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Modulation of microglial activation state following passive immunization in amyloid depositing transgenic mice.

Alzheimer's disease is a large and growing health problem. Several lines of transgenic mice overexpressing the amyloid precursor protein (APP) develop both diffuse and compacted amyloid deposits which increase in size and number with age. In the vicinity of compacted deposits, these mice develop neuritic dystrophy and activation of glia. Ultimately, these mice also develop memory deficits. Immunotherapy against the Abeta peptide has been effective in both clearing amyloid deposits from the brain, and improving the mnemonic performance of the transgenic mice. Associated with these actions, are changes in the expression of microglial markers. In some cases, the glial activation markers decline, consistent with reduced provocation from amyloid deposits. However, in a time course study, we found that some markers of microglial activation increase transiently once the immunotherapy is initiated. Still another marker continues to rise for up to 3 months of treatment, and remains elevated even after the parenchymal amyloid deposits are largely removed. These changes are consistent with a shift in the microglial phenotype, transitioning from a condition associated with inflammation and ineffective in clearing Abeta deposits to one with reduced inflammation, and capable of clearing deposited amyloid.

Alzheimer Disease↗

Active and passive immunization against Clostridium difficile diarrhea and colitis.

Clostridium difficile, a gram-positive bacterium, is the major cause of hospital-acquired infectious diarrhea and colitis in industrialized nations. C. difficile colonization results from antibiotic administration and subsequent loss of protection provided by intestinal flora. C. difficile induced-colitis is caused by the release of two exotoxins, toxin A and B. Host factors including advanced age, pre-existing severe illness and weakened immune defenses predispose individuals to symptomatic infection. The generation of antibody responses to toxin A through natural exposure is associated with protection from disease. In addition, an inability to acquire immunity to toxin A puts individuals at risk for recurrent and/or severe disease. Immunological approaches for the management of this disease are being developed which could reduce the reliance on antibiotics for treatment and allow for re-establishment of the natural barrier provided by an intact commensal flora. An active vaccine and various immunotherapeutic strategies under evaluation may prove to be effective against severe or relapsing C. difficile infection.

Animals↗

Therapeutic antibody gene transfer: an active approach to passive immunity.

Advances in gene transfer approaches are enabling the possibility of applying therapeutic antibodies using DNA. In particular gene transfer in combination with electroporation is promising and can result in generating in vivo antibody concentrations in the low therapeutic range. However, several important problems need to be dealt with before antibody gene transfer can become a valuable supplement to the current therapies. As antibody production following gene transfer is difficult to control, the danger of inducing autoimmune conditions or uncontrollable side effects occurs in cases in which autologous antigens are targeted. It is suggested that the most promising area of application therefore appears to be infectious disease in which heterologous antigens are targeted and concerns for long-term antibody exposure are minimal. Finally, genes encoding fully human antibodies will enhance long-term expression and decrease problems linked to immunogenicity.

Antibodies↗

The in vitro and in vivo protective activity of monoclonal antibodies directed against Hantaan virus: potential application for immunotherapy and passive immunization.

Hantaan virus (HTNV), a member of the genus Hantavirus, family Bunyaviridae, is an etiologic agent causing a serious human disease, hemorrhagic fever with renal syndrome (HFRS), with a mortality as high as 15% and is also a potential bioterrorism agent. It is urgently needed to develop anti-HTNV-neutralizing monoclonal antibodies (MAbs) for treatment and prevention of HTNV infection. In the present study, 18 murine MAbs directed against HTNV strain Chen were generated and characterized. Among these MAbs, 13 were directed against viral nucleocapsid protein (NP), four recognized the viral envelope glycoprotein G2 and one reacted with both NP and G2. Only those MAbs that recognize the epitopes on G2 were positive in hemagglutination inhibition (HI) test and had in vitro virus-neutralizing activity and in vivo protective activity against HTNV infection of susceptible mice. Since all the mice were protected by administration of the virus-neutralizing MAbs one day before and two days after HTNV challenge, these neutralizing MAbs are potentially useful for pre- and post-exposure prophylaxis and for immunotherapy of HTNV infection. Phase II clinical trials of these neutralizing MAbs for emergent treatment of patients with HTNV infection in early stages of HRFS are carried out in endemic areas in China.

Animals↗

Passive immunization with convalescent serum, or oral immunization with formalin-killed organisms, does not protect mice against gastrointestinal challenge with Listeria monocytogenes.

Listeria monocytogenes is an important foodborne pathogen in both humans and animals. In addition, murine listeriosis is a widely used model for studying the molecular pathogenesis of an intracellular pathogen, and the regulation of protective cellular immunity. Little attention has been paid to protective immunity against L. monocytogenes in the gastrointestinal tract, where a secretory immune response might prevent attachment of the bacteria to the intestinal epithelium. In this study we found that neither opsonization of L. monocytogenes with immune serum, nor repeated oral administration of killed L. monocytogenes, protected mice against gastrointestinal challenge with L. monocytogenes.

Administration, Oral↗

Associations between passive immunity and morbidity and mortality in dairy heifers in Florida, USA.

A prospective cohort study was undertaken to determine calf-level factors that affected calf health status between birth and 6 months of age. A convenience sample of approximately 3300 female Holstein calves born in 1991 on two large Florida dairy farms was used for the study. Data collected on each calf at birth included farm of origin, weight, height at the pelvis, birth date, and serum total protein (a measure of colostral immunoglobulin absorption). Birth season was dichotomized into summer and winter using meteorological data collected by University of Florida Agricultural Research Stations. Health data including date of initial treatment and number of treatments were collected for the diseases diarrhea, omphalitis, septicemia and pneumonia. All calves were followed for 6 months. Cumulative incidences of mortality and occurrence of diarrhea, omphalitis, septicemia and pneumonia were 0.12, 0.35, 0.11, 0.24 and 0.21, respectively. Serum total protein (TP) was a significant risk factor for mortality. The association of TP and mortality was quadratic and showed a dramatic decrease in mortality as TP increased from 4.0 to 5.0 g/dl, a small improvement from 5.0 to 6.0 g/dl and virtually no improvement in mortality rates as TP increased over 6.0 g/dl. The hazard mortality ratio was constant from birth to six months, indicating that the increased risk of mortality associated with low levels of TP was evident through six months of age. No interactions between TP, farm, season, or birth weight were found in these analyses. Serum total protein concentration was a significant risk factor for the occurrences, age of onset and severity of septicemia and pneumonia. The association between TP and septicemia was linear and an interaction with birth season was found. The association between TP and pneumonia was quadratic, and in contrast to the TP-and-septicemia relationship, the morbidity hazard ratio for pneumonia was not constant over the time measured; that is, colostral immunity protected the calf from developing pneumonia early in life, but this effect disappeared as the calf got older. Total protein was not a significant risk factor for diarrhea or omphalitis.

Animals↗

Active versus passive immunization against hepatitis A in the Israel defence forces: a cost-benefit analysis.

We compared cost-benefit and cost-effectiveness analyses of hepatitis A prevention with immune serum globulin (ISG) vs inactivated hepatitis A vaccine (iHAV) in the Israel Defence Forces. Personnel were grouped according to conditions and duration of service and analyses were performed based on maximum and minimum hepatitis A projected incidences for each group. For standing army soldiers in field units, iHAV is economically superior compared with ISG. For the five other groups studied, the reverse is true. Expected increases in production costs of ISG and expected decreases in costs of iHAV are likely to make iHAV more economical in the future.

Cost-Benefit Analysis↗

Protection against tick-borne encephalitis virus isolated in Japan by active and passive immunization.

In order to establish a firm preventive measure for tick-borne encephalitis (TBE) in Japan, we evaluated the immune response of European vaccine against Japanese TBE virus strain (Oshima 5-10) for man and mouse. Furthermore, the efficacy of pre- and post-exposure protection by a polyclonal rabbit anti-TBE virus serum was examined in the mouse model. 80% of vaccinees seroconverted against Oshima 5-10 strain after the 2nd immunization of vaccine and the remaining 20% seroconverted after the 3rd immunization. Two persons with pre-existing anti-Japanese encephalitis virus (JEV) antibodies showed low immune responses against TBE virus. In mouse vaccination and challenge tests, efficient protection was observed in mice challenged with lethal doses of Oshima 5-10 strain as well as those observed in mice with the Western subtype and the Far Eastern subtype of TBE strains. Pre-exposure treatment with rabbit anti-TBE virus serum provided complete protection against lethal challenge with Oshima 5-10 strain. For post-exposure treatment with the antibody, significant protection was observed when mice were treated 24 h after virus challenge, whereas it was not observed 48 h after virus challenge. reserved.

Animals↗

Passive immunization for hepatitis B.

Numerous studies have been conducted to assess the effectiveness of gamma globulin in preventing type B hepatitis. These investigations have evaluated the effectivenesses of standard immunoglobulin (IG) and hepatitis B immunoglobulin (HBIG) in pre-exposure and postexposure settings. The current data suggest that HBIG and standard IG containing some antibody to hepatitis B surface antigen may be effective for pre- and postexposure prophylaxis of hepatitis B. It is recommended that HBIG be used for the postexposure prophylaxis of individuals sustaining accidental needle-stick or mucosal exposure to blood known to contain hepatitis B surface antigen. If HBIG is unavailable, then standard IG may be beneficial. While pre-exposure prophylaxis with gamma globulin may be effective, there are appropriate environmental control methods available that may significantly reduce the transmission of hepatitis B, and these should be fully implemented.

Antibodies↗

Effect of passive immunization with buffalo follicular fluid antisera on ovarian activity in guinea pigs.

Ovarian activity and follicular populations were studied in guinea pigs (Cavia porcellus) following administration of antisera against buffalo follicular fluid (buFF). Antibodies were raised in rabbits and the titre tested by immunodiffusion assay. Fourteen guinea pigs cycling normally were randomized into two groups. Animals in Group I (n = 8) were treated (i.p.) with 0.5 ml antisera and in Group II (control, n = 6) with the same volume of normal rabbit serum at 12 h intervals on the 10th and 11th day of their oestrous cycle. They were sacrificed 24 h after onset of estrus when ovulation points were counted and ovaries processed for microscopical examination. Treatment with buFF-antisera increased ovulation rate (3.6 vs. 2.0; p < 0.01) but had no significant effect on the total number of follicles. However, the treatment reduced the percentages of atretic follicles in all size classes. These results indicated that the administration of a buFF-antisera produced in the rabbits increased ovulation rate in guinea pigs by reducing the incidence of atresia.

Animals↗

Effects of active and passive immunization in the Mycoplasma arthritidis infection of rats.

Viable, heat-inactivated, formalin-inactivated and sonicated Mycoplasma (M.) arthritidis antigens as well as immune sera against M. arthritidis and spleen cells from Lewis rats recovered from M. arthritidis infection were injected into naive Lewis rats prior to a challenge infection with 10(7) cfu of M. arthritidis and tested for their protective effects. Viable mycoplasmas induced arthritis combined with the production of high titers of antibodies against M. arthritidis and resistance to a second infection. The application of the inactivated M. arthritidis-antigens in emulsion of incomplete Freund's Adjuvant (ICFA) to naive rats, which also induced a strong antibody production, as well as the inoculation of reconvalescent serum from rats infected with M. arthritidis and hyperimmune serum against M. arthritidis from rabbits and mice protected rats also from an outbreak of arthritis after challenge. The injection of sonicated M. arthritidis antigen without ICFA which failed to induce the production of antibodies and the transfer of spleen cells from rats recovered from M. arthritidis infection had no protective function. The investigations showed, that antibodies play an important role in the prevention of M. arthritidis infections in Lewis rats.

Animals↗

Identification of protective outer membrane antigens of Brucella ovis by passive immunization of mice with monoclonal antibodies.

Outer membrane proteins (OMPs) and rough lipopolysaccharide (R-LPS), the main surface antigens of Brucella ovis, display surface-exposed epitopes. Mixtures of monoclonal antibodies (mAbs) to both antigens were previously shown to protect mice against a B. ovis challenge. To further identify the antigens involved, seven mAbs against Brucella OMPs (Omp10, Omp16, Omp19, Omp25, Omp31, Omp2b and Omp1) and three to R-LPS were tested for protection either individually or in combinations. Significant reduction in spleen infection in challenged mice, relative to controls, was used as the protection criteri. Controls included nonimmunized mice and mice given an irrelevant, anti-O-polysaccharide (OPS), mAb. For comparison, a group received a mouse serum containing antibodies to both OMPs and R-LPS; this serum was prepared by immunization with a B. ovis hot-saline extract which, as described previously, induces protective immunity in mice and rams. Significant protection was observed with both mAbs to OMPs and R-LPS. mAbs to Omp16, Omp19 and Omp31 afforded the highest protection and prevented the development of splenomegaly. The protective effect of mAb to Omp31 was not interfered with by nonprotective mAbs in different mixtures. The data presented confirm the protective role of antibodies to OMPs and R-LPS against B. ovis, and identify several OMPs, especially Omp31, which are promising candidates for a subunit vaccine against ram epididymitis.

Animals↗

Passive immunization against oral AIDS virus transmission: an approach to prevent mother-to-infant HIV-1 transmission?

To develop immunoprophylaxis regimens against mother-to-child human immunodeficiency virus type 1 (HIV-1) transmission, we established a simian-human immunodeficiency virus (SHIV) model in neonatal macaques that mimics intrapartum mucosal virus exposure (T.W. Baba, J. Koch, E.S. Mittler et al: AIDS Res Hum Retroviruses 10:351-357, 1994). We protected four neonates from oral SHIV-vpu+ challenge by ante- and postpartum treatment with a synergistic triple combination of immunoglobulin (Ig) G1 human anti-HIV-1 neutralizing monoclonal antibodies (mAbs) (T.W. Baba, V. Liska, R. Hofmann-Lehmann et al: Nature Med 6:200-206, 2000), which recognize the CD4-binding site of Env, a glycosylation-dependent gp120, or a linear gp41 epitope. Two neonates that received only postpartum mAbs were also protected from oral SHIV-vpu+ challenge, indicating that postpartum treatment alone is sufficient. Next, we evaluated a similar mAb combination against SHIV89.6P, which encodes env of primary HIV89.6. One of four mAb-treated neonates was protected from infection and two maintained normal CD4+ T-cell counts. We conclude that the epitopes recognized by the three mAbs are important determinants for achieving protection. Combination immunoprophylaxis with synergistic mAbs seems promising to prevent maternal HIV-1 transmission in humans.

Acquired Immunodeficiency Syndrome↗

Active and passive immunization with the Pseudomonas V antigen protects against type III intoxication and lung injury.

Pseudomonas aeruginosa is an opportunistic bacterial pathogen that can cause fatal acute lung infections in critically ill individuals. Damage to the lung epithelium is associated with the expression of toxins that are directly injected into eukaryotic cells through a type Ill-mediated secretion and translocation mechanism. Here we show that the P. aeruginosa homolog of the Yersinia V antigen, PcrV, is involved in the translocation of type III toxins. Vaccination against PcrV ensured the survival of challenged mice and decreased lung inflammation and injury. Antibodies to PcrV inhibited the translocation of type III toxins.

Animals↗