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PubMed1975

Techniques for eliciting mucosal immune response.

Development of techniques for eliciting an immune response on mucosal surfaces is a relatively new area of clinical research. With the recognition of the existence of secretory immunity, independent of the systemic system, there was renewed interest in re-examining the conventional approach for optimal immunization techniques. A large body of data indicate that the majority of the secretory immunoglobulins and antibody produced to antigenic stimulation of mucosal surfaces is locally produced. Thus, antibody to C. albicans in the cervical or vaginal mucus has been shown to be of local origin and it predominantly belongs to the secretory IgA immunoglobulin class. The mechanism of antigen processing by the secretory surface leading to antibody formation remains a mystery, but it might be determined by the selective localization of antigens in the reticuloendothelial cells of the lamina propria, bronchi or small intestine. Usually application of antigen topically to the mucosal surface elicits local antibody formation to a greater extent than does parenteral immunization. On the other hand, a more pronounced systemic immune response is seen when the antigen is administered systemically. However, a number of other factors determine the quality and quantity of the immune response, e.g., the physical state of the antigen, live vs killed vaccine, dose, adjuvant, previous exposure to similar or cross-reacting antigens, and site of application of the antigen. These factors are discussed in the review. Recent observations suggest that cell mediated immunity is a component of the secretory immune system, and like the humoral mechanism, also may be partially compartmentalized.

Animals↗
PubMed2001

Role and significance of the complement system in mucosal immunity: particular reference to the human breast milk complement.

The complement system plays an important role in a host's defence mechanisms, such as in immune bacteriolysis, neutralization of viruses, immune adherence, immunoconglutination and in enhancement of phagocytosis. The possible role of this important biological system in biological fluids on the mucosal surfaces, including breast milk, has however been largely neglected. Its contribution to the 'common' mucosal immunity is still enigmatic and largely speculative. Assessment of the complement system in human breast milk, which has so far largely been limited to different assays of the individual component proteins, is reviewed. A brief review of the classical and the alternative pathways of complement activation is presented. The potential physiological roles of various complement components and their activation fragments in human milk in particular, and other mucosal surfaces in general, are also presented. It was concluded that the complement system might play a complementary role to other immunological and non-immunological protective mechanisms on the mucosal surfaces.

Complement System Proteins↗
PubMed2001

Induction of mucosal immune responses by bacteria and bacterial components.

Bacteria have well documented abilities to induce protective as well as pathogenic mucosal immune responses, with the type of response dependent on the genetically programmed balance of pro- and anti-inflammatory cytokines and T-lymphocyte subsets. Inflammatory bowel disease, especially Crohn disease and periodontal disease, appear to be overly aggressive cellular immune responses to some, but not all, normal resident bacteria. Recent evidence suggests that the balance of protective (probiotic) and aggressive commensal luminal bacterial species is an additional determinant of mucosal homeostasis (tolerance) versus pathogenic immune responses (loss of tolerance) and that this balance can be therapeutically manipulated. Mucosal pathogens elicit a characteristic profile of cytokines from epithelial cells, including chemokines that recruit effector cells to the site of invasion to clear the invading organism. The molecular mechanisms of epithelial attachment and invasion of bacterial pathogens (eg, Salmonella, Shigella, pathogenic Escherichia coli, and Yersinia) and the mechanisms of injury induced by Clostridium difficile toxins and Helicobacter pylori are beginning to be understood, as are the innate and cognate host immune responses to these organisms, leading to novel means to effectively block bacterial injury and induce protective immune responses through immunization.

Journal Article↗
PubMed1998

Specific mucosal immunity and enhanced nasopharyngeal clearance of nontypeable Haemophilus influenzae after intranasal immunization with outer membrane protein P6 and cholera toxin.

Nontypeable Haemophilus influenzae (NTHi) is one of the leading pathogens in otitis media. Studies of vaccines against NTHi have focused on outer membrane proteins (OMPs). One outer membrane protein P6 is highly conserved among strains and is an attractive candidate for a subunit bacterial vaccine. In this study, mucosal immunity induced by intranasal immunization with P6 and cholera toxin (CT) was investigated in a mouse model. Intranasal immunization with P6 and CT evoked a good mucosal IgA as well as a systemic IgG response against P6. On the other hand, intranasal immunization with P6 alone induced a weak mucosal IgA response. Enzyme linked immunospot assay detected anti-P6 specific antibody producing cells in the nasopharyngeal mucosa of immunized mice. The protective response of intranasal immunization was demonstrated by enhancement of nasopharyngeal clearance of NTHi and inhibition of adherence of NTHi to cultured human epithelial cells. Based on these results, intranasal immunization with P6 and CT may be an effective approach to protect human from H. influenzae infections in the upper respiratory tract.

Administration, Intranasal↗
PubMed2001

Mucosal immunity and viral infections.

The mucosal surfaces are the first portals of entry for most infectious agents, among which respiratory and intestinal viruses are of greatest epidemiological importance. To combat these infections, the immune system uses unspecific and specific mechanisms. Unspecific responses include the production of virus-induced cytokines, such as type 1 interferons and natural killer (NK) cell activity, while specific immune responses mainly depend on cytotoxic T cells, which are important especially in the early course of a viral infection, and on antibodies. At the mucosal sites, antiviral secretory IgA antibodies play a major role in clearing viral infections and preventing or modifying disease after re-exposure. Passive transfer of virus-specific antibodies has been used in experimental and clinical settings to prevent or treat viral mucosal infections. In the future, the development of new mucosal vaccines promises to have the strongest impact on the epidemiology of viral infections.

Antiviral Agents↗
PubMed2002

Mucosal immune responses to meningococcal conjugate polysaccharide vaccines in infants.

BACKGROUND: Serogroup C meningococcal conjugate polysaccharide vaccines have been reported to induce significant serum IgG antibodies and immunologic memory in infants. Because meningococcus is a mucosal pathogen colonizing the nasopharynx, local mucosal immune responses may play an important role in host defense against infection and carriage. We have investigated the mucosal IgA and IgG antibody responses to two meningococcal C conjugate vaccines in the saliva of healthy infants. METHODS: Specific salivary IgA and IgG antibodies to two meningococcal C polysaccharide conjugate vaccines (Menjugate from Chiron Corp., n = 46; and Meningitec from Wyeth Lederle, n = 54) were investigated by immunoassay in infants after parenteral vaccinations at the ages of 2, 3 and 4 months. Unstimulated saliva samples were collected immediately before the first immunization and 1 month after the third immunizations. Forty healthy infants receiving the same routine vaccines but no meningococcal C vaccine were recruited as controls. RESULTS: There were significant increases in meningococcal C polysaccharide-specific IgG antibody concentrations postvaccination compared with prevaccination concentrations in both vaccinated groups (both P < 0.001), but no change in the control group. There were no significant increases in specific IgA postvaccination geometric mean concentrations in either the vaccine or the control groups. The number of IgA positives postvaccination increased slightly in the Wyeth vaccine group vs. controls (P < 0.05). CONCLUSIONS: Significant salivary IgG antibodies to meningococcal C polysaccharide were observed after parenteral immunization with two meningococcal C conjugate vaccines, whereas there was no significant increase in specific IgA antibody levels for these two vaccines.

Antibodies, Bacterial↗
PubMedDate not supplied

The middle ear mucosal immune system in otitis media with effusion.

The mucous membrane of the middle ear cavity in otitis media with effusion has a number of immunobiological mechanisms capable of defending the organ. A humoral immune mechanism, with all the attributes of a local mucosal immune system, appears to be present and capable of preventing viral and bacterial access to middle ear tissue. Putative cells of a cell-mediated immune response also appear to be present, and the distribution of T cells and B cells and T-helper and T-suppressor cells is described. The exact role of these cells in either cell-mediated immunity or delayed hypersensitivity remains to be defined in otitis media. Lymphocyte--macrophage interaction is briefly described and may represent an important aspect of immune modulation in the middle ear in otitis media with effusion. Finally, the effect of middle ear supernatants on natural killer cell activity is discussed. Serous effusions appear to augment natural killer cell activity of peripheral blood lymphocytes.

Antibody Formation↗
PubMedDate not supplied

Efficacy of intraduodenal, oral and parenteral boosting in inducing intestinal mucosal immunity to cholera toxin in rats.

Considerable effort has been directed toward developing effective mucosal vaccines, especially those targeted to the intestine, and appropriate delivery systems. Numerous studies have demonstrated that direct immunization of the intestinal mucosa is the most efficient route for generating an intestinal IgA response. The present study examined the effect of three different routes of secondary immunization (boosting), i.e. intraduodenal, oral and parenteral (subcutaneous) on the intensity of the intestinal mucosal immune response in rats subjected to primary intraduodenal immunization with cholera holotoxin. Specific antibody titers and the relative numbers of antibody-secreting cells in the peripheral blood and antibody-containing cells in the intestinal lamina propria concur that vaccination of the intestinal mucosa directly or in combination with an oral boost yields a more vigorous mucosal immune response in comparison to a parenteral boost.

Adjuvants, Immunologic↗
PubMed2006

Adjuvants modulating mucosal immune responses or directing systemic responses towards the mucosa.

In developing veterinary mucosal vaccines and vaccination strategies, mucosal adjuvants are one of the key players for inducing protective immune responses. Most of the mucosal adjuvants seem to exert their effect via binding to a receptor/or target cells and these properties were used to classify the mucosal adjuvants reviewed in the present paper: (1) ganglioside receptor-binding toxins (cholera toxin, LT enterotoxin, their B subunits and mutants); (2) surface immunoglobulin binding complex CTA1-DD; (3) TLR4 binding lipopolysaccharide; (4) TLR2-binding muramyl dipeptide; (5) Mannose receptor-binding mannan; (6) Dectin-1-binding ss 1,3/1,6 glucans; (7) TLR9-binding CpG-oligodeoxynucleotides; (8) Cytokines and chemokines; (9) Antigen-presenting cell targeting ISCOMATRIX and ISCOM. In addition, attention is given to two adjuvants able to prime the mucosal immune system following a systemic immunization, namely 1alpha, 25(OH)2D3 and cholera toxin.

Adjuvants, Immunologic↗
PubMed2002

Oral mucosal immunity and HIV infection: current status.

There is a paradox that profound HIV-induced immunodeficiency is present systemically, whereas the majority of infections associated with HIV disease are present or initiated at mucosal surfaces. There is therefore a need to understand both specific and non-specific mechanisms of mucosal protection against HIV and its copathogens. The majority of HIV infections occur as a result of the passage of virus across mucosal membranes. Resistance to HIV infection at mucosal surfaces may be related to HIV-specific CD8+ T cell responses in some individuals and may be the basis for protective vaccine design. However, T-cells, macrophages and dendritic cells in mucosa may be a portal of entry for HIV. Transcytosis of HIV can occur from the mucosal to the submucosal surface and vice versa, and may be inhibited by mucosal immunoglobulins and neutralizing IgA within epithelial cells. HIV-induced alterations to oral epithelial cells, together with impairment of mucosal CD4+ T-cells and consequent altered cytokine secretion, may contribute to secondary infections. It also appears that HIV infection is associated with decreased salivary IgA levels, although a dichotomy between IgA concentrations in saliva and serum has been reported. Mucosal antibody responses, however, seem to be maintained. Considerable attention has been given to the possibility of mucosal immunization against HIV and there is evidence that secretory IgA antibody is neutralizing to different HIV strains. In addition to specific immune factors, it is likely that innate nonspecific factors may be significant in protecting mucosal surfaces, including lactoferrin, secretory leukocyte protease inhibitor, mucins, proline rich proteins and cystatins. These may be useful candidate virucides in topical preparations. Thus humoral, cellular and innate immune mechanisms, as well as lymphocyte-epithelial interactions, may all be impaired at mucosal surfaces as a result of HIV infection and may contribute to the susceptibility of mucosa to infective processes.

Antibodies, Viral↗
PubMed1984

Cholera toxin B subunit as a carrier protein to stimulate a mucosal immune response.

Horseradish peroxidase (HRP) was covalently coupled to the binding subunit of cholera toxin (CTB) via a two-step glutaraldehyde procedure. The HRP-CTB conjugate was characterized by physiochemical as well as immunochemical methods. Mice were immunized intraduodenally with the HRP-CTB conjugate, with HRP alone, or with a mixture of uncoupled CTB and HRP. The functionally active dose of CTB was 50 micrograms and the HRP dose was in the 30- to 90-micrograms range. Both IgA and IgG antibody responses were measured in serum, intestinal washes, and bile by using a solid phase immunoradiometric assay. Mice immunized with the HRP-CTB conjugate showed a significantly higher level of IgA anti-HRP in intestinal washes and bile, as well as increased levels of serum IgG anti-HRP. Animals that received only HRP or the mixture of CTB and HRP had reduced levels of HRP-specific antibody of either class in both gut washes and bile. The IgA anti-HRP responses in the gut washes were 33- to 120-fold higher when the conjugate was used as the immunogen in comparison with immunization with the CTB + HRP or the HRP alone. Vaccines to stimulate mucosal immunity to any antigenic determinant might thus be prepared by covalent conjugation to effective mucosal immunogens such as CTB.

Animals↗
PubMed2001

Lung mucosal immunity: immunoglobulin-A revisited.

Mucosal defence mechanisms are critical in preventing colonization of the respiratory tract by pathogens and penetration of antigens through the epithelial barrier. Recent research has now illustrated the active contribution of the respiratory epithelium to the exclusion of microbes and particles, but also to the control of the inflammatory and immune responses in the airways and in the alveoli. Epithelial cells also mediate the active transport of polymeric immunoglobulin-A from the lamina propria to the airway lumen through the polymeric immunoglobulin receptor. The role of IgA in the defence of mucosal surfaces has now expanded from a limited role of scavenger of exogenous material to a broader protective function with potential applications in immunotherapy. In addition, the recent identification of receptors for IgA on the surface of blood leukocytes and alveolar macrophages provides an additional mechanism of interaction between the cellular and humoral immune systems at the level of the respiratory tract.

Animals↗
PubMed2000

Targeting the mucosa: genetically engineered vaccines and mucosal immune responses.

The discovery that inoculation of DNA leads to strong and long lasting immune responses generated enthusiasm to assess the efficacy of various genetically engineered vaccines against mucosally acquired infections. Various techniques have been used to generate the most suitable DNA vaccines, ranging from immunization with naked DNA to utilizing genetically engineered recombinant viruses and bacteria to deliver the DNA. Different DNA vaccine modalities and mucosal immune responses to them have been discussed. It has been shown that even though intramuscular and intradermal immunization with these vaccines generates strong systemic responses, mucosal responses are not induced. It has been proposed that the site of immunization determines mucosal immune responses and that primed lymphocytes preferentially accumulate at sites where they have been induced thus generating the strongest cellular and antibody responses at the site of vaccination. The impact of the site of induction on mucosal immune responses to vaccines is discussed. It is possible to enhance desired vaccine effects in the mucosa and to modify the undesirable side effects. Cytokines such as IL-2, IL-12, IL-15 and IL-18 have been used to enhance CTL activity while IL-5, IL-6 and the chemokine MIP-1 alpha have shown the capacity to increase IgA responses to vaccines.

Animals↗
PubMed1993

Mucosal immunization with a subunit respiratory syncytial virus vaccine in mice.

The protective efficacy of mucosal immunization with purified respiratory syncytial virus (RSV) fusion protein (F) using cholera toxin (CT) as an adjuvant was assessed in mice. Intranasal vaccination with F+CT induced F-specific serum IgG and nasal IgA and resulted in 75% protection from nasal virus replication compared with control mice. Intranasal CT+F with simultaneous parenteral F provided complete protection equivalent to intranasal live virus immunization.

Adjuvants, Immunologic↗
PubMed2006

Systemic and mucosal immunity induced by oral somatic transgene vaccination against glycoprotein B of pseudorabies virus using live attenuated Salmonella typhimurium.

Glycoprotein B mediates the absorption and penetration of the pseudorabies virus in the form of an immunodominant Ag, and represents a major target for the development of new vaccines. This study evaluated the efficiency of live attenuated Salmonella typhimurium SL7207 for the oral delivery of DNA vaccine encoding the pseudorabies virus glycoprotein B (pCI-PrVgB) in vivo, leading to the generation of both systemic and mucosal immunity against the pseudorabies virus Ag. An oral transgene vaccination of pCI-PrVgB using a Salmonella carrier produced a broad spectrum of immunity at both the systemic and mucosal sites, whereas the intramuscular administration of a naked DNA vaccine elicited no mucosal immunoglobulin (Ig)A response. Interestingly, the Salmonella-mediated oral transgene vaccination of the pseudorabies virus glycoprotein B biased the immune responses to the Th2-type, as determined by the IgG2a/IgG1 ratio and the cytokine production profile. However, oral vaccination mediated by Salmonella harbouring pCI-PrVgB showed inferior protection to systemic immunization against virulent pseudorabies virus infection. The expression of transgene delivered by Salmonella bacteria in antigen-presenting cells of both the systemic and mucosal-associated lymphoid tissues was further demonstrated. These results highlight the potential use of live attenuated S. typhimurium for an oral transgene pseudorabies virus glycoprotein B vaccination to induce broad immune responses.

Administration, Oral↗
PubMedDate not supplied

Mucosal immunization with Salmonella typhimurium expressing Lassa virus nucleocapsid protein cross-protects mice from lethal challenge with lymphocytic choriomeningitis virus.

OBJECTIVES: Lassa fever virus (LAS) is transmitted to man by rodent carriers and is fatal in a third of untreated cases. Our goal is to provide immune protection from Lassa fever by mucosal vaccination. STUDY DESIGN/METHODS: Mice were vaccinated intragastrically with control vectors or with vectors (vaccinia or Salmonella) expressing LAS nucleocapsid protein (NP). Mice were challenged intracranially with a lethal dose of the related arenavirus, lymphocytic choriomeningitis virus (LCMV), as a measure of the vaccine's ability to elicit cross-protection. RESULTS: Salmonella and vaccinia vectors expressing LAS NP each protected a third of the mice from lethal challenge with LCMV. All mice vaccinated with a vector expressing LCMV NP were protected as expected. CONCLUSIONS: The LAS recombinant Salmonella vector is comparable to the LAS recombinant vaccinia vector in its ability to cross-protect mice from lethal challenge. Nucleocapsid protein is an inadequate immunogen on its own, but provides sufficient cross-protection to make it a useful component of a broadly reactive arenavirus vaccine.

Animals↗
PubMed1993

Enhanced triggering of mucosal immune responses by reducing splenic phagocytic functions.

The role of the spleen in the rat mucosal immune response was investigated to three structural different pneumococcal polysaccharides, type 3, 4, and 14. Following immunization with pneumococcal polysaccharides, a larger amount of free antigen was found in several lymphoid tissues and an increased trapping of immune complexes was seen in follicles of splenectomized animals, as compared to control animals. Thus, clearance of the polysaccharides seems to be less effective after splenectomy. An increase in specific IgA antibody-containing cells (ACC) was found in mesenteric lymph nodes, villi and Peyer's patches in splenectomized rats. Apparently, splenectomy and subsequent decreased clearance of the antigen causes a prolonged stay of the antigen in the system and therefore specific ACC can be induced in different lymphoid tissues. After splenectomy the specific IgM and IgG antibody titers in serum decreased significantly for pneumococcal polysaccharides types 4 and 14, but not for type 3. Furthermore, the serum IgA antibody titers against the three types of polysaccharides under study were not affected. After elimination of macrophages in the spleen by treatment with dichloromethylene diphosphonate liposomes no ACC against type 14 were evoked in the marginal zone of the spleen, and again, an increase was observed in specific IgA ACC in mucosa-associated lymphoid tissues. The IgA antibody titers were also enhanced. In conclusion, IgA responses against pneumococcal polysaccharides can be elicited in absence of the spleen, i.e. at mucosal sites or in the draining lymph nodes. Furthermore, polysaccharide-specific IgA responses are enhanced after reduction of splenic phagocytic functions.

Animals↗
PubMed1998

Systemic and mucosal immune responses in young children and adults after parenteral influenza vaccination.

The effect of natural mucosal priming on systemic and mucosal immune responses was investigated in young children after parenteral influenza vaccination. Eighteen young children and 8 adults were vaccinated with trivalent influenza vaccine at various time intervals before tonsillectomy. The influenza-specific IgG, IgA, and IgM immune responses were examined in tonsillar lymphocytes and frequent samples of peripheral blood and oral fluid. Young children were divided into primed and unprimed groups on the basis of presence of prevaccination serum antibodies. In peripheral blood, adults and primed children had significantly higher IgG and IgA antibody responses than did unprimed children. Irrespective of priming, children elicited weaker IgA responses than adults in both tonsils and oral fluid. While natural priming was essential to elicit strong systemic response in young children after parenteral influenza vaccination, it did not influence the local responses, which were significantly lower in both primed and unprimed children than in adults.

Adult↗