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PubMed1998

Antigen-releasing polymer rings and microspheres stimulate mucosal immunity in the vagina.

Several recent studies suggest that direct application of antigen to the vaginal surface may enhance local IgA secretion, but the most effective methods for stimulating immunity at the vaginal surface have not been identified. We used antigen-loaded, biocompatible, vaginal rings to provide controlled and sustained antigen delivery directly to the vaginal mucosal surface. Mice were primed with ferritin, either subcutaneously or orally by ferritin-loaded polymer microspheres, and vaginally boosted by insertion of a ferritin-loaded polymer ring. We found that the vaginal rings were a convenient method for providing controlled antigen delivery to the vagina. Subcutaneously primed mice receiving ferritin-loaded vaginal rings had ferritin-specific IgA in their mucus secretions, while mice receiving blank rings did not. Oral priming with ferritin-loaded poly(lactic acid) microspheres also produced significant levels of ferritin-specific IgA in the vaginal secretions, but required the presence of cholera toxin. Controlled ferritin delivery to mucosal surfaces, either by oral, biodegradable microspheres or vaginal rings, provides a convenient and reliable method for enhancing vaginal IgA production in mice.

Animals↗
PubMed2003

Enhancement of mucosal immunization with virus-like particles of simian immunodeficiency virus.

Cholera toxin (CT) is the most potent known mucosal adjuvant, but its toxicity precludes its use in humans. Here, in an attempt to develop safe and effective mucosal adjuvants, we compared immune responses to simian immunodeficiency virus (SIV) virus-like particles (VLPs) after intranasal coimmunization with RANTES, CpG oligodeoxynucleotides (ODN), or CT. Antibody analysis demonstrated that RANTES and CpG ODN had capacities for mucosal adjuvanticity, i.e., for enhancing serum and vaginal antibodies specific to SIV Env, similar to those for CT. RANTES and CpG ODN skewed serum antibodies predominantly to the immunoglobulin G2a isotype. Most importantly, RANTES and CpG ODN were more effective than CT in increasing neutralizing titers of both serum and vaginal antibodies. After intranasal coadministration with VLPs, RANTES or CpG ODN also induced increased levels of gamma interferon (IFN-gamma)-producing lymphocyte and cytotoxic T-lymphocyte activities in both spleen and lymph nodes but did not increase the levels of interleukin-4-producing lymphocytes. The results suggest that RANTES and CpG ODN enhance immune responses in a T-helper-cell-type-1 (Th1)-oriented manner and that they can be used as effective mucosal adjuvants for enhancing both humoral and cellular immune responses in the context of VLPs, which are particulate antigens.

Adjuvants, Immunologic↗
PubMed2000

The role of M cells in mucosal immunity.

Mucosa-associated lymphoid tissue in the respiratory and digestive tracts are covered by a specialized epithelium, the follicle-associated epithelium, which includes M cells, which are specialized for the uptake and transcytosis of macromolecules and microorganisms. Following transcytosis, antigens are released to cells of the immune system in lymphoid aggregates beneath the epithelium where antigen processing and presentation and stimulation of specific B and T lymphocytes are achieved. Circulation of the lymphoid cells enables their homing to their original, and other, mucosal sites where they exert the effector function. Such a response may be dominated by secretory immunoglobulin A release and may include cytotoxic T lymphocyte action. Binding of particles to the apical M cell membrane may be nonspecific or due to specific interaction between molecules such as integrins and lectins. Exploiting the specific binding to M cells is an aim for mucosal vaccination, for example to increase the efficiency of uptake of an oral vaccine by its conjugation to an M-cell-specific molecule. Alternatively, an M-cell-specific live vector, such as attenuated Salmonella bacteria, may be used to deliver epitopes of other organisms. Mucosal vaccination efficiency may also be enhanced by a temporary increase in the number of M cells. Therefore, investigation of the properties and ontogeny of M cells must be pursued to allow the development of better mucosal vaccines for the future.

Animals↗
PubMed2000

Mucosal immunity and gastrointestinal antigen processing.

The intestine is the largest lymphoid organ in the body by virtue of lymphocyte numbers and quantity of immunoglobulin produced. This is largely related to the enormous antigen load to which these cells are exposed on a daily basis. However, despite this, the mucosa-associated lymphoid tissue appears to be regulated by unique mechanisms, and this is reflected in specific phenomena (oral tolerance, controlled or physiologic inflammation) as well as unusual lymphoid populations (intraepithelial lymphocytes) that respond to alternative pathways of activation. This, coupled with the existence of novel antigen-presenting cells (intestinal epithelial cells) sets the scene for distinct immune responses. It is these distinct regulatory factors that support immunosuppression or tolerance rather than active immunity at a site juxtaposed to the external environment. This review defines these novel interactions and suggests how alteration in normal function may result in allergic or inflammatory responses. A clearer understanding of mucosal immunoregulation may lead to new therapeutic approaches for these diseases.

Antigen Presentation↗
PubMed2004

Mucosal immunity: overcoming the barrier for induction of proximal responses.

Vaccination represents one of the most efficacious and cost-effective medical interventions. It is the only medical intervention proven to eliminate disease at a global level. Many of the pathogens against which we most require adequate vaccines infect via the highly exposed mucosal surfaces. For this reason the mucosa is often considered the first, and sometimes only, line of defense. Therefore, responses that protect the local mucosa are vital. In this review, we first explore the immunological mechanisms that protect the mucosa. We then review the literature of mucosal vaccines within the principles of antigenic composition, dose, and danger, highlighting the need and niche for the next generation of mucosal vaccines.

Adjuvants, Immunologic↗
PubMed1997

[Mucosal immune responses against influenza virus].

The respiratory tract-mucosa is the site of either contact with influenza virus or defense against the virus. Such a defense is mediated by immune competent cells. The precursors of IgA-producing B cells and immune T cells are first induced in the mucosal inductive sites such as nasal-associated lymphoid tissues (NALT) or bronchus-associated lymphoid tissues (BALT). They are disseminated to mucosal effector sites for the development of immune responses, where IgA-producing cells in the lamina propria produce polymeric IgA, which are secreted through the epithelial cell into the external. The secretory IgA and serum IgG are mainly involved in protection against influenza in the upper respiratory tract and pneumonia in the lower respiratory tract, respectively. CD8+ cytotoxic T cells and Th1 cells are involved in recovery from influenza.

Animals↗
PubMed2001

Impairment of mucosal immunity by parenteral nutrition: depressed nasotracheal influenza-specific secretory IgA levels and transport in parenterally fed mice.

OBJECTIVE: To examine the effects on mucosal selective transport of polymeric IgA (pIgA) and the ability of exogenous pIgA to provide protection despite altered mucosal transport. SUMMARY BACKGROUND DATA: Parenteral nutrition significantly impairs established antipseudomonal immunity and IgA-mediated antiviral immunity in association with gut-associated lymphoid tissue mass atrophy. Lack of enteral feeding also induces mucosal effects. METHODS: After immunization, nasotracheal levels of influenza-specific IgA were measured in cannulated mice randomized to chow feeding or parenteral nutrition. Nonimmune animals were randomized to chow or total parenteral nutrition, and after 5 days of diet were given a mixture of two antiinfluenza monoclonal antibodies, pIgA and IgG. Four hours after injection, nasal washes were collected and influenza-specific antibody levels were determined by enzyme-linked immunosorbent assay to calculate the selective transport index of IgA relative to IgG. In the final experiment, immunized animals were randomized to chow or parenteral feeding, and after 5 days, parenterally fed animals received either normal mouse serum or antiviral pIgA before viral challenge. Viral shedding was measured at 42 hours after challenge. RESULTS: Parenteral nutrition significantly reduced virus-specific IgA in nasotracheal washes. Parenteral nutrition depressed the selective transport index, demonstrating impaired mucosal transport of pIgA. Parenterally fed animals given specific antiviral pIgA but not normal mouse serum eliminated virus from the airway and regained mucosal protection, demonstrating adequate residual transport for immunity if adequate pIgA is present. CONCLUSION: Although both decreased IgA production due to gut-associated lymphoid tissue atrophy and impaired mucosal transport occur when enteral feeding is not provided, residual transport can provide antiviral protection if exogenous antiviral pIgA is available. Production, rather than transport, may be the most important factor in maintaining established respiratory tract IgA-mediated immunity.

Analysis of Variance↗
PubMed2001

The mucosal immune system: primary target for HIV infection and AIDS.

Despite intensive research, several questions remain regarding the pathogenesis of infection with HIV-1. Recently, it has been shown that simian immunodeficiency virus (SIV) selectively targets and destroys specific subsets of CD4+ T cells that are abundant in mucosal tissues but rare in peripheral lymphoid tissues. This finding could be highly relevant in explaining a major paradox in the infection and elimination of CD4+ T cells during HIV infection: the progressive decline in the number of CD4+ T cells in the blood, despite the paucity of HIV-infected cells in this tissue. This article discusses the hypothesis that infection with HIV and SIV, and the resulting disease, is governed by the state of cellular activation and the expression of chemokine receptors by specific subsets of CD4+ T cells residing in mucosal lymphoid tissues, rather than those found in the peripheral blood or lymph nodes.

Acquired Immunodeficiency Syndrome↗
PubMed2006

Induction of protective and mucosal immunity against diphtheria by a immune stimulating complex (ISCOMS) based vaccine.

There is increasing concern over the efficacy of existing vaccines for diphtheria and there is interest in the development of a mucosally active formulation which might improve local protection. Lipophilic immune stimulating complexes (ISCOMS) containing Quil A are active by both parenteral and mucosal routes and here we have established methods for incorporating palmitified diphtheria toxoid (DT) into ISCOMS. The resulting formulation was immunogenic by the subcutaneous, oral and intranasal routes, with very low doses of DT inducing systemic humoral immune responses, as well as cell mediated immunity including both gammaIFN and IL5 production. Intranasal immunisation with DT in ISCOMS also stimulated significant local antibody production in tracheal washes, as well as cellular immunity in draining lymphoid tissues and serum neutralising antibodies. Finally, subcutaneous immunisation of guinea pigs with DT in ISCOMS primed protective immunity against challenge with diphtheria holotoxin more efficiently than the equivalent doses of DT in the conventional alum vaccine. ISCOMS based vaccines may provide a novel strategy for mucosal and systemic immunisation against diphtheria.

Adjuvants, Immunologic↗
PubMed2001

Recombinant bovine/human parainfluenza virus type 3 (B/HPIV3) expressing the respiratory syncytial virus (RSV) G and F proteins can be used to achieve simultaneous mucosal immunization against RSV and HPIV3.

Recombinant bovine/human parainfluenza virus type 3 (rB/HPIV3), a recombinant bovine PIV3 (rBPIV3) in which the F and HN genes were replaced with their HPIV3 counterparts, was used to express the major protective antigens of respiratory syncytial virus (RSV) in order to create a bivalent mucosal vaccine against RSV and HPIV3. The attenuation of rB/HPIV3 is provided by the host range restriction of the BPIV3 backbone in primates. RSV G and F open reading frames (ORFs) were placed under the control of PIV3 transcription signals and inserted individually into the rB/HPIV3 genome in the promoter-proximal position preceding the nucleocapsid protein gene. The recombinant PIV3 expressing the RSV G ORF (rB/HPIV3-G1) was not restricted in its replication in vitro, whereas the virus expressing the RSV F ORF (rB/HPIV3-F1) was eightfold restricted compared to its rB/HPIV3 parent. Both viruses replicated efficiently in the respiratory tract of hamsters, and each induced RSV serum antibody titers similar to those induced by RSV infection and anti-HPIV3 titers similar to those induced by HPIV3 infection. Immunization of hamsters with rB/HPIV3-G1, rB/HPIV3-F1, or a combination of both viruses resulted in a high level of resistance to challenge with RSV or HPIV3 28 days later. These results describe a vaccine strategy that obviates the technical challenges associated with a live attenuated RSV vaccine, providing, against the two leading viral agents of pediatric respiratory tract disease, a bivalent vaccine whose attenuation phenotype is based on the extensive host range sequence differences of BPIV3.

Animals↗
PubMed2001

T-cell-mediated mucosal immunity in the absence of antibody: lessons from Helicobacter pylori infection.

Approximately 50% of humanity is infected with Helicobacter pylori. This lifelong infection elicits a marked host response, including a robust gastric IgA response. However, natural infection fails to yield protective immunity. Rather than providing protection, the chronic inflammatory response associated with natural infection can contribute to tissue damage and the pathogenesis of gastroduodenal disease, including atrophic gastritis, peptic ulcer, and gastric cancer. These immune responses are attributed to a subset of helper T cells, so-called Th1 cells, that enhance cell-mediated immunity and induce damage to the gastric epithelium. Thus, it is desirable to have effective vaccines that could prevent and cure infection and that may modify the host response in a manner that prevents immune-mediated disease. Using animal models as a tool to understand the immunobiology of Helicobacter infections, several investigators have shown that effective vaccines can be developed. Thus, prophylactic and even therapeutic vaccines have been described in various animal models. The basis for the effectiveness of these vaccines appears related to their ability to alter the gastric immune response, from a homogeneous Th1 response to a mixed Th1 and Th2 response. Interestingly, immunity can occur in the absence of B cells, suggesting that novel IgA-independent mechanisms exist that confer protection against a luminal infection. Thus, H. pylori infection provides a model with which new mechanisms of immunological protection can be identified and applied to other mucosal infections.

Animals↗
PubMed2004

Production of secretory immunoglobulin A against Shiga toxin-binding subunits in mice by mucosal immunization.

The toxicity of Shiga toxins (Stx) depends on the binding of their B subunits to carbohydrate ligands on host cells. The production of antibodies against B subunits, especially immunoglobulin A (IgA) secreted on the mucosal surface, should contribute to host defense. One of the major problems in attempts to produce IgA against Stx was the poor immunogenicity of B subunits. We were able to produce serum IgA as well as IgG against Stx1B in mice of the H-2d haplotype by means of intranasal immunization with recombinant B subunits of Stx (Stx1B) together with cholera toxin as a mucosal adjuvant. Secretory IgA (S-IgA) was detected in nasal washes but not in feces. We prepared chemically cross-linked Stx1B for use as an immunogen, and the formation of stable oligomers was revealed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and mass spectrometry. When the cross-linked Stx1B was used together with cholera toxin for the intranasal immunization of BALB/c mice, strong enhancement of the immune response was observed. The S-IgA titers in nasal washes were 16- to more than 64-fold higher than those in mice immunized with native Stx1B plus cholera toxin. Furthermore, fecal IgA was detectable when the cross-linked Stx1B was used. The use of cholera toxin was necessary for the induction of high titers of S-IgA in the nasal washes. However, the effect of cross-linking was dependent on the major histocompatibility complex haplotype; that is, no enhancement of IgA production was observed in C57BL/6 mice. The present results provide a practical means of producing IgA against Stx1B in BALB/c mice.

Animals↗
PubMed1999

Mucosal immune system of the human genital tract.

In contrast to the pronounced dominance of secretory IgA over other immunoglobulin isotypes in human saliva, tears, milk, and gastrointestinal fluids, secretions of both female and male genital tracts contain more IgG than secretory IgA. Both IgG and IgA are derived, to a variable degree, from the systemic immunoglobulin pool as well as from local synthesis. The origin of IgG- and IgA-plasma cell precursors destined for the genital tract is unknown, but indirect evidence suggests that mucosal inductive sites localized in the rectum, small intestine, and especially in the nasal cavity contribute such precursors to the female genital tract. Several studies indicated that intranasal immunization of various species, including humans, was efficient at inducing antigen-specific antibody responses in the female genital tract; however, whether this route is also effective in males has not been explored.

Female↗
PubMed1998

Induction of mucosal immunity against herpes simplex virus type 1 in the mouse protects against ocular infection and establishment of latency.

Immune responses were assessed after intranasal immunization of mice with a mixture of herpes simplex virus type 1 (HSV-1) glycoproteins with cholera toxin and its B subunit as adjuvant. Antigen-specific serum antibodies, which were largely IgG with IgG1 the major subclass, neutralized virus in vitro with a titer equivalent to that elicited by active infection. Significant levels of antigen-specific IgA were found in mucosal fluids of the eye as well as the vagina. Lymphocytes from draining lymph nodes showed secondary proliferative responses when cultured with HSV-1 in vitro, in immunized mice only, with the production of interleukin-2, interferon-gamma, interleukin-4, and interleukin-5. After ocular challenge, immunized mice were protected against the development of severe eye disease, zosteriform spread, or encephalitis, whereas the incidence of clinical symptoms in mock-immunized mice was 83%, 74%, and 52%, respectively. Finally, the incidence of latency was reduced from 88% to 13% after intranasal immunization.

Adjuvants, Immunologic↗
PubMed1996

Mucosal immune responses to intestinal bacterial pathogens.

Current advances in the study of gut mucosal immunology and molecular biology have enhanced our ability to understand the pathogenesis of enteric bacterial infections as well as the role of the immune system in mediating both tissue injury and protection. In this article, we review the immunopathogenesis and the protective immune response to three enteric pathogens, Vibrio cholerae, Shigella, and Salmonella. Each of these pathogens has a distinctive mechanism by which it causes disease, ie, epithelial attachment, epithelial invasion, and epithelial invasion with systemic dissemination. Pathogenicity and immune response can be conceptualized in terms of the interaction of these enteric pathogens with the gut epithelial compartment, immune inductive sites (Peyer's patch of the small intestine and lymphoid follicles of the colon), and a common immune effector compartment in the laimina propria where protective antibody is secreted. V cholerae, the representative noninvasive pathogen, has fimbrial adhesins that mediate attachment and colonization of the luminal surface of epithelial cells where organisms secrete cholera toxin (CT), a potent enterotoxin that induces a voluminous diarrhea via adenylate cyclase-dependent chloride secretion. Protective immunity is based on secretory (s) immunoglobulin A directed against whole-cell components that prevent attachment to gut epithelial cells and is enhanced by CT, an immunogen with potent adjuvant activity. Shigella, an enteric pathogen that locally invades gut epithelium, subverts the usual mechanism of immune sampling by initially invading via M cells overlying inductive sites. Subsequent macrophage invasion induces apoptosis and the release of interleukin-1, a proinflammatory cytokine. This seems to be a critical initiating event in immune-mediated tissue injury. Protective immunity is serotype specific. Infection caused by Salmonella is characterized by mucosal invasion and systemic spread mediated by the organisms ability to survive within macrophages. Both antibody and cell-mediated immunity are important for protection against Salmonella.

Antibodies, Bacterial↗
PubMed2004

Enteral nutrition and mucosal immunity: implications for feeding strategies in surgery and trauma.

Systemic inflammatory responses to severe trauma and surgical illnesses may be partly responsible for numerous complications, including sepsis, multiple organ failure and unregulated hypermetabolism leading to protein-calorie malnutrition. The integrity of the gastrointestinal tract appears to be an important factor in the pathogenesis of the systemic inflammatory response and sepsis. Resuscitation and nutrition support strategies for preserving gut mucosal integrity have therefore been strongly promoted. This review summarizes the scientific rationale for emphasizing enteral nutritional support of surgical patients, discusses some important limitations of enteral feeding and argues for a flexible approach to nutrition support for these complex patients.

Critical Illness↗
PubMed1998

Systemic and mucosal immune responses after intranasal administration of recombinant Mycobacterium bovis bacillus Calmette-Guérin expressing glutathione S-transferase from Schistosoma haematobium.

A major goal of current vaccine development is the induction of strong immune responses against protective antigens delivered by mucosal routes. One of the most promising approaches in that respect relies on the use of live recombinant vaccine carriers. In this study, Mycobacterium bovis BCG was engineered to produce an intracellular glutathione S-transferase from Schistosoma haematobium (Sh28GST). The gene encoding Sh28GST was placed under the control of the mycobacterial hsp60 promoter on a replicative shuttle plasmid containing a mercury resistance operon as the only selectable marker. The recombinant Sh28GST produced in BCG bound glutathione and expressed enzymatic activity, indicating that its active site was properly folded. Both intraperitoneal and intranasal immunizations of BALB/c mice with the recombinant BCG resulted in strong anti-Sh28GST antibody responses, which were enhanced by a boost. Mice immunized intranasally produced a mixed response with the production of Sh28GST-specific immunoglobulin G1 (IgG1), IgG2a, IgG2b, and IgA in the serum. In addition, high levels of anti-Sh28GST IgA were also found in the bronchoalveolar lavage fluids, demonstrating that intranasal delivery of the recombinant BCG was able to induce long-lasting secretory and systemic immune responses to antigens expressed intracellularly. Surprisingly, intranasal immunization with the BCG producing the Sh28GST induced a much stronger specific humoral response than intranasal immunization with BCG producing the glutathione S-transferase from Schistosoma mansoni, although the two antigens have over 90% identity. This difference was not observed after intraperitoneal administration.

Administration, Intranasal↗
PubMed2005

Human immunodeficiency virus type 1 stimulates the expression and production of secretory leukocyte protease inhibitor (SLPI) in oral epithelial cells: a role for SLPI in innate mucosal immunity.

The innate immune response is a key barrier against pathogenic microorganisms such as human immunodeficiency virus type 1 (HIV-1). Because HIV-1 is rarely transmitted orally, we hypothesized that oral epithelial cells participate in the innate immune defense against this virus. We further hypothesized that secretory leukocyte protease inhibitor (SLPI), a 12-kDa mucosal antiviral protein, is a component of the host immune response to this virus. Here we demonstrated constitutive expression and production of SLPI in immortalized human oral keratinocytes. Brief exposure of cells to HIV-1 BaL and HXB2 significantly increased SLPI mRNA and protein production compared to that in mock-exposed cells (P < 0.01), as evaluated by real-time quantitative reverse transcription-PCR and enzyme-linked immunosorbent assay. HIV-1-mediated stimulation of SLPI occurred at the transcriptional level, was dose and time dependent, was elicited by heat-inactivated and infectious viruses, and did not depend on cellular infection. Experiments with purified retroviral proteins showed that the stimulatory effect was induced specifically by external envelope glycoproteins from HIV-1 and simian immunodeficiency virus. SLPI responsiveness to HIV-1 was also observed in an unrelated oral epithelial cell line and in normal (nonimmortalized) human oral epithelial cells isolated from healthy uninfected gingival tissues. In this first report of SLPI regulation by HIV-1, we show that the expression and production of the antimicrobial and anti-inflammatory protein can be stimulated in oral epithelial cells by the virus through interactions with gp120 in the absence of direct infection. These findings indicate that SLPI is a component of the oral mucosal response to HIV-1.

Cells, Cultured↗