Immunization of Alzheimer model mice with adenovirus vectors encoding amyloid beta-protein and GM-CSF reduces amyloid load in the brain.

Induction of anti-amyloid beta-protein (Abeta) antibodies in transgenic mouse models of Alzheimer disease (AD) by repeated injection of synthetic Abeta was shown to be effective in preventing and removing deposition of Abeta aggregates in the brain. Here, we have tested a non-invasive modality whereby a replication-defective adenovirus vector encoding Abeta was intranasally administered to mice to elicit immune responses against Abeta. Intranasal immunization only with the adenovirus vector failed to induce significant immune responses. When an adenovirus vector encoding granulocyte/macrophage-colony stimulating factor (GM-CSF) was used as an adjuvant in conjunction with the adenovirus encoding Abeta, a marked immune response was elicited against Abeta. Immunoglobulin isotyping revealed that the induced anti-Abeta antibodies are predominantly of the IgG2b and IgG1 isotypes, suggesting a Th-2 anti-inflammatory type. Furthermore, amyloid load in the brain of AD model mice (Tg2576) vaccinated with adenovirus vectors encoding Abeta and GM-CSF was much smaller than that in control Tg2576 mice. Thus, intranasal administration of adenovirus vectors encoding Abeta and GM-CSF may be effective in prevention and treatment of AD.

Automated mass immunization of poultry: the prospect for nonreplicating human adenovirus-vectored in ovo vaccines.

Automated in ovo vaccination is an efficient method for mass immunization of poultry. Although in ovo vaccination has been used to mass immunize chickens against several infectious diseases, there are common poultry diseases for which in ovo-compatible vaccines are not commercially available. It was recently demonstrated that in ovo administration of a nonreplicating human adenovirus vector encoding an avian influenza virus hemagglutinin induced protective immunity against highly pathogenic avian influenza. The advantages of this new class of poultry vaccine include in ovo delivery of a wide variety of pathogen-derived antigens, high potency in a single-dose regimen, rapid production in response to increased demand, no replication of the vector, no pre-existing immunity to human adenovirus in chickens, compatibility with automated in ovo administration and no interference with epidemiological surveys of natural infections.

Nasal inoculation of an adenovirus vector encoding 11 tandem repeats of Abeta1-6 upregulates IL-10 expression and reduces amyloid load in a Mo/Hu APPswe PS1dE9 mouse model of Alzheimer's disease.

BACKGROUND: One of the pathological hallmarks of Alzheimer's disease (AD) is deposits of amyloid beta-peptide (Abeta) in neuritic plaques and cerebral vessels. Immunization of AD mouse models with Abeta reduces Abeta deposits and improves memory and learning deficits. Because recent clinical trials of immunization with Abeta were halted due to brain inflammation that was presumably induced by a T-cell-mediated autoimmune response, vaccination modalities that elicit predominantly humoral immune responses are currently being developed. METHODS: We have nasally immunized a young AD mouse model with an adenovirus vector encoding 11 tandem repeats of Abeta1-6 fused to the receptor-binding domain (Ia) of Pseudomonas exotoxin A (PEDI), AdPEDI-(Abeta1-6)(11), in order to evaluate the efficacy of the vector in preventing Abeta deposits in the brain. We also have investigated immune responses of mice to AdPEDI-(Abeta1-6)(11). RESULTS: Nasal immunization of an AD mouse model with AdPEDI-(Abeta1-6)(11) elicited a predominant IgG1 response and reduced Abeta load in the brain. The plasma IL-10 level in the AD mouse model was upregulated after immunization and, upon the stimulation with PEDI-(Abeta1-6)(11), marked IL-10 responses were found in splenic CD4(+) T cells from C57BL/6 mice that had been immunized with AdPEDI-(Abeta1-6)(11). CONCLUSIONS: These results suggest that the induction of Th2-biased responses with AdPEDI-(Abeta1-6)(11) in mice is mediated in part through the upregulation of IL-10, which inhibits activation of dendritic cells that dictate the induction of Th1 cells.

Topical application of Escherichia coli-vectored vaccine as a simple method for eliciting protective immunity.

We report here that animals can be protected against lethal infection by Clostridium tetani cells and Bacillus anthracis spores following topical application of intact particles of live or gamma-irradiated Escherichia coli vectors overproducing tetanus and anthrax antigens, respectively. Cutaneous gammadeltaT cells were rapidly recruited to the administration site. Live E. coli cells were not found in nonskin tissues after topical application, although fragments of E. coli DNA were disseminated transiently. Evidence suggested that intact E. coli particles in the outer layer of skin may be disrupted by a gammadeltaT-cell-mediated innate defense mechanism, followed by the presentation of E. coli ligand-adjuvanted intravector antigens to the immune system and rapid degradation of E. coli components. The nonreplicating E. coli vector overproducing an exogenous immunogen may foster the development of a new generation of vaccines that can be manufactured rapidly and administered noninvasively in a wide variety of disease settings.

Induction of anti-inflammatory immune response by an adenovirus vector encoding 11 tandem repeats of Abeta1-6: toward safer and effective vaccines against Alzheimer's disease.

Induction of an immune response to amyloid beta-protein (Abeta) is effective in treating animal models of Alzheimer's disease. Human clinical trials of vaccination with synthetic Abeta (AN1792), however, were halted due to brain inflammation, presumably induced by T cell-mediated immune responses. We have developed an adenovirus vector as a "possibly safer" vaccine. Here, we show that an adenovirus vector encoding 11 tandem repeats of Abeta1-6 can induce an immune response against amyloid beta-protein. Much higher titers against amyloid beta-protein were observed when an adenovirus vector encoding GM-CSF was co-administered. Immunoglobulin isotyping revealed a predominant IgG1 response, indicating anti-inflammatory Th2 type. Immunohistochemical analysis revealed no inflammation-related pathology in the brain of mice immunized with the adenovirus vector. Induced antibodies strongly reacted with amyloid plaques in the brain, demonstrating functional activity of the antibodies. Thus, the adenovirus vector encoding 11 tandem repeats of Abeta1-6 may be a safer alterative to peptide-based vaccines.

Induction of a Th2 immune response by co-administration of recombinant adenovirus vectors encoding amyloid beta-protein and GM-CSF.

Lines of experimental evidence indicate that induction of humoral immune responses in transgenic mouse models of Alzheimer disease (AD) by repeated injection of synthetic amyloid beta-protein (Abeta) is effective in prevention and clearance of deposits of Abeta aggregates in the brain of the mice. We have tested a non-injection modality whereby replication-defective adenovirus vectors encoding Abeta or the 99-amino acid carboxyl terminal fragment of Abeta precursor were intranasally administered to mice to elicit immune responses against Abeta. When mice were immunized only with the adenovirus vectors, immune responses against Abeta were negligible. By co-immunization with an adenovirus vector encoding granulocyte-macrophage colony stimulating factor (GM-CSF), the adenovirus vector encoding Abeta effectively elicited an immune response against Abeta. Immunoglobulin isotyping demonstrated a predominant IgG1 and IgG2b response, suggesting a Th2 anti-inflammatory type. Thus, adjuvantation is essential for induction of an immune response against Abeta by adenovirus-mediated nasal vaccination.

Reversible disruption of thymic function by steroid treatment.

The effect of steroid treatment on the thymic output of T cells was examined in an avian model. Recent thymic emigrants in chickens transiently express the chicken T cell Ag 1 thymocyte marker, and thymic function can be monitored indirectly by measuring the levels of TCR gene rearrangement excision circles in peripheral T cells. Both parameters were used to show that intensive steroid treatment induces thymic involution and a profound reduction in the supply of naive T cells to the periphery. Conversely, resident T cells in the peripheral lymphocyte pool were relatively spared. Thymopoiesis immediately recovered following cessation of steroid treatment, concurrent with restoration of the thymic output of newly formed T cells. Repopulation of the peripheral T cell pool recapitulated the ontogenetic pattern of gamma delta T cell replenishment before alpha beta T cell reseeding, thereby indicating the complete recovery of thymic function after a course of steroid treatment.