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Biomedical subjects

P A Small

Publications and source records attributed to P A Small.

At least 19 recordsLinked to original sources
PubMed1992

Transgenic mice lacking class I major histocompatibility complex-restricted T cells have delayed viral clearance and increased mortality after influenza virus challenge.

To investigate the role of CD8+ T lymphocytes in recovery from influenza pneumonia, we used transgenic mice either homozygous (-/-) or heterozygous (+/-) for beta 2-microglobulin (beta 2-M) gene disruption. These mice lack major histocompatibility complex-restricted class I (CD8+) T cells. We found that after challenge with a nonlethal influenza virus, the beta 2-M (-/-) mice had significantly delayed pulmonary viral clearance. Furthermore, after challenge with a more virulent influenza virus, the beta 2-M (-/-) mice had a significantly higher mortality rate than did control mice. Thus, CD8+ T cells are important in recovery from virulent influenza infections, but other host defense mechanisms can clear the respiratory tract of more benign infections.

Animals↗
PubMed1992

Influenza: pathogenesis and host defense.

Our understanding of the host defense and pathogenesis of influenza has come from parallel studies in animal models and humans. Infection is initiated by deposition of influenza particles on either the upper respiratory tract epithelium or directly into the alveoli, with the former method having a lethal dose several orders of magnitude greater than the latter. The virus attaches to its cellular receptor by its hemagglutinin (HA); if this step is blocked by specific antibody, infection does not take place. The major role of antibody is in the prevention of disease. Even though serum antibody (primarily antihemagglutinin, but also antineuraminidase) has been known for decades to prevent viral pneumonia, it has only more recently been shown that passive administration of anti-influenza serum to virgin mice prevents pneumonia, but not rhinotracheitis. Further, intravenously administered anti-influenza IgA has been shown to be specifically transported into the nasal secretions and protect the murine nasopharynx against influenza infection. Whereas antibody is clearly required for protection against influenza, cytotoxic T-lymphocyte (CTL) activity is both necessary and sufficient for recovery from influenza. This was best shown in studies using nude (athymic) mice. Influenza-infected nude mice shed virus from their lungs indefinitely. Adoptive transfer of anti-influenza CTLs to influenza-infected nude mice will clear the virus from their lungs, whereas administration of anti-influenza antibody will lead to a cessation of viral shedding only as long as antibody is present. Influenza in aging presents a serious clinical problem. Recent studies suggest that the age-related decrease in anti-influenza CTL activity causes both prolonged viral shedding and increased viral spread through the respiratory tract.

Aging↗
PubMed1991

Passive transfer of local immunity to influenza virus infection by IgA antibody.

Secretory IgA is presumed to be the mediator of mucosal immunity based on many studies that show a correlation between protection and secretory IgA titers; however, a causal relationship has not yet been established. Classically, passive transfer of antibody has been used to demonstrate causality, but the passive transfer of local immunity with physiologically transported IgA has not been previously reported. In this study mice were injected intravenously with polymeric IgA (pIgA), monomeric IgA (mIgA), or IgG1 mAb specific for the H1 hemaglutinin of PR8 influenza virus. pIgA was shown to be specifically transported into nasal secretions relative to the mIg. The transported pIgA was functional, as evidenced by its ability to bind to virus in an ELISA assay and to protect nonimmune mice against intranasal infection with H1N1 but not H3N2 influenza virus. Intravenous injection of similar virus-neutralizing doses of anti-influenza IgG1 mAb did not protect against nasal viral challenge. IgA-mediated protection could be abrogated by the intranasal administration of antiserum against the alpha chain of IgA. These data demonstrate the passive transfer of local immunity by the i.v. administration of pIgA antibody and show that the IgA in secretions can protect against influenza virus infection. This general approach could provide a model for the evaluation of the role of local IgA in host defense against other pathogens.

Animals↗
PubMed1991

Influenza immunization: intranasal live vaccinia recombinant contrasted with parenteral inactivated vaccine.

To compare the efficacy and duration of the immune response to local and systemic vaccination, Balb/c mice were vaccinated either intraperitoneally (i.p.) with an inactivated A/PR/8/34 (H1N1) vaccine or intranasally (i.n.) with a vaccinia recombinant containing the H1 gene of influenza. The i.p. inactivated vaccine stimulated high serum IgG anti-influenza titres and protected the lungs against viral challenge for the duration of the experiment (17 months). Little nasal wash IgA was induced and the noses were susceptible to challenge. Animals vaccinated i.n. with the recombinant had lower serum IgG titres and the lungs showed poor protection against challenge. Nasal wash IgA titres were higher, however, and the noses were largely protected from viral challenge for 17 months.

Administration, Intranasal↗
PubMed1991

Immunoglobulin A mediation of murine nasal anti-influenza virus immunity.

Most mice which have recovered from influenza virus infection are immune to reinfection with the same influenza virus. This immunity could be abrogated by the intranasal instillation of anti-immunoglobulin A (anti-IgA) but not of anti-IgG or anti-IgM antiserum. Thus, IgA is the major, if not the sole, mediator of nasal immunity to influenza virus in immunocompetent mice.

Animals↗
PubMed1991

Influenza in senescent mice: impaired cytotoxic T-lymphocyte activity is correlated with prolonged infection.

Influenza and pneumonia are leading causes of death in the elderly. Cytotoxic T-lymphocyte activity is responsible for viral clearance after infection and declines with age. We hypothesized that following intranasal infection with influenza virus, aged mice would have decreased anti-influenza cytotoxic T-lymphocyte activity that would correlate with prolonged pulmonary viral shedding. To test this, young (1.5-4.0 month) and aged (22-25 month) BALB/c mice were infected intranasally with influenza A/Port Chalmers/1/73(H3N2). Mice were killed at 3-19 days following infection. Their splenic cytotoxic T-lymphocyte activity was measured by a secondary in vitro chromium release assay. Pulmonary viral titres were quantified by growth of titrated lung specimens in fertilized hens' eggs. Serum antibody titres were measured by an ELISA. Young mice responded in a relatively homogeneous fashion. They developed maximal cytotoxic T-lymphocyte activity of 60.9 +/- 2.0% by Days 11-13, and all except one cleared virus from the lung by Day 7. In contrast, old mice were heterogeneous. Their cytotoxic T-lymphocyte activity peaked at 46.9 +/- 5.0% and was delayed by 5-7 days. Forty-five per cent were still shedding virus at Days 7 and 8, and shedding persisted for at least 13 days in some mice. There was a strong correlation in both young and aged mice between the presence of virus in the lungs and decreased splenic cytotoxic T-lymphocyte activity (chi 2 = 30.2, P much less than 0.001). No significant difference was found between young and aged animals in serum IgG1 anti-H3 antibody titres. We conclude that following influenza infection in aged mice, impaired cytotoxic T-lymphocyte activity leads to prolonged duration of infection. These observations may lead to a better understanding of the excess morbidity and mortality in elderly persons that occur with influenza.

Aging↗
PubMed1990

Influenza: pathogenesis and host defense.

Why does influenza virus variously eventuate in mild upper respiratory tract infection, bacterial pneumonia, or rapidly fatal viral pneumonia? The depth of infection is important. So is competence of immunologic effectors--local antibody (secretory IgA) for preventing URI, systemic antibody for preventing pneumonia, and cellular immunity for recovery from either.

Adult↗
PubMed1990

Enhancement of anti-influenza cytotoxic T-lymphocyte activity in senescent mice by vaccination early in life.

The elderly suffer significantly from influenza and respond poorly to influenza vaccines. This may be due to the fact that cytotoxic T-lymphocyte (CTL) activity is responsible for recovery from viral infections and is decreased in the elderly. We hypothesized that vaccination early in life might increase activity in senescence. To test this, groups of BALB/c mice were infected with influenza virus and/or vaccinated with an inactivated vaccine. CTL activity was measured by 51Cr release from H1N1-infected P815 cells. We found that aged mice have low CTL activity when initially vaccinated at 22 months (4 +/- 4% vs. 23 +/- 6% for vaccinated young mice). However, CTL activity was significantly increased when animals were initially vaccinated when young and then re-vaccinated when old (28 +/- 10% vs. 13 +/- 17% for mice vaccinated twice in old age). We next measured CTL activity in response to infection. We found a very high level of activity (57 +/- 11%) in animals vaccinated at 1.5 months and then infected at 23 months. This was indistinguishable from young controls (56 +/- 7%). These data suggest that primary inoculation at an early age induces a relatively larger number of precursor CTLs than does inoculation in senescence.

Aging↗
PubMed1989

Virus infection as a stressor: influenza virus elevates plasma concentrations of corticosterone, and brain concentrations of MHPG and tryptophan.

Balb/c mice were infected with influenza virus PR8 (H1N1) by the intranasal route. At various subsequent times, brain samples were examined for their content of catecholamine and indoleamine metabolites, and plasma corticosterone was measured. Virus infection was associated with a progressive loss of body and thymus weights, and an increase in plasma corticosterone. Spleen weight initially increased then decreased. There were also increases in the cerebral content of free tryptophan throughout the brain, and of MHPG, a major catabolite of norepinephrine, especially prominent in the hypothalamus. Thus influenza virus can be regarded as a stressor because, like behavioral stressors, it activates the hypothalamic-pituitary-adrenal axis, and increases cerebral concentrations of tryptophan and norepinephrine catabolites. These changes resemble those observed following administration of sheep red blood cells and Newcastle disease virus, noninfectious activators of the immune system, suggesting that noradrenergic and HPA activation are common concomitants of antigenic stimulation. The mediator of these effects may be interleukin-1 released by activated macrophages. It should be noted that animals infected with viruses can be expected to exhibit stress-like endocrine and neurochemical changes.

Animals↗
PubMed1989

Intranasal immunization with proteoliposomes protects against influenza.

Worldwide, influenza virus remains a serious disease which has successfully eluded numerous attempts to design a consistently effective vaccine. In part, these attempts have been thwarted because of a lack of basic understanding of the mechanisms which mediate protection and recovery from influenza infection. A better understanding of the roles of secretory antibody, serum antibody and cell mediated immunity vis-à-vis protection and recovery from influenza infection has allowed us more rationally to approach the design and administration of a vaccine for influenza. We have constructed a vaccine composed of glycoproteins from the envelopes of either influenza of Sendai virus embedded in a lipid bilayer (immunosomes) mimicking the presentation of the virus to the cells during natural infection. Intranasal immunization with these immunosomes induces an adequate systemic Ir compared with intramuscular immunization and a superior local IgA response. These animals were specifically protected from virus challenge.

Administration, Intranasal↗
PubMed1988

Consequences for medical education of problem-solving in science and medicine.

The problem-solving process used by scientists and by clinicians is compared and contrasted. The most creative step for both groups is the ability to make an association between some external stimulus or situation and concepts stored in memory. Medical education must put more emphasis on teaching that improves students' abilities to make these associations. Two teaching methods that can promote development of the necessary association skills in clinical contexts--"wait time" and "concept mapping"--are briefly reviewed. Concept mapping consists of connecting words that represent concepts with lines that represent relationships and then labeling the lines. Wait time is waiting three to five seconds between asking a group of students a question and calling on a student to answer or waiting three to five seconds before responding to the student's answer.

Association↗
PubMed1988

Passive serum antibody causes temporary recovery from influenza virus infection of the nose, trachea and lung of nude mice.

BALB/c normal and nude mice were infected with a non-lethal mouse-passaged A/PC/1/73 (H3N2) influenza virus in order to assess the role of T cells on the course of disease of the nose, trachea and lung. The tracheal epithelium of both mouse strains was desquamated by 3 days after infection. Although normal regeneration began, nude mice never completed that regeneration whereas normal mice had fully regenerated tracheas by Day 14. This failure to complete the recovery was also evident from the continued virus shedding by the nude mouse. In order to assess the role of serum antibody on recovery from infection, ferret, goat or mouse antibody to H3N2 influenza virus was passively administered to nude mice after infection. It resulted in a transient decrease in virus shedding from the nose, trachea and lung, and complete but temporary regeneration of the tracheal epithelium. However, later in the course of the infection, when serum antibody levels were no longer detectable, the tracheal epithelium of these animals redesquamated and large amounts of virus were again shed from nose, trachea and lungs. We conclude that: (i) desquamation of the ciliated epithelium of the trachea is not T-cell dependent; and (ii) serum antibody can contribute to temporary recovery from infection, but by itself is insufficient for permanent recovery of the nose, trachea or lung.

Animals↗
PubMed1988

Maternal-infant transfer of influenza-specific immunity not detectable by haemagglutination inhibition.

Evidence was sought for the transfer from mother to infant mouse of influenza-specific immunity other than that associated with haemagglutination inhibition (HI) specific antibody. Data were analysed for infant mice born to three groups of mothers: influenza immunized mothers with high levels of HI antibody. influenza immunized mothers in whom influenza-specific HI antibody was suppressed to undetectable levels by passive administration of antibody prior to influenza immunization, and non-immunized control mothers. At 4 weeks of age, infants were given either a lethal or a non-lethal influenza challenge. After a lethal influenza challenge, infants of immunized mothers with HI antibody showed no mortality. Infants of immunized mothers in whom HI antibody was suppressed showed a mortality of 8 to 33%, which was significantly lower than the 71% mortality found in infants of non-immunized control mothers (P less than 0.001). The lower mortality in infants of immunized mothers without HI antibody appeared to be associated with breast feeding, but could not be attributed to the transfer from mother to infant of a local immune response, an influenza specific cytotoxic response, or a secondary antibody response after non-lethal influenza infection. When sera were additionally tested for anti-influenza IgG by ELISA, this lower mortality was found to correlate with anti-influenza serum IgG measurable by ELISA but not detectable by HI. Protective immunity in infants undetectable by HI could be attributable to very low levels of antibody detected by more sensitive ELISA.

Animals↗
PubMed1987

Effect of passive maternal antibody on influenza illness in children: a prospective study of influenza A in mother-infant pairs.

To determine the effect of passive antibody on the incidence of influenza in infants, infants born to mothers with serum antibody to influenza A (immune) and those born to mothers without evidence for this serum antibody (non-immune) were followed during the influenza H1N1 epidemic of 1979. Immune mothers had higher H1-specific antibody titers before the epidemic (P less than 0.001), were less frequently culture positive, showed fewer titer rises (P less than 0.001) and were less symptomatic than were nonimmune mothers. Infants of immune mothers had higher H1-specific passive antibody titers that correlated with their mother's antibody titers. Although infants of both groups showed no difference in incidence of influenza infection, infants of immune mothers had influenza symptoms that were delayed in onset (P = 0.02) and were of shorter mean duration compared with infants of nonimmune mothers. These findings suggest that passive maternal antibody delays the onset and decreases the severity of influenza disease in young infants.

Antibodies, Viral↗
PubMed1985

Protection and recovery in influenza virus-infected mice immunosuppressed with anti-IgM.

BALB/c mice, immunosuppressed from birth with goat anti-mouse IgM, were able to recover from influenza virus infection in the absence of detectable serum and nasal antibody. Recovery was delayed a few days when compared with control animals. Antibody-deficient mice, that had recovered from an initial influenza virus infection, i.e., convalescent mice, were subsequently rechallenged with homologous influenza virus in order to study the importance of nasal and serum antibody in prevention of infection. Convalescent mice were susceptible to reinfection when nasal and serum antibody were not detectable. The mice were resistant to reinfection when serum and/or nasal antibody was detectable by radioimmunoassay. Normal mice that were passively immunized with high titer mouse anti-influenza virus serum were susceptible to challenge with homologous influenza virus. The serum antibody levels in these mice were higher than most of those found in the immune convalescent mice suppressed with anti-IgM, thereby suggesting that the serum antibody, found in convalescent suppressed mice, is not protective. We conclude that 1) mice can recover from influenza virus infection in the absence of detectable levels of nasal and serum antibody, thus indirectly confirming the role of cell-mediated immunity in recovery; 2) serum IgM, IgG2A, IgG2B, IgG3, and probably IgG1 antibody levels are not responsible for protection against influenza virus infection of the upper respiratory tract; and 3) nasal IgA antibody correlates best with protection against reinfection of the upper respiratory tract, but some other locally protective agent cannot be excluded.

Animals↗
PubMed1984

A case report of the successful treatment of recurrent aphthous stomatitis with some preparations of orally administered transfer factor.

A patient with severe disabling recurrent aphthous stomatitis (RAS) was treated with four different preparations of oral human transfer factor (TF), as well as placebo, following a double-blind protocol. Two of the TF preparations had a significant effect upon the course of the patient's illness by prolonging the interval between attacks and decreasing the severity of attacks. No side effects attributable to any of the preparations were noted by the patient. Thus, some but not all preparations of human transfer factor given orally are an effective therapy for RAS.

Administration, Oral↗
PubMed1983

Influenza infection in the infant mouse.

A nonlethal influenza infection [A/PC/1/73 (H3N2)] was given to infant mice to determine (1) the pathology of tracheal epithelium and lung, (2) the time course of viral shedding from the nose and lung, and (3) the subsequent development of protective immunity during adulthood. Both desquamation of the tracheal epithelium and lung pathology similar to that described in adults after influenza infection were observed in the infant. Animals infected at 3 days of age show virus shedding in 12 of 13 infant mice that persists for at least 2 days longer than in the adult. This longer duration of influenza infection did not result from either malnutrition or from intralitter transmission of virus. Recovery from virus shedding in both the upper and lower airway occurred in the absence of detectable serum antibody in six of seven mice. Infants that recover from infection, when rechallenged during adulthood, manifest complete protection in 11 of 13 mice after nonlethal challenge and no mortality after lethal challenge.

Animals↗