Adjuvant bacterial

Micormet, L, Coste, L, Beermann, F., Haeuw, J.F., Cerottini, J.C., Bormefoy, J.Y., Romero, P. and Rermo, T., 2001, Cancer vaccine design a novel bacterial adjuvant for peptide-specific CTL induction. J. Immunol. 166 4612-4619. 

Vaccination to induce an adaptive immune response is expected for a broad range of infectious diseases and cancers. Traditional vaccines are mainly composed of live attenuated viruses, whole inactivated pathogens, or inactivated bacterial toxins. In general, these approaches have been successful for developing vaccines that can induce an immune response based on antigen-specific antibody and cytotoxic T lymphocyte (CTL) responses, which kill host cells infected with intracellular organisms (Fig. 1) [1,2], One of the most important current issues in vaccinology is the need for new adjuvants (immunostimulants) and delivery systems. Many of the vaccines currently in development are based on purified subunits, recombinant... 

The structure of the native immunostimulatory MDPs was found to be IV-acetyl muramyl-L-alanyl-D-isoglutamine. (/V-Acetyl muramic acid is a base component of bacterial peptidoglycan.) Native TDM is a potent pyrogen and is too toxic for general use as an adjuvant. The molecular basis underlining MDP s adjuvanticity remains to be fully elucidated. Administration of MDP, however, is known to activate a number of cell types that play direct/indirect roles in immune function, and induces the secretion of various immunomodulatory cytokines (Table 13.14). 

Toxoids are inactivated bacterial toxins. They retain the ability to stimulate the formation of antitoxin, which are antibodies directed against the bacterial toxin. Adjuvants are inert substances, such as aluminum salts (i.e., alum), which enhance vaccine antigenicity by prolonging antigen absorption. 

Woodard, L.F., Surface Chemistry and Classification of Vaccine Adjuvants and Vehicles, in Bacterial Vaccines, A. Mizrahi, ed., Alan R. Liss, New York, 281, 1990. 

Jones, D.E. et al., Bacterial motif DNA as an adjuvant for the breakdown of immune selftolerance to pyruvate dehydrogenase complex, Hepatology, 36, 679, 2002. 

Ellouz, F. et al., Minimal structural requirements for adjuvant activity of bacterial pepti-doglycan derivatives, Biochem. Biophys. Res Commun., 59, 1317, 1974. 

Another example that can be included in the subunit vaccine class is the use of bacterial toxoids. Many bacteria produce toxins which play an important role in the development of the disease caused by a particular organism. Thus, vaccines against some agents, for example tetanus and diphtheria, consist of the toxin inactivated with formaldehyde conjugated to an adjuvant. Immunization protects from disease by stimulating antitoxin antibody which neutralizes the effects of the toxin. 

Polyclonal antibodies are produced by injecting an antigen into an animal in the presence of an adjuvant containing bacterial lipopolysaccharides that stimulate the immune system. Serum prepared from the blood contains several different classes of antibodies that interact with different domains in the antigen molecule, each of... 

Bessler WG, et al. Bacterial lipopeptides constitute efficient novel immunogens and adjuvants in parenteral and oral immunization. Behring Inst Mitt 1997 98 390. 

Combating infectious diseases (viral, protozoal, fungal, bacterial, helminthic) Anti-cancer agent Alleviating allergic reactions Vaccine adjuvant... 

The issue was one of getting the DNA into a cell and this gave rise to the use of viral delivery systems and bacterial plasmid DNA (pDNA) vectors. pDNA vectors are useful since they are much safer to manufacture on a large scale, inexpensive, and easily customized—apart from being safer for the patient. However, the down side is that these systems are poorly immunogenic although, as noted above, this might be improved by the addition of an appropriate adjuvant. 

Although there are a number of advantages associated with the use of subunit vaccines (e.g., highly purified peptides, proteins or DNA) as vaccines (e.g., specificity), one feature they all have in common is that they are generally poorly immunogenic. The more traditional vaccines contain many other components, some of which elicit additional T-cell assistance or function as adjuvants. An adjuvant is a substance that acts as an immunostimulator, one example being the bacterial DNA in a whole cell vaccine. The overall result is a more robust immune response than that provided by the antigen alone. 

Bacterial toxins such as diphtheria and tetanus can damage host cells but the isolated toxins can also be immunogenic. However, the induced response may not always be very strong and booster shots are required every 10 years. Adjuvants could improve the response and both diphtheria and tetanus toxoids are more effective when combined with pertussis subunit vaccines, the DPT combination at present used clinically. 

It has recently been established that bacterial DNA, but not vertebrate DNA, has direct immunostimulatory effects on leukocytes in vitro. The immunostimulatory effect is due to unmethylated CpG dinucleotides, which are underrepresented and methylated in vertebrate DNA. CpG DNA and synthetic oligonucleotides from a variety of sources have shown significant promise as new adjuvants (10-12). CpG induces a strong Thl response, mainly by stimulating cytokine induction and through the expression of costimulatory molecules on antigen-presenting cells. CpG is currently in clinical trials and may become part of a licensed product in the future. 

Although not catalytic in the usual sense, certain substances, known as adjuvants, arc capable of enhancing the immunogenicity of certain antigens. Among the adjuvants are aluminum salts, bacterial endotoxins, bacillus Calmette-Guirin (BCG), Bordetella pertussis, and mycobacteria. These materials and this phenomenon have been important in immunity research. Sometimes adjuvants are used clinically in connection with certain immunizations, such as against tetanus. 

When crude endotoxin from the heptose-less mutant of Salmonella typhimurium is combined with trehalose dimycolate from mycobacteria in oil droplets and injected directly into established tumors (line 10 hepatocellular carcinoma) in syngeneic guinea pigs, rapid regression of the tumors occurs and over 90% of the animals are cured. The three required components for activity in this tumor model are (a) the endotoxin (b) the mycobacterial adjuvant, trehalose dimycolate and (c) a compound satisfying the minimal structural requirement (muramyl dipeptide) for adjuvant activity by bacterial cell wall materials. The mycobacterial cell wall skeleton is able to replace the latter two components. 

A wide variety of novel approaches for the development of mucosal immune responses by administration of antigens in different delivery systems have been investigated, in many cases, with considerable success. These approaches include (1) the coadministration of immunogens with adjuvants active at the mucosal surface, (2) the coupling of immunogens to carrier molecules that promote their uptake at the mucosal inductive site, and (3) the expression of antigens in live attenuated bacterial or viral vectors, which can promote the colonization of mucosal tissue and the incorporation of antigens into a variety of microparticulate and adhesive vehicles, which are taken up in mucosal inductive sites. 

Most antigens require an adjuvant to increase their immunogenicity and a number of formulations can be used. Regulations on their use should be consulted prior to embarking on a course of immunizations. For many years Freund s complete and incomplete adjuvant were the formulation of choice for all immunization work. In recent years welfare issues have been raised over the use of these adjuvants and a number of alternatives based on water-soluble bacterial cell wall components have become available. 

Effects on respiration are similar to those of thiopental at usual anesthetic doses. However, propofol causes a marked decrease in systemic blood pressure during induction of anesthesia, primarily through decreased peripheral resistance. In addition, propofol has greater negative inotropic effects on the heart than etomidate and thiopental. Apnea and pain at the site of injection are common adverse effects of bolus administration. Muscle movements, hypotonus, and (rarely) tremors have also been reported following its use. Clinical infections due to bacterial contamination of the propofol emulsion have led to the addition of antimicrobial adjuvants (eg, ethylenediaminetetraacetic acid and metabisulfite). 

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