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PubMed2002

Host/pathogen interactions at mucosal surfaces: immune consequences.

The mucosal immune system has evolved to protect the host against the establishment of infections at or through the mucosal surfaces of the body. Protective immunity must be activated to specific pathogenic agents or their products but inappropriate immune responses to food/environmental antigens must be avoided. Thus, the mucosal immune system is under tight regulation. Pathogenic bacteria and their products can be exploited as specific probes of mucosal immune responses. Bacterial enterotoxins such as cholera toxin are potent mucosal immunogens and adjuvants that activate both mucosal and systemic immune responses. Infection models involving microorganisms such as Citrobacter rodentium can also be used to investigate the consequences of mucosal colonisation that lead to immune disfunction.

Animals↗

PubMed2000

Transcutaneous immunization induces mucosal and systemic immunity: a potent method for targeting immunity to the female reproductive tract.

Female BALB/c mice were immunized with tetanus toxoid (TT) admixed with cholera toxin by direct application to shaved skin (Transcutaneous immunization, TCI). Tetanus toxoid-specific IgG and IgA in serum, saliva, vaginal lavage and fecal pellets were assayed by ELISA. Tetanus toxoid specific antibody-secreting cell (ASC) numbers were also determined by immunohistochemistry in sections of vagina, uterus, salivary gland and small intestine of immunized mice. TCI elicited significant levels of TT-specific IgG in serum, saliva and vaginal lavage, with the greatest increases over background seen in saliva (80-400 fold) and vaginal lavage (2-87 fold). TCI induced only modest levels of IgA in any of the samples tested (range 2-7 fold increase). In the absence of cholera toxin, application of TT alone did not result in detectable TT-specific antibodies in mucosal secretions. ASCs were found in all tissues following TCI. Cells were most frequent in uterus and vaginal tissues with ASC numbers less frequent in small intestine and salivary gland. This suggests that local production, rather than transudation from serum, is a major contributor of antibody in reproductive tract secretions. Further studies focussed on the role of sex hormones and immune induction following TCI. Animals immunized at the stage of oestrus cycle at which estrogen is abundant (Estrus), showed significantly lower levels of TT-specific IgG in vaginal lavage samples. Collectively, these data confirm the findings of Glenn and colleagues (1998), who showed TCI using cholera toxin can elicit high levels of serum IgG to both the toxin and co-administered antigen and further demonstrates that this route of immunization is particularly effective at eliciting humoral immunity in saliva and in the female reproductive tract.

Animals↗

PubMed1994

Strategies for the induction of immune responses at mucosal surfaces making use of cholera toxin B subunit as immunogen, carrier, and adjuvant.

The concept of a common mucosal immune system, through which specific antigen-activated lymphocytes from the gut can disseminate immunity both along the intestinal tract and to various other mucosal and glandular tissues, has generated much current interest in the possibility of developing oral vaccines, not only for enteric infections but also for infections in the respiratory and urogenital tracts. However, to date it has proven difficult in practice to stimulate strong mucosal IgA immune responses by either parenteral or oral-mucosal administration of most antigens, and experience with soluble protein antigens has, on the whole, been disappointing. A notable exception in this regard is cholera toxin (CT) and in humans more than in other species, its nontoxic B subunit pentamer moiety (CTB). Based on this, CTB has become an important component in recently developed oral vaccines against cholera as well as against diarrhea caused by enterotoxigenic Escherichia coli producing CT-like heat-labile enterotoxin(s). Since the strong immunogenicity of CT and CTB can, to a large extent, be explained by their ability to bind to receptors on the intestinal mucosal surface, there has recently been much interest in approaches using CTB as an oral delivery carrier system for other vaccine-relevant antigens, and much progress has been made in preparing immunogenic hybrid proteins by coupling various protein or peptide antigens chemically or genetically to CTB. Indeed, in several systems, oral administration of such hybrid antigens has been found to markedly potentiate both intestinal and extraintestinal IgA immune responses against the CTB-coupled antigens and also to elicit substantial circulating antibody responses. Besides the mucosal immunopotentiating effect of either CT or CTB owing to their similar capacity as oral antigen-delivery vehicles, CT, but in most systems tested not CTB, also has strong adjuvant properties for stimulating mucosal IgA immune responses to admixed (not coupled) unrelated antigens after oral immunization. This adjuvant activity appears to be closely linked to the ADP-ribosylating action of CT (and specifically of its A subunit) leading to enhanced cyclic AMP formation in the affected cell, and efforts to eliminate the enterotoxic activity without losing adjuvanticity have so far not met with success.

Adjuvants, Immunologic↗

PubMed2006

Novel approaches to pediatric vaccine delivery.

Although currently available vaccines represent an outstanding success story in modern medicine and have had a dramatic effect on morbidity and mortality worldwide, it is clear that improvements in vaccine delivery are required. Vaccine delivery improvements may include the addition of novel injectable adjuvants, or the use of novel routes of delivery, including mucosal immunization. Mucosal delivery may be required to provide protection against pathogens that infect at mucosal sites, including sexually transmitted diseases. Alternatively, novel approaches to delivery, including mucosal administration, may be used to improve compliance for existing vaccines. Of particular interest for safer mass immunization are needle-free delivery devices, which would avoid problems due to needle re-use in many parts of the world, or needle-stick injuries.

Adjuvants, Immunologic↗

PubMed2004

Novel approaches to vaccine delivery.

Although the currently available vaccines represent an outstanding success story in modern medicine and have had a dramatic effect on morbidity and mortality worldwide, it is clear that improvements are required in the current vaccine delivery technologies. Improvements are required to enable the successful development of vaccines against infectious diseases that have so far proven difficult to control with conventional approaches. Improvements may include the addition of novel injectable adjuvants or the use of novel routes of delivery, including mucosal immunization. Mucosal delivery may be required to provide protection against pathogens that infect at mucosal sites, including sexually transmitted diseases. Alternatively, novel approaches to delivery, including mucosal administration, may be used to improve compliance for existing vaccines. Of particular interest for safer mass immunization campaigns are needle-free delivery devices, which would avoid problems due to needle re-use in many parts of the world and would avoid needle-stick injuries.

Adjuvants, Immunologic↗

PubMed1991

Immediate hypersensitivity in colon of children with chronic Trichuris trichiura dysentery.

There are few data on mucosal immune responses to intestinal helminths in human beings, especially those involving the IgE system, which is thought to be important in parasite expulsion. We sought evidence of an immediate hypersensitivity reaction in the colon of children with chronic dysentery due to Trichuris trichiura. 28 children with Trichuris dysentery syndrome (TDS) were compared with 16 control children (with no TDS or worms visible on colonoscopy). All children were aged 1-11 years. Rectal biopsy samples were taken before and after expulsion of the worms by means of mebendazole treatment. Children with TDS had significantly greater numbers than controls of mast cells (mean [SD] 10.9 [1.3] vs 3.9 [0.6]% of all cells; p less than 0.0003) and of cells with surface IgE (median [range] 11.1 [7.5-11.6] vs 1.0 [0-1.5]%; p less than 0.001) in the subepithelial region of the mucosa. On electronmicroscopy, degranulating mast cells were prominent in parasitised children. In culture, rectal biopsy samples from parasitised children showed high rates of spontaneous histamine release, but only low rates of antigen-specific release. After treatment, spontaneous histamine release was significantly reduced and antigen-specific histamine release could be provoked. Thus, an IgE-mediated immune mucosal response to a helminth infection does occur in human beings but is not sufficient to cause appreciable parasite expulsion.

Anaphylaxis↗

PubMed2001

Development, acceptance, and use of immunologic correlates of protection in monitoring the effectiveness of combination vaccines.

The establishment of immunologic correlates of protection for all vaccine antigens is a worthwhile goal. It allows new vaccines to be licensed on the basis of attainment of defined immunologic benchmarks, without the need for large-scale efficacy trials for each new product. This is particularly important for the evaluation of new combination products. Efficacy trials of each new mixture would be unethical because routinely recommended vaccines would be denied children in the control group. The establishment of immunologic correlates of protection should be a defined goal of every efficacy trial. Additional ways to evaluate the immune responses-such as cell-mediated immunity, mucosal immunity, memory responses, and antibody avidity-should also be studied. Finally, ongoing surveillance efforts are also needed, to monitor the impact of new and combined vaccines on disease rates.

Animals↗

PubMed1999

[Intraepithelial enteroendocrine cells in cecum and appendix from ovoalbumin sensitized rabbits].

Intraepithelial enteroendocrine cells (IEC) produce peptides which influence motility, secretion and absorption of nutrients. Recently the role of these cells in the immune mucosal system is under study. The aim of the present study was to evaluate the modifications in number of IEC in cecum and appendix from Ovalbumin (OVA) sensitized rabbits. Twenty adult New Zealand rabbits were separated in two groups: Group 1 (G1 = 10) not sensitized normal control. Group 2 (G2 = 10) were sensitized twice intraperitoneally with 70 mg OVA and 30 mg ALUM/ml (aluminium hydroxide). Anti OVA specific IgE was evaluated by means of PCA test (passive cutaneous anaphylaxis). Samples form cecum and appendix were fixed in buffered formaldehyde 10%, paraffin embedded and stained with anti-Chromogranin A for neuroendocrine cells. 400 high power fields were counted in each animal, referred as IEC/100 enterocytes. In cecum surface epithelium and crypt were considered. Surface epithelium, deep crypts and superficial crypts were evaluated in appendix. Results showed in cecum in G1:1,6 IEC/100 enterocytes in surface epithelium and 3/100 in crypts; G2 6 IEC/100 in surface epithelium and 12/100 in crypts. The difference between G1 and G2 was statistically significant (p < 0.05). In appendix surface epithelium from G1 showed 5.2/100 while G2 5.4/100. Superficial crypts 8.5 (G1) and 11.3 (G2) (p < 0.05) and deep crypts 4.9 (G1) and 8.5 (G2) (p < 0.01). The results showed that OVA-sensitized animals presented increment in the number of IEC in surface epithelium and crypts which may indicate a relationship between these cells and rabbit mucosal immune system.

Animals↗

PubMed2006

Needle-free vaccine delivery.

The search for methods of vaccine delivery not requiring a needle and syringe has been accelerated by recent concerns regarding pandemic disease, bioterrorism, and disease eradication campaigns. Needle-free vaccine delivery could aid in these mass vaccinations by increasing ease and speed of delivery, and by offering improved safety and compliance, decreasing costs, and reducing pain associated with vaccinations. In this article, we summarize the rationale for delivery of needle-free vaccines and discuss several methods currently in use and under development, focusing on needle-free injection devices, transcutaneous immunization, and mucosal immunization. Jet injectors are needle-free devices that deliver liquid vaccine through a nozzle orifice and penetrate the skin with a high-speed narrow stream. They generate improved or equivalent immune responses compared with needle and syringe. Powder injection, a form of jet injection using vaccines in powder form, may obviate the need for the "cold chain." Transcutaneous immunization involves applying vaccine antigen and adjuvant to the skin, using a patch or "microneedles," and can induce both systemic and mucosal immunity. Mucosal immunization has thus far been focused on oral, nasal, and aerosol vaccines. Promising newer technologies in oral vaccination include using attenuated bacteria as vectors and transgenic plant "edible" vaccines. Improved knowledge regarding the immune system and its responses to vaccination continues to inform vaccine technologies for needle-free vaccine delivery.

Administration, Topical↗

PubMed1986

Significance of immune responses to mucosal carcinogens: a hypothesis and a workable model system.

Carcinogens must enter the tissues before neoplastic transformation of cells can occur. The present report describes the 2-AAF model system being used to test our hypothesis that development of mucosal immunity to carcinogens will interfere with their passage through mucosal epithelial cells. The 2-AAF model is ideal for testing this hypothesis. 2-AAF is a carcinogen which passes through the intestinal epithelium following oral administration, is transported to the liver and is there metabolized with the ultimate formation of hyperplastic nodules and neoplasms. Further, neoplasms form at other sites including the ear duct, gastrointestinal tract and the lungs. Our studies indicate that 2-AAF alone given orally does not elicit an immune response. However, 2-AAF is immunogenic when conjugated to carrier proteins and administered in CFA. Such conjugates of 2-AAF are not carcinogenic when administered in doses needed to achieve a systemic immune response in rats. Future studies will document the optimal conditions required to stimulate mucosal immunity to 2-AAF and the effect of such immunity on carcinogenesis in this model.

2-Acetylaminofluorene↗

PubMed1995

Local and systemic antibody responses to dextran-cholera toxin B subunit conjugates.

This study was designed to test local and systemic immunity following mucosal immunization with a polysaccharide-protein conjugate. After preparing and characterizing dextran-cholera toxin B subunit (CTB) conjugates, we studied their immunogenicity in mice following systemic or mucosal immunizations. Dextran was chosen as a model polysaccharide antigen and conjugated via adipic acid dihydrazide and N-succinimidyl-3-(2-pyridyldithio)propionate to CTB. Mice were immunized either subcutaneously, intranasally, or perorally three times, and cholera toxin was used as an adjuvant for the mucosal immunizations. Three conjugates with different molecular weights for dextran (40,000 and 76,000) or varying dextran/CTB molar ratios were tested. Peroral immunizations with all conjugates evoked local immunoglobulin A (IgA) antibody responses against dextran in the small intestine, and intranasal immunizations did the same in the lung. Intranasal immunizations also elicited serum antibody titers that were significantly higher than or equal to those after subcutaneous immunizations. Intranasal immunizations evoked serum IgG antidextran titers which were dependent on the dextran/CTB molar ratio and inversely related to the local IgA response, which was not the case for subcutaneous immunizations. This is the first study of local and systemic immunity following mucosal immunization with a polysaccharide-protein conjugate. The results show that it is possible to evoke a local as well as a systemic antibody response against a polysaccharide by conjugating it to CTB and using an appropriate route of immunization.

Administration, Intranasal↗

PubMed2000

CCR6 mediates dendritic cell localization, lymphocyte homeostasis, and immune responses in mucosal tissue.

Chemokine-directed migration of leukocyte subsets may contribute to the qualitative differences between systemic and mucosal immunity. Here, we demonstrate that in mice lacking the chemokine receptor CCR6, dendritic cells expressing CD11c and CD11b are absent from the subepithelial dome of Peyer's patches. These mice also have an impaired humoral immune response to orally administered antigen and to the enteropathic virus rotavirus. In addition, CCR6(-/-) mice have a 2-fold to 15-fold increase in cells of select T lymphocyte populations within the mucosa, including CD4+ and CD8+ alphabeta-TCR T cells. By contrast, systemic immune responses to subcutaneous antigens in CCR6(-/-) mice are normal. These findings demonstrate that CCR6 is a mucosa-specific regulator of humoral immunity and lymphocyte homeostasis in the intestinal mucosa.

Animals↗

PubMed2002

The role of immunity in protection from mucosal SIV infection in macaques.

The need for an effective vaccine against HIV has prompted a refocusing of attention on mucosal immunity. More than 75% of all infections are acquired across a mucosal surface. It is therefore a prerequisite for a vaccine to target directly the mucosal tissues or indirectly the regional lymph nodes in order to prevent or control viral replication. Although mucosal immunization has induced responses at the genital or rectal surfaces, immune mechanisms alone have not been shown to be sufficient to contain infections in macaques. A growing body of evidence suggests that a dual mechanism may be required for effective mucosal protection, mediated by specific CD4 and CD8 T cell and antibody responses to the immunizing agents, plus innate antiviral factors and beta chemokines that down-regulate CCR5 coreceptors. Targeted iliac lymph node immunization with SIV gp 120 and p27 in alum prevents SIV infection or significantly decreases the viral load when immunized macaques were challenged with SIV by the rectal route. Indeed, in addition to specific immunity, including significant SIgA antibody secreting cells in the iliac lymph nodes, CD8-suppressor factor and the 3beta chemokines (RANTES, MIP-1alpha and MIP-1beta) are significantly associated with protection against rectal mucosal SIV infection.

Animals↗

PubMed2001

The use of CpG DNA as a mucosal vaccine adjuvant.

CpG DNA has been shown to be a potent adjuvant in many disease models. Most studies using CpG DNA as adjuvant have used parenteral delivery, but more effective protection against mucosal pathogens could be achieved with effective mucosal immunization. Recently, mucosal immunization with CpG DNA as an adjuvant has been shown to induce both systemic (humoral and cellular) and mucosal antigen-specific immune responses. This review will concentrate on the use of CpG DNA as an adjuvant for the induction of mucosal immunity.

Adjuvants, Immunologic↗

PubMed2001

A revisit of mucosal IgA immunity and oral tolerance.

Induction of mucosal immunity by oral immunization with protein antigen alone is difficult: potent mucosal adjuvants, vectors, or other special delivery systems are required. Cholera toxin (CT) has been shown to be an effective adjuvant for the development of mucosal vaccines and, when given with vaccine, induces both mucosal and systemic immune responses via a Th2 cell-dependent pathway. However, and in addition to potential type-I hypersensitivity, a major concern for use of mucosal adjuvants such as CT is that this molecule is not suitable for use in humans because of its inherent toxicity. When we examined the potential toxicity of CT for the central nervous system, both CT and CT-B accumulated in the olfactory nerves/epithelium and olfactory bulbs of mice when given by the nasal route. The development of effective mucosal vaccines for the elderly is also an important issue; however, only limited information is available. When mucosal adjuvanticity of CT was evaluated in aged mice, an early immune dysregulation was evident in the mucosal immune system. The present review discusses these potential problems for effective mucosal vaccine development. Tolerance represents the most common and important response of the host to environmental antigens, including food and commensal bacterial components, for the maintenance of an appropriate immunological homeostasis. We have examined whether Peyer patches could play a more important role for the maintenance of oral tolerance. Using Peyer patch-null mice, we found that mice lacking this gut-associated lymphoid tissue retained their capability to produce secretory IgA antibodies but did not develop normal oral tolerance to protein antigens.

Administration, Inhalation↗

PubMed1995

Paradoxical IgA immunity in CD4-deficient mice. Lack of cholera toxin-specific protective immunity despite normal gut mucosal IgA differentiation.

Using normal and CD4 gene-targeted (CD4-/-) mice, we asked whether mucosal immune responses and IgA B cell differentiation require the presence of CD4+ T helper cells. We found that CD4-/- mice had numerous B cell germinal centers in Peyer's patches and other gut-associated lymphoid tissues. Membrane IgA+ B cells were found to co-localize to germinal center areas and CD4-CD8- double negative CD3+ T cells had replaced CD4+ T cells in the follicular areas of the Peyer's patches. CD4-/- mice had normal levels of IgA-producing cells in gut-associated lymphoid tissues, and gut lavage contained unaltered levels of total IgA. However, despite T cell help for IgA B cell differentiation, CD4-/- mice did not respond with Ag-specific intestinal IgA following oral immunization with the powerful mucosal immunogen cholera toxin (CT). By contrast, these mice demonstrated serum alpha-CT IgG following oral immunization, suggesting that double negative CD3+ T cells provided some help for systemic immune responses after oral immunization. Perorally immunized CD4-/- mice were completely unprotected against CT-induced diarrhea while both normal and CD8-/- mice were well protected and also demonstrated high levels of gut mucosal alpha-CT IgA. After reconstitution of the CD4-/- mice by adoptive transfer of naive mesenteric lymph node CD4+ T cells, the mice acquired the ability to respond with specific mucosal immune responses following oral immunization and also developed resistance against CT-induced diarrhea. Thus, paradoxically, although IgA B cell differentiation appears to proceed normally in CD4-/- mice, specific gut mucosal immune responses are grossly impaired in the absence of CD4+ T cells.

Animals↗

PubMed1996

Systemic and mucosal protective immunity to pneumococcal surface protein A.

To date our studies demonstrate that PspA is a highly immunogenic molecule in mice and that it can elicit immunity to otherwise fatal infections following iv, ip, in, and it challenge. Although the molecule is serologically variable, it is sufficiently cross-reactive so that immunization with a single PspA can protect against strains of highly diverse serotypes. It is anticipated that a vaccine composed of a mixture of carefully chosen PspA molecules will be able to elicit protective immunity to virtually all pneumococci. If this vaccine proved efficacious in man, it would provide a more simple and less costly means of immunizing against pneumococcal infection than using recombinant vaccines. This could be especially important in the developing world where the cost of successful vaccines must be no more than pennies per dose. If PspA is found to be less efficacious than capsular polysaccharides, it may be valuable as a protein component of a PS-protein conjugate vaccine. In this capacity, PspA might expand the breath of protection elicited by a vaccine composed of only a few polysaccharide-protein conjugates representing capsule types most commonly associated with infectious pneumococci.

Animals↗

PubMed2006

The gut flora as a forgotten organ.

The intestinal microflora is a positive health asset that crucially influences the normal structural and functional development of the mucosal immune system. Mucosal immune responses to resident intestinal microflora require precise control and an immunosensory capacity for distinguishing commensal from pathogenic bacteria. In genetically susceptible individuals, some components of the flora can become a liability and contribute to the pathogenesis of various intestinal disorders, including inflammatory bowel diseases. It follows that manipulation of the flora to enhance the beneficial components represents a promising therapeutic strategy. The flora has a collective metabolic activity equal to a virtual organ within an organ, and the mechanisms underlying the conditioning influence of the bacteria on mucosal homeostasis and immune responses are beginning to be unravelled. An improved understanding of this hidden organ will reveal secrets that are relevant to human health and to several infectious, inflammatory and neoplastic disease processes.

Animals↗