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PubMed2001

The B-cell targeted CTA1-DD vaccine adjuvant is highly effective at enhancing antibody as well as CTL responses.

A novel immunomodulating gene-fusion protein, CTA1-DD, has been developed which combines the ADP-ribosylating ability of cholera toxin (CT) with a dimer of an Ig-binding fragment, D, of Staphylococcus aureus protein A. The CTA1-DD adjuvant is non-toxic and greatly augmented T-cell-dependent and T-cell-independent responses to soluble admixed antigens after systemic as well as mucosal immunizations. CTL and antibody responses of all classes were increased by 10- to 100-fold above those observed in control mice immunized without adjuvant. CTA1-DD does not appear to form immune complexes or bind to soluble Ig following injection, but rather it binds directly to B-cells of all isotypes, including naïve IgD+ cells. No binding was observed to macrophages or dendritic cells, and immunizations in Fc gamma R-deficient mice demonstrated unaltered enhancing effects. As shown by inactive mutants, the CTA1-DD adjuvant is dependent on ADP-ribosyltransferase activity and requires the binding to Ig- via the DD moiety. The enhancing effect is associated with enlarged germinal centers, and binding of CTA1-DD to the B-cells strongly upregulates co-stimulatory molecules and counteracts apoptosis by inducing intracellular Bcl-2.

Adjuvants, Immunologic↗
PubMed2000

Vaccinia virus recombinants encoding the truncated structural gene region of Venezuelan equine encephalitis virus (VEEV) give solid protection against peripheral challenge but only partial protection against airborne challenge with virulent VEEV.

Vaccinia virus (VV) recombinants that contain the genes encoding the Venezuelan equine encephalitis virus (VEEV) structural gene region (C-E3-E2-6 K-E1) solidly protect mice against peripheral challenge with virulent VEEV, but provide only partial protection against airborne challenge. To improve upon these results we focussed on the principal antigens involved in protection. VV recombinants encoding the structural genes E3-E2-6 K-E1, E3-E2-6 K or 6 K-E1 were prepared and evaluated for their ability to protect Balb/c mice after a single dorsal scarification with 10(8) PFU against peripheral or airborne challenge with virulent VEEV. The antibody response was also examined. Our experiments provide new evidence that truncates of the VEEV structural region (E3-E2-6 K-E1, E3-E2-6 K), cloned and expressed in VV, protect against challenge with virulent virus. They also confirm the important role of E2 in protection. However, we were unable to improve upon previously reported levels of protection against airborne challenge. A substantial level of circulating antibodies and the presence of local IgA (not always induced by mucosal immunization) (Greenway et al., 1992) appear essential for protection against the airborne virus. Current VV-VEEV recombinants seem unable to elicit this level of immune response and further improvements are therefore required to increase the immunogenicity of VV-VEEV vaccines.

Animals↗
PubMed2001

[A fusion protein of rotavirus VP6 and cholera toxin B subunit: expression in Escherichia coli and analysis of biological activities].

Rotavirus infection is a major cause of dehydrating diarrhea in infants worldwide. The non-toxic cholera toxin B subunit(CTB), known as an immunomodulatory carrier, might help to stimulate mucosal immune response when coupled to rotavirus antigens in oral immunization. Here we report for the first time the construction of a translational fusion of CTB gene 5' to the VP6 gene of a human rotavirus A(field strain T114), and expression of the CTB-VP6 fusion protein in E. coli BL21(DE3). The expressed fusion protein has a molecular weight of 56 kD, as expected, and accounts for about 15% of the total E. coli protein. Western blottings with the hyperimmune serum against rotavirus strain WA and the antibody against cholera toxin indicated that the fusion protein retains the antigenicity identical to the native CTB and VP6. The GM1-ELISA analysis proves that the renatured CTB-VP6 has strong affinity for GM1 ganglioside.

Antibodies↗
PubMed2006

Analysis of the Candida albicans - specific T-cell response and oropharyngeal Candida colonization in a cohort of HIV-1-infected patients.

To investigate Candida epidemiology and immunologic correlates of protection in HIV-1 infected patients, we analyzed oral Candida colonization in correlation to the Candida-specific T-cell response measured by g-IFN ELISPOT using different Candida (C.) albicans strains. In 16/46 patients (13 asymptomatic, 3 with oral thrush), but in 0/28 controls, Candida (13 C. albicans, 1 C. lusitaniae, 1 C. krusei, 1 C. parapsilosis) was isolated. Candida specific T-cells were detected more frequently in controls (20/28) than in HIV-1+ subjects (16/46, p= 0.03). We observed a significant association of higher CD4 cell numbers with both detection of Candida specific T-cells and lack of oral Candida colonization, but there was no significant correlation of oral Candida colonization to the detection of Candida specific T-cells, viral load or antiretroviral therapy. Thus, local mucosal immunity seems to be more important in the pathogenesis of Candida colonization than circulating Candida specific T-cells. The pathogenic C. albicans strain K24122 was less frequently recognized by patients (6/46) than the laboratory adapted strain SC5314 (14/46, p= 0.03), whereas a similar recognition of both strains was observed in healthy controls. This indicates an impaired Candida-specific T-cell repertoire in HIV+ patients that could increase the risk of immune evasion by C. albicans.

AIDS-Related Opportunistic Infections↗
PubMed1995

Assessment of attenuated Salmonella typhimurium strains designed as potential carriers of foreign antigens for mucosal localization and immuno-genicity in a rabbit model.

Neither wild type nor attenuated S. typhimurium strains induced diarrheal illness in rabbits. All strains localized to the Peyer's patch at higher concentrations than in lumenal contents or adjacent ileum. Wild type S. typhimurium C5 induced a typhoid-like illness in rabbits with severe weight loss, bacteremia, persistent splenic colonization, and serum IgG response. Both attenuated strains were disseminated to spleen (day 3) but produced minimal systemic illness. They induced biliary IgA responses greater than the wild type (day 7), but minimal serum IgG responses. Both mutants of S. typhimurium are suitable for further development as live enteric vaccines to carry foreign antigens since they localize to Peyer's patch after oral inoculation, induce biliary antibody, and produce minimal systemic disease. The attenuated strains tested are systemically disseminated. It remains to be determined whether dissemination (determined by a large virulence plasmid) is necessary for the desired mucosal immune response or acceptable for an oral vaccine strain.

Administration, Oral↗
PubMed1996

Targeting to intestinal M cells.

The specialised, antigen-transporting, epithelial M cells in the follicle-associated epithelium (FAE) overlying gut-associated lymphoid tissues constitute the primary target for oral delivery of vaccines. Our studies have shown that polystyrene microspheres selectively bind to, and are efficiently transcytosed by, rabbit Peyer's patch M cells in closed intestinal loops. Binding of biodegradable poly(DL-lactide-co-glycolide) microspheres to rabbit Peyer's patch FAE is an order of magnitude lower than that of polystyrene microspheres. Although poly(DL-lactide-co-glycolide) microspheres are not selectively targeted to M cells, a high proportion of those which bind to M cells are transcytosed, supporting the potential of such microspheres as vehicles for oral vaccine delivery. Comparison of the binding of polystyrene microspheres by murine FAE revealed this to be markedly less extensive than by rabbit FAE. These data demonstrate that microsphere binding by M cells depends on the surface properties of both cells and microspheres and suggest that surface modification may enhance the efficacy of microsphere delivery vehicles. One such approach is the incorporation of molecules with inherent binding specificity for M cells. Lectin-binding studies have revealed that M cells exhibit pronounced regional and species variation in glycoconjugate expression. In murine intestine, certain lectins bind selectively to M cells either in Peyer's patches or caecum, or at both sites. Selective targeting to, and transcytosis of, lectin-conjugates by M cells in ligated segments of murine intestine have also been demonstrated. While several lectins display strong selectivity for rabbit caecal M cells, none to date have been identified with specificity for rabbit or rat Peyer's patch M cells. Knowledge of human M cells is limited and no lectin has yet been identified with specificity for these cells. However, at least one lectin exhibits binding specificity for FAE in the human ileum. In the future, knowledge of the regional patterns of M cell carbohydrate expression within a species may allow lectins to be utilised to target selectively antigenic material to the mucosal immune system at specific locations.

Administration, Oral↗
PubMedDate not supplied

[The interrelations of mucosal epithelial cells with microbes--intracellular parasites].

On the basis of information at hand, it can be concluded that there are principal limits on the capture of bacteria by epithelial cells in the gastrointestinal tract and other cavities. Although entry is, however, a result both of bacteria and epithelial cells, it is frequently induced by parasite-directed endocytosis and may also accompanied by passive entry of nonpathogenic bacteria. The induction of parasite-induced endocytosis should be regarded as a consequence of a fundamental concept in biology, namely: molecular and cellular recognition wherein bacterial adhesion to the host's cell receptors is of great importance. In this connection, discussion covers the origin of corresponding receptors. The authors share the opinion in that epithelial cells, those of the gastrointestinal tract in particular, are part of the human common mucosal immune system.

Animals↗
PubMedDate not supplied

Comparison of Salmonella typhimurium challenge models in chickens.

Experimental infection of chickens with controlled quantities of Salmonella typhimurium is often achieved by administration of a single oral inoculum of live bacteria to caged chickens. However, this method is a poor simulation of the natural process of S. typhimurium infection in the field, making the practical application of results obtained under such conditions tenuous. This experiment was designed to evaluate the use of horizontal transmission for the challenge/infection of chickens with S. typhimurium with the expectation that it may more closely resemble the natural situation and, therefore, the in-field physiological response of chickens. Further, the experiment allowed for comparison of both the kinetics and magnitude of the mucosal immune response following each mode of challenge by exposing the chickens to challenge by placing them on litter with S. typhimurium-infected seeder birds. Overall, birds challenged via seeded litter exhibited a slower rate of infection and a more gradual increase in serum antibody production compared with birds receiving a single oral inoculum.

Administration, Oral↗
PubMed1998

Secretory component delays the conversion of secretory IgA into antigen-binding competent F(ab')2: a possible implication for mucosal defense.

Secretory component (SC) represents the soluble ectodomain of the polymeric Ig receptor, a membrane protein that transports mucosal Abs across epithelial cells. In the protease-rich environment of the intestine, SC is thought to stabilize the associated IgA by unestablished molecular mechanisms. To address this question, we reconstituted SC-IgA complexes in vitro by incubating dimeric IgA (IgAd) with either recombinant human SC (rSC) or SC isolated from human colostral milk (SCm). Both complexes exhibited an identical degree of covalency when exposed to redox agents, peptidyl disulfide isomerase, and temperature changes. In cross-competition experiments, 50% inhibition of binding to IgAd was achieved at approximately 10 nM SC competitor. Western blot analysis of IgAd digested with intestinal washes indicated that the alpha-chain in IgAd was primarily split into a 40-kDa species, a phenomenon delayed in rSC- or SCm-IgAd complexes. In the same assay, either of the SCs was resistant to degradation only if complexed with IgAd. In contrast, the kappa light chain was not digested at all, suggesting that the F(ab')2 region was left intact. Accordingly, IgAd and SC-IgAd digestion products retained functionality as indicated by Ag reactivity in ELISA. Size exclusion chromatography under native conditions of digested IgAd and rSC-IgAd demonstrates that SC exerts its protective role in secretory IgA by delaying cleavage in the hinge/Fc region of the alpha-chain, not by holding together degraded fragments. The function of integral secretory IgA and F(ab')2 is discussed in terms of mucosal immune defenses.

Animals↗
PubMed1998

Design and delivery of non-parenteral vaccines.

Non-parenteral delivery of vaccines is reviewed focusing on the delivery systems that have been used for various mucosal routes of administration. Systems considered include biodegradable micro- and nanoparticles, liposomes, live bacterial and viral vectors and mucosal adjuvants. New approaches to mucosal vaccine formulation using: (i) gene fusion technology to create non-toxic derivatives of mucosal adjuvants, (ii) genetically inactivated antigens with a deletion in an essential gene, (iii) coexpression of an antigen and a specific cytokine that is important in the modulation and control of a mucosal immune response, and (iv) genetic material itself that would allow DNA or RNA uptake and its endogenous expression in the host cell are described.

Animals↗
PubMed1999

Cutting edge: coordinate regulation of IFN regulatory factor-1 and the polymeric Ig receptor by proinflammatory cytokines.

The polymeric IgR (pIgR) mediates transcytosis of IgA across epithelial barriers of mucous membranes and exocrine glands. Synthesis of pIgR is up-regulated by the proinflammatory cytokines TNF-alpha, IFN-gamma, and IL-1 in HT-29 human colon carcinoma cells. We previously reported that IFN-gamma and TNF-alpha induce production of the transcription factor IFN regulatory factor-1 (IRF-1) in HT-29 cells and that IRF-1 binds to an element in exon 1 of the PIGR gene. We now report that levels of IRF-1 and pIgR mRNA are coordinately regulated in HT-29 cells by TNF-alpha, IFN-gamma, and IL-1beta. Furthermore, we demonstrate that in vivo expression of pIgR mRNA is greatly depressed in the intestine and liver of IRF-1-deficient mice. Our findings indicate a major role for the IRF-1 transcription factor in regulation of the PIGR gene and suggest a model for regulation of important genes in the mucosal immune system by proinflammatory cytokines.

Animals↗
PubMed2001

A vaccine against dental caries: an overview.

Dental caries continues to be a costly and prevalent oral disease. Research efforts towards developing a well tolerated and effective vaccine against dental caries were initiated following the demonstration of a specific bacterial aetiology for this disease. The cariogenic mutans streptococci are the principal bacteria causing this disease. Specific immune defence against these bacteria is provided mainly by secretory immunoglobulin (Ig) A antibodies present in saliva, which are generated by the common mucosal immune system. Progress in the development of a vaccine against dental caries has increased due to both advancements in molecular biology and our understanding of the mucosal immune system and mucosal vaccines. Advancements in molecular biology have facilitated the cloning and functional characterisation of virulence factors of the mutans streptococci, including the cell-surface fibrillar proteins, which mediate adherence to the tooth surface, and the glucosyltransferase enzymes, which synthesise adhesive glucans and allow microbial accumulation on the teeth. Current strategies for immunisation against dental caries are using these virulence factors as key antigens and incorporating them into novel mucosal vaccine systems and delivering them with or without adjuvants to mucosal IgA inductive sites. The most popular routes of mucosal immunisation are via the oral or nasal route. The mucosal immune system is functional in newborn infants, who develop salivary IgA antibodies as they become colonised by oral micro-organisms. Mucosal immunisation strategies result in the induction of salivary IgA antibody responses and pose fewer problems than parenteral injection of antigen. Therefore, mucosal immunisation of infants prior to the appearance of their first teeth may be a well tolerated and effective way to induce immunity against the colonisation of teeth by mutans streptococci and protection against subsequent dental caries. The purpose of this article is to provide an overview of the recent progress on the development of a vaccine against infection by Streptococcus mutans for the prevention of dental caries, with emphasis on the mucosal immune system and vaccine design.

Animals↗
PubMed1999

Secretory immunity in defense against cariogenic mutans streptococci.

Specific immune defense against cariogenic mutans streptococci is provided largely by salivary secretory IgA antibodies, which are generated by the common mucosal immune system. This system is functional in newborn infants, who develop salivary IgA antibodies as they become colonized by oral microorganisms. The mechanisms of action of salivary IgA antibodies include interference with sucrose-independent and sucrose- dependent attachment of mutans streptococci to tooth surfaces, as well as possible inhibition of metabolic activities. The goal of protecting infants against colonization by mutans streptococci might be accomplished by applying new strategies of mucosal immunization that would induce salivary IgA antibodies without the complications of parenteral immunization. Strategies of mucosal immunization against mutans streptococci currently under development include the use of surface adhesins and glucosyltransferase as key antigens, which are being incorporated into novel mucosal vaccine delivery systems and adjuvants. The oral application of preformed, genetically engineered antibodies to mutans streptococcal antigens also offers new prospects for passive immunization against dental caries.

Adhesins, Bacterial↗
PubMed1999

Humoral immune responses in periodontal disease may have mucosal and systemic immune features.

The humoral immune response, especially IgG and IgA, is considered to be protective in the pathogenesis of periodontal disease, but the precise mechanisms are still unknown. Immunoglobulins arriving at the periodontal lesion are from both systemic and local tissue sources. In order to understand better the local immunoglobulin production, we examined biopsy tissue from periodontitis lesions for the expression of IgM, IgG, IgA, IgE and in addition the IgG and IgA subclasses and J-chain by in situ hybridization. Tissues examined were superficial inflamed gingiva and the deeper granulation tissue from periodontal sites. These data confirm that IgM, and IgG and IgA subclass proteins and J-chain can be locally produced in the periodontitis tissues. IgG1 mRNA-expressing cells were predominant in the granulation tissues and in the gingiva, constituting approx. 65% of the total IgG-expressing plasma cells. There was a significantly increased proportion of IgA-expressing plasma cells in the gingiva compared with the granulation tissue (P < 0.01). Most of the IgA-expressing plasma cells were IgA1, but a greater proportion expressed IgA2 mRNA and J-chain mRNA in the gingival tissues (30.5% and 7.5%, respectively) than in the periodontal granulation tissues (19% and 0-4%, respectively). The J-chain or dimeric IgA2-expressing plasma cells were located adjacent to the epithelial cells, suggesting that this tissue demonstrates features consistent with a mucosal immune response. Furthermore, we were able to detect the secretory component in gingival and junctional epithelial cells, demonstrating that the periodontal epithelium shares features with mucosal epithelium. In contrast, deeper tissues had more plasma cells that expressed IgM, and less expressing IgA, a response which appears more akin to the systemic immune response. In conclusion, this study suggests that immune mechanisms involved in the pathogenesis of periodontitis may involve features of both the mucosal and systemic immune systems, dependent on tissue location.

Adult↗
PubMed2001

Modified immunogenicity of a mucosally administered antigen.

Streptococcus mutans is present in the saliva of most individuals and is modified by salivary components bound to the cells. These saliva-bound S. mutans are swallowed, exposed to high levels of acidity in the stomach, and presented to the common mucosal immune system. Much effort has been directed to identifying the specific S. mutans antigens that the mucosal immune responses are directed against. However, little is known about the host-altered antigenic determinants that the mucosal immune system recognizes. The immunogenicity of gastrically intubated untreated S. mutans cells, cells coated with whole human saliva, cells treated with HCl (pH 2.0), and saliva-coated and acid-treated cells in mice was investigated. Saliva and serum samples were assayed by enzyme linked immunosorbent assay for immunoglobulin A (IgA) and IgG antibodies, respectively, against the untreated or treated S. mutans cells. In general, the levels of salivary IgA and serum IgG antibodies to the antigen against which the mice were immunized were significantly higher (P < or = 0.05). In addition, human saliva and serum samples from 12 subjects were assayed for naturally occurring antibody against the untreated or treated S. mutans cells. In every case, significantly higher reactivity was directed against the saliva-coated and acid-treated cells followed by the saliva-coated S. mutans. These results provide evidence for the altered immunogenicity of swallowed S. mutans in humans by coating native S. mutans antigens with salivary components and/or denaturing surface S. mutans antigens in the acidic environment of the stomach, which would lead to an immune response to modified S. mutans determinants and not to native S. mutans antigens.

Animals↗
PubMed2001

Evidence for early local viral replication and local production of antiviral immunity upon mucosal simian-human immunodeficiency virus SHIV(89.6) infection in Macaca nemestrina.

Transmission of human immunodeficiency virus type 1 (HIV-1) is largely a result of heterosexual exposure, leading many investigators to evaluate mucosal vaccines for protection against intravaginal (i.vag.) transmission in macaque models of AIDS. Relatively little is known, however, about the dynamics of viral replication and the ensuing immune response following mucosal infection. We have utilized a simian-human immunodeficiency virus (SHIV) to study the differences in viremia, CD4 T-cell percentages, and mucosal and systemic anti-SHIV humoral and cellular immune responses during primary infection of animals infected either intravenously (i.v.) or i.vag. Positive viral cocultures, peripheral blood mononuclear cell viral load peaks, and CD4 cell declines were delayed by 1 week in the i.vag. inoculated animals compared to the animals infected i.v., demonstrating delayed viral spreading to the periphery. In contrast, mucosal anti-SHIV antibody levels were greater in magnitude and arose more rapidly and mucosal CD8(+) T-cell responses were enhanced in the i.vag. group animals, whereas both the magnitudes and times of onset of systemic immune responses for the animals in the two groups did not differ. These observations demonstrate that compartmentalization of viral replication and induction of local antiviral immunity occur in the genital tract early after i.vag. but not i.v. inoculation. Induction of mucosal immunity to target this local, contained replication should be a goal in HIV vaccine development.

Animals↗
PubMed1996

Development of immune function in the intestine and its role in neonatal diseases.

This review has traced the ontogeny of the human mucosal immune system, speculating that appropriate gut immune responses are essential in preventing many significant neonatal enteric diseases. Because the gastrointestinal tract serves as the portal of entry for many potential antigens, its mucosal immune function is essential in controlling antigenic responses and ensuring systemic tolerance. A thorough under standing of the development of the entire immune system is essential in defining intestinal mucosal immune function. From the protective barrier covering the enterocyte to the intraepithelial T lymphocytes, these components work together to limit antigen passage from the gut lumen to the underlying immune cells and, thus, promote normal immunity and tolerance. When abnormalities exist or when this immune barrier has not matured fully, conditions afflicting newborns, especially preterm infants, occur. Necrotizing enterocolitis, milk-protein enteropathy, and enteric bacterial infections are only three clinical examples of how aberrant gut immune-mediated defenses may have a significant role in their pathogenesis. In clinical practice, it is not only important to recognize these conditions at their onset but also to understand the basis for the underlying illness and identify newborns who are at an increased risk of acquiring them.

Bacterial Adhesion↗
PubMed2000

Bombesin recovers gut-associated lymphoid tissue and preserves immunity to bacterial pneumonia in mice receiving total parenteral nutrition.

OBJECTIVE: To study the ability of bombesin (BBS) to recover gut-associated lymphoid tissue (GALT) and preserve immunity in a lethal model of Pseudomonas aeruginosa (Ps) pneumonia in mice receiving total parenteral nutrition (TPN). SUMMARY BACKGROUND DATA: TPN causes depression of mucosal immunity compared with enterally fed animals, which may explain the increased incidence of pneumonia in parenterally fed trauma patients. BBS prevents this TPN-induced GALT atrophy, depressed gastrointestinal and respiratory tract IgA levels, and impaired antiviral IgA-mediated mucosal immunity. The authors examined whether some supplement could be added to TPN to avoid this GALT atrophy and lower the incidence of infectious complications in the parenterally fed animal. METHODS: Male mice were randomized to chow or intravenous (IV) TPN. After 5 days of IV TPN, mice received 0, 1, 2, or 3 days of BBS IV three times a day and then were killed to harvest Peyer's patch, intraepithelium, and lamina propria for cell yields. Gastrointestinal and respiratory tract IgA levels were analyzed by enzyme-linked immunosorbent assay. Next, mice underwent intranasal inoculation with liposomes alone (nonimmune) or liposome-containing Ps polysaccharide. Ps immune mice were catheterized and randomized to chow, IV TPN, or IV TPN + BBS. The liposome group received chow but no IV catheter. These mice were given an LD90 dose of intratracheal Ps, and death rates were recorded. RESULTS: GALT and gastrointestinal and respiratory tract IgA levels improved to those in chow-fed mice after 3 days of BBS. Immunization reduced the death rate from 92% in chow-fed liposome-only animals to 20% in immunized animals. TPN-fed animals lost their mucosal immunity, with a death rate of 86% compared with 21% in the TPN + BBS group. CONCLUSION: The results demonstrate that BBS reverses TPN-induced changes in GALT and preserves mucosal immunity. Ps immunization reduces the death rate in a gram-negative pneumonia model and maintains gastrointestinal and respiratory immunity in Ps immune mice receiving IV TPN.

Animals↗