Amyloid β Protein Dimer-Containing Human CSF Disrupts Synaptic Plasticity: Prevention by Systemic Passive Immunization
Igor KlyubinVicki BettsAlfred T. WelzelKaj BlennowHenrik ZetterbergAnders WallinCynthia A. LemereWilliam K. CullenYing PengThomas WısnıewskıDennis J. SelkoeRoger AnwylDominic M. WalshMichael J. Rowan
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The current development of immunotherapy for Alzheimer's disease is based on the assumption that human-derived amyloid beta protein (Abeta) can be targeted in a similar manner to animal cell-derived or synthetic Abeta. Because the structure of Abeta depends on its source and the presence of cofactors, it is of great interest to determine whether human-derived oligomeric Abeta species impair brain function and, if so, whether or not their disruptive effects can be prevented using antibodies. We report that untreated ex vivo human CSF that contains Abeta dimers rapidly inhibits hippocampal long-term potentiation in vivo and that acute systemic infusion of an anti-Abeta monoclonal antibody can prevent this disruption of synaptic plasticity. Abeta monomer isolated from human CSF did not affect long-term potentiation. These results strongly support a strategy of passive immunization against soluble Abeta oligomers in early Alzheimer's disease.Keywords:
Amyloid (mycology)
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The nature of the enhanced resistance to Pseudomonas aeruginosa sepsis induced by type-specific lipopolysaccharide vaccine was examined in a mouse model of cyclophosphamide-induced granulocytopenia. Mice actively immunized with type-specific vaccine survived significantly longer than did nonimmune mice (P < .002) when challenged 8, 12, or 16 days after immunization. This protection was nonspecific eight days after immunization and specific 12 days after immunization. Passive immunization of mice with specific antibody resulted in significant, though minimal, protection. In contrast, long-term protection was observed when the passive transfer of specific antibody was combined with nonspecific immunization. This observation suggests that the specific protection observed with type-specific active immunization results from the interaction of specific antibody and an immunization-induced nonspecific cellular effector. While no significant effect of immunization on granulocyte counts in peripheral blood was demonstrated, studies of phagocytosis performed with peritoneal mononuclear cells suggest that the macrophage may be the immunization-induced, nonspecific cellular effector.
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Immunization has reduced the morbidity and mortality of many diseases. Immunizing agents have been available for many years, with many newer vaccines under investigation. The mechanisms of action of immunizing agents have only been clarified within the last several decades. Immunity may be attained by active immunization using a toxoid, or living or killed organisms. Passive immunity is achieved with serum immune globulins and antitoxins. Mechanisms of human immunity, routine immunization schedules and the pharmacology of immunizing agents are discussed.
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【The treatment of pseudomonal infection is a perplexed problem because of its modest susceptibility to most of the major antibiotics. A novel Pseudomonas vaccine(CFC-101) was prepared from the outer membrane protein fractions of several Pseudomonas strains. In this study, we examined CFC-101's effectiveness in both active and passive immunization models. CFC-101 in mice at 0.2 mg/kg, i.p., given three times at two-day intervals, completely prevented the death caused by Pseudomonas aeruginosa. Antibody titer, in accordance with the protective effect in this active immunization, was elevated to its peak level following three consecutive administrations of CFC-101. Thereafter, antibody titer stayed at a constantly high level. Each outer membrane protein fraction from the four CFC-101 producers, exhibited good cross-protective effects in mouse infection models against different Fisher types of P. aeruginosa. In the passive immunization model, 21~336 $\mu\textrm{g}$ /kg of anti-rabbit IgG to CFC-101, when mice being infected with a challenge strain, prevented the Pseudomonhas-induced death up to 60%. Therefore, the preventive effect of CFC-101 was verified in both the active and passive immunization models.】
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Abstract Recent studies have demonstrated that the basal core structure of the lipopolysaccharides of most Gram-negative bacilli are of similar or identical chemical structure. The current investigations evaluate the protective effect of immunization with these shared antigens against challenge with two heterologous Gram-negative bacilli, K. pneumoniae and E. coli 107. Active and passive immunization of mice with the Ra, Rb, Rc and Rd1 mutants of S. minnesota failed to protect against challenge with K. pneumoniae. In contrast, active and passive immunization with the Rd2 and Re mutants of S. minnesota afforded significant protection against challenge with K. pneumoniae. Similarly, active immunization with Re and passive immunization with Ra, Rc, Rd2 and Re provided significant protection against challenge with E. coli 107. In all instances, immunization with Re afforded greater protection than any of the other rough mutants of S. minnesota. Active immunization with the Re mutant was considerably less effective than type specific immunization. Immunization with Re increased the LD50 of E. coli 107 by 10-fold and K. pneumoniae by 100-fold over that of controls, while type specific immunization increased the LD50 to these organisms by greater than 100-fold and 10,000-fold respectively. The specificity of the protection induced was demonstrated by the loss of the protective activity of rabbit antiserum to Re after adsorption of the serum with dead Re mutants.
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This chapter examines the long-lasting immunity against many serious infectious diseases that can be elicited through active immunization by the administration of specific antigens that stimulate the recipient host's production of protective antibodies. Protective levels of specific antibodies usually develop within 2 to 4 weeks after completion of the primary immunization regimen. The vaccine doses may be given orally, administered as mucosal vaccines, or given by injection using intradermal, subcutaneous, or intramuscular routes. The chapter also discusses passive immunization as the process by which protective immunity is obtained through transfer of preformed antibodies from an immune host to a nonimmune recipient, either as immunoglobulin or antibody-specific immunoglobulin. The chapter highlights host factors that influence protective efficacy resulting from active immunization. Vaccines used for recommended immunization coverage of children, adolescents, and adults are reviewed, along with relevant contraindications.
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Based on the long-term follow-up of the incidence of some infectious diseases in the district and calculations of the actual number of infected subjects, the authors present an estimate of the ratio of susceptible and immune subjects during the unimpaired epidemic process. The epidemic process develops from the lowest range of immune subjects and stops at the highest range. The highest range thus gives the ratio of immune subjects which must be achieved or maintained by active immunization to achieve elimination of a given infection. The authors demonstrate on the model infection the mechanism by which after immunization the shift of infections to higher age groups occurs, and during introduction of the infection not only contact infections occur, but epidemic incidence develops. The restoration of some infections after years of elimination is to a restricted extent a natural phenomenon and does not imply failure of active immunization.
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Antibody activity specific to antigens (PSA, DSA and BGG) which served for immunization of mothers could be measured in extracts of 0‐9‐day‐old embryos spawned by these mothers, using a modified ELISA. The level of antibody activity in embryos varied according to the interval of time between mother immunization and spawning. This activity peaked between 14 and 37 days post‐immunization, then it underwent a significant gradual decrease. The activity of the extract was found to be specific only to the antigen which served for the mother immunization and could be adsorbed only by these antigens. The need of mother immunization against selected pathogens for the prevention of larvae and fry mortality is discussed.
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Bacteroides fragilis
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The authors immunized mice by repeated injections of a suspension of cancer cells. Experiments with vaccination of such animals showed that such immunization has no prophylactic value - vaccinated mice turn out to be as susceptible to cancer as unvaccinated ones.
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