, and Env before boosting with the viral vector. Biodistribution of recombinant adenovirus (rADV) vectors administered intranasally revealed infection of the central nervous system, specifically in the olfactory bulb, possibly via retrograde transport by olfactory neurons in the nasal epithelium, which may limit the utility of this route of delivery of ADV vector-based vaccines.
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| 3. |
- Xu, Ling-Yun
(författare)
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Mechanisms and modulation of experimental allergic encephalomyelitis as basis for treatment of multiple sclerosis
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Its etiology is unknown and there exists no cure. Experimental allergic encephalomyelitis (EAE) can be induced in susceptible rat or mouse strains by immunization with myelin, proteins or peptides plus adjuvants, providing a model to explore the possible immunopathogenesis and therapeutic strategies. Aims of the study: (1) To examine the interactions between autoreactive T cells and astrocytes, with emphasis on nitric oxide (NO); (2) To evaluate the effects of nasal administration of cytokines (IL-4, IL-10 and TGF- [beta]1) on prevention and treatment of EAE, especially in relation to the role of dendritic cells (DC); (3) To study synergistic effects of encephalitogenic peptide plus anti-inflammatory cytokine IL-4 or IL-10 on treatment of ongoing EAE. Materials and methods: Astrocytes were prepared from newborn Lewis rats. EAE was induced in Lewis rats by immunization with myelin basic protein peptide 68-86 (MBP 68-86) or, in DA rats, with guinea pig spinal cord homogenate. For EAE prevention, IL-4, IL-10 or TGF-[beta]1 was administered nasally prior to immunization, or at the time of immunization. For EAE treatment, nasal administration of MBP 68-86 + IL-4 or IL- 10 was executed from day 7 to day I I post immunization. Proliferation assay, ELISPOT assay, immunohistochemistry, in situ hybridization and apoptosis assay were employed to evaluate immunological parameters. Results: Cell-cell contact between autoreactive T cells and astrocytes induced NO production by astrocytes in the presence of specific autoantigen, which may contribute to elimination of autoactive T cells from the CNS through apoptosis pathway. Nasal administration of low dose of anti-inflammatory or regulatory cytokines, such as IL-4, IL- 10 or TGF-[beta]1, effectively prevented EAE, but by different mechanisms. DC were actively involved in IL-4- and TGF- [beta]1-induced EAE prevention, while the inhibitory effect of IL- 10 was associated with reduced immune responses. Neither MBP peptide nor cytokine alone delivered via nasal route suppressed ongoing EAE. However, Lewis rats with ongoing EAE receiving MBP 68-86 + IL-4 or IL-10 developed mild EAE both clinically and histologically, accompanied by restricted Th1 cell responses by lymph node cells. Nasal administration of MBP 68-86 + IL-4 also induced Th2 and Th3 responses. Conclusion: These studies focus on immunoregulatory mechanisms and immunotherapeutic strategies of EAE. T cell-astrocyte interactions may regulate local immune responses within the CNS via the NO pathway and influence the fate of infiltrating T cells. Nasal administration of low dose IL-4, IL-10 and TGF-[beta]1 is effective in EAE prevention, but failed in EAE treatment. Combined nasal administration of autoantigen peptide and IL-4 or IL-10 suppressed ongoing EAE in Lewis rats, suggesting a new antigen-specific therapeutic principle for autoimmune diseases.
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