The management of dental pain: a review of possible alternatives to drug therapy.
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Biomedical subjects
Publications and source records attributed to M W Russell.
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Protection against smooth surface dental caries was investigated in fifteen young rhesus monkeys which were immunized subcutaneously with Streptococcus mutans serotype c in Freund's incomplete adjuvant. Monkeys immunized with killed whole organisms developed significantly less caries than control animals. Monkeys immunized with pronase-treated cell walls developed significantly more caries than control animals while monkeys immunized with untreated cell walls showed no such enhancement of caries. Haemagglutinating and complement-fixing antibodies to cell walls and culture supernatant antigens (SN Ag) of S. mutans developed in the sera of all immunized animals to a similar degree. Antibodies to lipoteichoic acid and to an insoluble dextran preparation were found in all immunized animals and showed no relationship to the prevalence of caries. Antibodies to the serotype c polysaccharide were also found in animals immunized with whole cells and pronase-treated cell walls. However, precipitating antibody levels to partially purified antigens I/II and II, derived from SN Ag, but present also in cells, were related to the development of caries. Animals immunized with whole cells and with untreated cell walls developed a brisk antibody response to antigen I/II, while those immunized with pronase-treated cell walls responded more slowly. The results suggest that immunization may induce both caries reduction and enhancement, depending on the antibody response which is developed.
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Rhesus monkey IgG, IgA and IgM were purified from pooled normal serum and labelled with 125I. Four monkeys were injected intravenously with approximately 50 microgram of each purified immunoglobulin containing between 25 muCi and 50 muCi of 125I. Iodination was approximately 1 atom per 14 molecules of IgG and IgA and per 2.5 molecules of IgM. Samples of serum were taken for up to 22 days after injection and radioactivity compared with that in a sample taken within 30 min of injection. Sucrose density ultracentrifugation of serum samples revealed that in animals given IgG or IgA, radioactivity was associated with 7S protein peaks, and in animals given IgM radioactivity was associated predominantly with a 19S protein peak. Most of the radioactivity could be precipitated from serum samples with the appropriate monospecific antiserum. The mean half-life of rhesus monkey IgG was estimated as 8.3 days, IgA as 4.5 days and IgM as 4.7 days.
A protein, designated antigen III, was extracted from cells and culture supernatant of Streptococcus mutans serotype c, and purified by ammonium sulphate precipitation followed by chromatography on anion-exchanged and gel filtration columns. Monospecific antisera were raised by injecting purified antigen III in rabbits. Antigen III prepared from cells and supernatants appeared identical by reaction with antisera and were of similar chemical composition and physico-chemical properties. Antigen III was resistant to most proteolytic enzymes, but pepsin digestion decreased its molecular weight from 44,000 to 24,000 without destroying antigenic activity. Immunofluorescence showed that antigen III was located at or near the cell surface of S. mutans serotypes b, c, e and f.
Active immunisation with Streptococcus mutans induced protection against dental caries in rhesus monkeys, and this was associated with serum antibodies. Passive transfer of immune serum with IgG, IgM, and IgA antibodies to Strep. mutans failed to induce protection against dental caries. However, when separated IgG, IgM, and IgA sera were given, IgG induced significant protection but IgA or IgM antibodies to Strep. mutans did not. IgA and IgM may compete or interfere with the protective effect of IgG antibodies, and the ratio of IgG/IgA and IgG/IgM antibodies might be an important factor in immunisation against dental caries.
1) The immunological mechanism of protection against dental caries has been investigated by passive immunization with antisera to S. mutans in the rhesus monkey. 2) Passive immunization with separated IgG, IgM and IgA from sera of immunized monkeys supports the concept that IgG, unlike IgA or IgM antibodies are protective. 3) The role of cell-mediated immunity has been explored by the use of transfer factor. This showed that protection against dental caries can be elicited by passive transfer of whole immune serum and cellular immunity, but not by cellular immunity or immune serum alone. 4) The results of active and passive immunization suggests that immuno-regulation of T and B cell interactions plays an important part in the effector mechanism of opsonization, phagocytosis and killing of S. mutans.
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The passage of immunoglobulin from plasma to the oral cavity was studied in rhesus monkeys. Immunoglobulins G, A and M were purified from pooled rhesus monkey serum, radiolabelled with 125I and injected intravenously into twelve monkeys. Sequential samples of oral fluids were taken over a 24 h period and were assayed for radioactivity. Radioactivity could be detected in crevicular fluid washings after 0.5 h in monkeys injected with IgG and IgA, and after 2 h in monkeys given IgM. Maximal levels were found after 4 h with each immunoglobulin. Radioactivity in parotid and mixed saliva could be detected in all animals after 30 min, reaching a maximal level after 4 h. Ultracentrifugation on sucrose density gradients revealed that most of the radioactivity in crevicular fluid washings was in the 7S zone in the animals given IgG and IgA, and in a 19S zone in animals given IgM. The radioactivity in partoid saliva did not represent intact immunoglobulin molecules, since all the activity was present in zones of low molecular weight in animals given IgG, IgA or IgM. In mixed saliva a small amount of radioactivity was found in the immunoglobulin zones. The results suggest that intact molecules of IgG, IgA and IgM can pass from plasma to the oral cavity via crevicular fluid, and could contribute to oral defence mechanisms particularly in the crevicular domain. The volume of crevicular fluid in the approximal space of deciduous molars of rhesus monkeys was estimated to be approximately 0.3 microliter.
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Polymorphonuclear leucocytes (PMN) obtained from lactating cows' udders were deficient in their ability to kill Staphylococcus aureus compared with PMN isolated from blood. However, blood PMN suspended in separated milk or in the presence of casein were similarly impaired. Casein was found to inhibit in vitro the bactericidal activities of histone, the lactoperoxidase-H2O2-KI system and PMN lysates. Electron microscopy showed that casein was ingested by PMN with the formation of phagocytic vacuoles. These observations provide the basis of a hypothesis explaining the bactericidal deficiency of milk PMN and the consequent susceptibility of the udder to infection.
Serum antibodies to glucosyltransferase (GTF) of Streptococcus mutans serotype c were assayed sequentially by means of an enzyme inhibition radio-assay in twenty-six Rhesus monkeys immunized with S. mutans. Pre-immune and control sera had a GTP-enhancing effect which was shown also by albumin and non-immune immunoglobulin fractions. GTF-inhibitory activity was found in IgG fractions from some immune sera and could be absorbed by S. mutans cells possessing cell-bound GTF. Inhibitory antibodies to GTF developed in the sera of four monkeys immunized with hydroxylapatite extract of culture supernatant (HACS), and in four out of fifteen monkeys immunized with S. mutans cells, but in none of the seven sham-immunized control animals. The monkeys immunized with HACS showed no reduction in caries. A correlation has been demonstrated between protection against caries and the early development of serum IgG antibodies to antigens present in HACS but there was no consistent association between protection against caries and GTF-inhibitory antibodies. The results also suggest the possibility that other antibodies, possibly present in the IgM or IgA fractions and having an enhancing effect on GTF, may increase the incidence of caries.
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A case report of a patient with a large pulmonary arteriovenous fistula and valvar pulmonary stenosis is presented. The fistula was diagnosed prenatally and its effect on in utero cardiovascular growth and development documented. Due to concerns about massive intrapulmonary shunting potentially causing profound cyanosis after delivery, an EXIT (EX-utero Intrapartum Treatment) procedure was used to transfer the infant from placental to extracorporeal membrane oxygenation (ECMO) support. Severe pulmonary microvascular disease resulted in prohibitive pulmonary hypertension despite surgical ligation of the fistula. Prenatal and postnatal hemodynamic assessments of the fistula are presented and are compared to the pathologic findings.
Intranasal (i.n.) immunization with Streptococcus mutans surface protein AgI/II mixed with cholera toxin B subunit (CTB) containing a trace amount of cholera toxin (CT) induces strong immune responses in mucosal and systemic sites, but whether pure CTB alone has an adjuvant effect has been questioned. To determine the adjuvant effect of recombinant (r) CTB, mice were immunized with 10 micrograms of AgI/II either mixed with or conjugated to 5 micrograms of rCTB, and antibody responses in saliva, nasal wash, gut wash, vaginal wash, and serum were assayed by ELISA. The results showed that AgI/II either mixed with or conjugated to rCTB could induce both mucosal IgA and systemic IgG antibodies to higher levels than in mice similarly immunized with AgI/II alone. Some responses, especially serum IgG antibodies, were enhanced by adding 5 micrograms CT to the immunogen, whereas overall mice immunized with AgI/II mixed with CTB contaminated with CT tended to generate the strongest mucosal IgA and serum IgG responses to AgI/II. However, rCTB used as an adjuvant induced lower antibody responses against itself than CTB intentionally or inadvertently mixed with CT. These results show that rCTB can serve as an adjuvant for protein immunogens administered by the i.n. route.
Secretory IgA (SIgA), which is one of the humoral factors responsible for the immune protection of large areas of mucosal surfaces, is produced by plasma cells resident in the submucosae and glandular stroma. However, specific induction of SIgA antibodies occurs largely through the common mucosal immune system, whereby antigens presented to the mucosa-associated lymphoid tissues, such as intestinal Peyer's patches, stimulate B lymphocytes committed to IgA synthesis. These cells enter the circulation via lymphatics and finally home to several remote secretory tissues. The regulatory cells and factors that govern the mucosal immune response are beginning to be elucidated. Several bacterial and viral antigens have been used to evoke SIgA antibodies experimentally in humans, but only a few oral vaccines have been developed for clinical application. Considerable scope exists for the identification of appropriate immunogens and their formulation in delivery vehicles with suitable adjuvants to induce protective antibodies against a variety of pathogens that invade through mucosal surfaces. Several mucosal pathogens, however, secrete proteases that specifically cleave human IgA1. The full significance of this evasion mechanism and the ways of circumventing it must be addressed to maximize the effectiveness of mucosal immunity.