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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
PubMed1995

Induction of a secretory IgA response in the murine female urogenital tract by immunization of the lungs with liposome-supplemented viral subunit antigen.

This study demonstrates that liposomes administered to the lower respiratory tract of mice have the capacity to stimulate secretory IgA (s-IgA) antibody production in the female urogenital system. Total respiratory tract immunization of mice with influenza virus subunit antigen simply mixed with negatively charged liposomes induced antigen-specific s-IgA in vaginal secretions, in addition to systemic IgG and s-IgA in the respiratory tract. Immunization of the upper respiratory tract alone or oral immunization were ineffective. These observations demonstrate that, upon stimulation with liposomes, the lymphoid tissue associated with the lung can act as an inductive site for migration of IgA-committed B cells to distant mucosal tissues, including the female urogenital tract. It is concluded that liposomes administered to the lower respiratory tract provide a promising adjuvant system for stimulation of both systemic and mucosal antibody responses against coadministered antigen, including production of s-IgA at distant mucosal sites.

Adjuvants, Immunologic↗
PubMed1994

Enteric immunization of mice against influenza with recombinant vaccinia.

Intrajejunal administration to mice of a recombinant vaccinia virus containing the influenza virus hemagglutinin gene induced IgA antibody in nasal, gut, and vaginal secretions. It also induced IgG antibody in serum and cell-mediated immunity. The immunization provided significant protection against an influenza virus challenge. This work suggests that enteric-coated recombinant vaccinia could be an orally administered, inexpensive, multivalent, temperature-stable, safe, and effective vaccine for children that could be particularly useful in developing nations, where multiple injections are not easily administered. Oral administration of vaccines should also reduce children's fear of shots at the doctor's office.

Animals↗
PubMed1994

Effects of influenza virus-specific cytotoxic T-lymphocyte responses induced by a synthetic nucleoprotein peptide on the survival of mice challenged with a lethal dose of virus.

Even though virus-induced cytotoxic T lymphocytes (CTLs) recognize antigens as peptides presented on infected cells, short synthetic peptides without any modifications are generally considered unsuitable for inducing antigen-specific CTLs in vivo. Our results demonstrate rapid induction of influenza virus-specific CTLs in Balb/c mice by an unmodified core protein peptide known to be a dominant H-2d-restricted CTL epitope. Additionally, the immunization procedure we employed in these studies produced significant influenza virus-specific CTLs in lymph nodes, spleen and lungs. When challenged with a lethal dose of influenza virus, a statistically significant delay in the day of death was observed in peptide-immunized mice. However, viral clearance was only slightly different from that in control mice. While these results are encouraging, they suggest a requirement for multiple CTL-inducing peptides, helper T cell-inducing peptides and/or virus-specific IgA responses in order to achieve protection from influenza infection.

Amino Acid Sequence↗
PubMed1994

Class I major histocompatibility complex-restricted cytotoxic T lymphocytes are not necessary for heterotypic immunity to influenza.

Mice transgenic for beta 2-microglobulin deletion (beta 2M-/-) were immunized intranasally with either a recombinant vaccinia virus that expressed both nucleoprotein and interleukin-2 or by infection with H3N2 influenza virus; 3-4 weeks later they were challenged with H1N1 influenza virus. The immunized beta 2M-/- mice had increased survival and enhanced clearance of virus relative to nonimmune controls. This protection correlated with the development of class II major histocompatibility complex-restricted pulmonary cytotoxic T lymphocyte activity and nasal IgA anti-nucleoprotein antibody. Heterotypic immunity can therefore be generated by a mechanism that does not involve class I major histocompatibility complex-restricted T cells.

Animals↗
PubMed1993

Use of incompatible plasmids to control expression of antigen by Salmonella typhimurium and analysis of immunogenicity in mice.

Salmonella spp. have been investigated as live vaccine vectors because they are heat stable and can elicit humoral, cellular, and secretory immune responses. However, the expression of some foreign antigens is toxic to bacterial vectors. We therefore studied an approach for the controlled expression of antigen in Salmonella typhimurium wherein the antigen is not expressed in vitro but is expressed in vivo. A model antigen, beta-galactosidase, was expressed from the trc promoter on one plasmid, while repression was achieved by Lacl expressed in trans from a second plasmid. The second repressor plasmid was incompatible with the expression plasmid encoding beta-galactosidase. Loss by segregation of the repressor plasmid in vitro correlated with increased expression of beta-galactosidase. Oral inoculation of mice with salmonellae containing both plasmids induced serum IgG but not nasal, salivary, or biliary IgA antibody to beta-galactosidase. Serum IgG as well as biliary IgA anti-S. typhimurium antibody, but not salivary or nasal IgA, were also detected. This salmonella vector system for the controlled expression of recombinant antigens may be of value for inducing systemic but not mucosal immunity to antigens that are toxic to bacterial vectors.

Animals↗
PubMed1993

Recombinant vaccinia immunization in the presence of passively administered antibody.

Mice were injected with immune serum to vaccinia and/or influenza virus and then immunized by scarification with a recombinant vaccinia virus expressing the influenza haemagglutinin H1. The serum IgG antibody response to the foreign gene product, influenza H1, was suppressed by the passively administered anti-influenza antibody in a dose-dependent manner. Anti-vaccinia antibody alone had no effect on the anti-haemagglutinin antibody response to the recombinant vaccinia and did not suppress an anti-vaccinia antibody response. Secondary cytotoxic T-lymphocyte killing of influenza virus-infected target cells was relatively low in all animals that were immunized with the recombinant vaccinia, and showed some dose-dependent suppression by the passively administered antibody. The dose dependence of the inhibition suggests that while immunization with recombinant vaccinia viruses may not be effective at birth, they may be useful at several months of age.

Animals↗
PubMed1993

Heterotypic immune mice lose protection against influenza virus infection with senescence.

Influenza causes significant morbidity and mortality in the elderly. To determine whether this could be due to loss of heterotypic immunity, young and aged BALB/c mice were made heterotypically immune by H3N2 influenza virus infection and then challenged, while anesthetized, with H1N1 virus. Viral clearance was delayed by 2 days in the aged mice. Naive and heterotypic immune mice were next challenged with H1N1 virus while awake. Under these conditions, initial infection was restricted to the nose in all animals. The virus spread to the lungs of the young and aged naive mice but not of heterotypic immune young mice. Heterotypic immunity of aged mice did not prevent spread of the virus to the lungs. The impaired recovery of aged mice correlated with lower antiinfluenza cytotoxic T lymphocyte (CTL) activity. Thus, a possible explanation for the increased severity of influenza in elderly humans is loss of CTL-mediated heterotypic immunity.

Aging↗
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↗