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PubMed1999

A role for mucosal immunity in resistance to HIV infection.

In a recent, thought-provoking novel by Elizabeth McCracken (The Giant's House. Avon Books, New York, 1997), two characters discuss love and its impossibilities. One brashly claims to be "immune to love", explaining the concept to his perplexed interlocutor, "...people become immune to love like they become immune to any disease. Either they had it bad early in life, like chicken pox and that's that; or they keep getting exposed to it in little doses and build up an immunity; or somehow they just don't catch it, something in'em is born resistant. I'm the last type. I'm immune to love and poison ivy". (p. 275) (E. McCracken, The Giant's House. Avon Books, New York, 1997). Substitute the words 'HIV infection' for 'love' and this intriguing metaphor summarizes the state of the art working hypotheses for the phenomenon of resistance to HIV infection in HIV-exposed individuals who, against all odds, do not seroconvert. These hypotheses will be discussed hereafter and particular emphasis will be placed upon a possible role for mucosal immunity in this phenomenon.

Chemokines↗
PubMed2003

Mucosal immunity: integration between mother and the breast-fed infant.

Lactating mammary glands are part of an integrated mucosal immune system with local production of antibodies, mainly consisting of secretory immunoglobulin A (SIgA). These antibodies generally reflect antigenic stimulation of mucosa-associated lymphoid tissue (MALT) by common intestinal and respiratory pathogens. Antibodies in breast milk are thus highly targeted against infectious agents in the mother's environment, which are those likely to be encountered by the infant shortly after birth. Therefore, breast-feeding represents an ingenious immunological integration of mother and child. The mucosae are favored as portals of entry by most infectious agents, and the neonatal period is particularly critical in this respect. Mucosal pathogens are a major killer of children below the age of 5 years, being responsible for more than 14 million deaths annually. Diarrheal disease alone claims a toll of 5 million children per year in the developing countries. Epidemiological data suggest that the risk of dying from diarrhea could be reduced 14-24 times in breast-fed children. A beneficial clinical effect is also apparent in the industrialized world, even in relation to relatively common diseases such as otitis media and acute lower respiratory tract infections.

Breast Feeding↗
PubMed1999

Modulating dendritic cells to optimize mucosal immunization protocols.

Oral administration of soluble protein Ag induces tolerance, a phenomenon that has hampered mucosal vaccine design. To provoke active immunity, orally administered Ag must be fed together with a mucosal adjuvant such as cholera toxin (CT). Unfortunately, CT is not suitable for clinical use because of its associated toxicity. There is, therefore, a need to develop alternative mucosal immunization regimens. Here we have attempted to alter the intrinsically tolerogenic nature of the intestine and improve immunization potential by expanding and activating intestinal APC in vivo. Previous studies have indicated that intestinal dendritic cells (DC) present oral Ag, but do so in a tolerogenic manner. In the present study we investigated whether DC can be converted from tolerogenic into immunogenic APC by treating mice with Flt3 ligand (Flt3L), a DC growth factor, and then immunizing with CT. We observed increased local and systemic responses to CT in the presence of elevated numbers of intestinal DC. In parallel, CT induced up-regulation of CD80 and CD86 on these Flt3L-expanded DC. In an attempt to develop a toxin-free adjuvant system, we investigated whether IL-1 could be used as an alternative DC-activating stimulus. Using a combination of Flt3L and IL-1alpha, we observed a potent active response to fed soluble Ag, rather than the tolerogenic response normally observed. These data suggest that Flt3L-expanded DC are well positioned to regulate intestinal responses depending on the presence or the absence of inflammatory signals. Flt3L may therefore be a reagent useful for the design of mucosal immunization strategies.

Adjuvants, Immunologic↗
PubMed1994

Mucosal immunity in the female genital tract: relevance to vaccination efforts against the human immunodeficiency virus.

The development of vaccines that induce specific immune responses in the genital tract secretions would have far-reaching implications for the prevention of AIDS and other sexually transmitted diseases. Most of the currently studied vaccines utilize systemic routes of immunization that are of limited value for the prevention of mucosa-contracted diseases. The relative contribution of antigen-sensitized cells and IgA-committed lymphocytes from IgA inductive sites (e.g., Peyer's patches and rectal tonsils) to remote or adjacent effector sites (e.g., salivary glands and female genital tract) as manifested by the appearance of corresponding secretory antibodies has not been studied in humans despite its unquestionable practical importance. Exploitation of immunization routes that are effective for induction of mucosal immune responses and reflect our current knowledge of the origin of antibodies and of specific antibody-forming cells in mucosal tissues is likely to reduce the incidence of many infectious diseases including AIDS.

AIDS Vaccines↗
PubMed1996

Induction of pneumococcal polysaccharide-specific mucosal immune responses by oral immunization.

Liposome and cholera toxin (CT) are considered to be effective antigen delivery vehicles and adjuvants for mucosal vaccines. The effect of these antigen delivery systems on adjuvant responses to mucosally administered pneumococcal polysaccharide (Pnup) was investigated in this study. Both mucosal (e.g. oral) and systemic (i.p.) immunization of mice with purified preparations of Pnup type 23F induced antigen-specific IgM responses in sera. Interestingly, oral immunization of as little as 10 micrograms of Pnup type 23F was sufficient to induce systemic IgM responses. Pnup-specific IgM antibodies peaked by day 7 and no booster responses were evident after a second dose on day 14. In order to examine whether IgG and IgA Pnup-specific immune responses are induced by mucosal immunization, the mucosal adjuvant CT was mixed with Pnup type 23 as an oral vaccine. Co-oral administration of CT and Pnup type 23F resulted in the induction of Pnup-specific faecal IgA antibodies. These results were confirmed by detecting antigen-specific IgA-spot-forming cells in mononuclear cell suspensions prepared from the intestine of immunized mice. These findings suggest that oral immunization with Pnup in the presence of mucosal adjuvants, such as CT, could induce Pnup-specific IgA responses whereas Pnup alone did not. In an attempt to further enhance antigen-specific antibody responses, Pnup type 23F was encapsulated in liposomes and used as mucosal vaccine. However, immunogenicity of Pnup was not improved.

Administration, Oral↗
PubMed2005

Lipid microparticles for mucosal immunization against hepatitis B.

Parenteral administration of vaccines often does not lead to optimal or long lasting protection against disease causing organisms particularly those that are inhaled, ingested or sexually transmitted. For optimal mucosal protection induction of immune response via mucosal routes is therefore highly desirable. Double emulsion-solvent evaporation (w/o/w) method best suited for water-soluble bioactives was selected for the preparation of hepatitis B surface antigen (HBsAg) loaded lipid microparticles. Intranasal route was considered for mucosal administration and hence to prepare the delivery system biocompatible and least irritable, soyalecithin (phospholipid) was taken instead of polymer because phosphatidylcholine is the major component of endogenous lung surfactant. The studies performed in present work included antigen characterization, development of lipid microparticles, stability studies of the prepared lipid microparticle formulations, percent mucoadhesion, ex vivo cellular uptake studies and in vivo studies. The general order obtained from in vivo studies for mucosal immune response (IgA) followed the sequence: LMST-HBsAg (IN)>LM-HBsAg (IN)>alum-HBsAg (IN)>LMST-HBsAg (IM)>alum-HBsAg (IM)>or=LM-HBsAg (IM)>plain HBsAg (IN)>plain HBsAg (IM).

Administration, Intranasal↗
PubMed2006

In vivo induction of mucosal immune responses by intranasal administration of chitosan microspheres containing Bordetella bronchiseptica DNT.

In vitro immune-stimulating activities of Bordetella bronchiseptica dermonecrotoxin (BBD)-loaded in chitosan microspheres (CMs) were reported with a mouse alveolar macrophage cell line (RAW264.7). Based on the report, in vivo activity of immune-induction was investigated by intranasal administration of the BBD-loaded CMs into mice. BBD was loaded into the CMs prepared by an ionic gelation process with tripolyphosphate. Mice were immunized by direct administration of the BBD-loaded CMs into the nasal cavity. After immunization of the mice, BBD-specific immune responses (IgG and IgA titers) were measured in sera, nasal wash, and saliva by ELISA. BBD-specific IgA titers in the nasal cavity were time- and dose-dependently increased by the administration. Similar phenomena were observed in the analysis of systemic IgA and IgG in sera. However, the antibody in saliva was undetectable by ELISA. These results suggested that direct vaccination via the nasal cavity was effective for targeting nasal-associated lymphoid tissues, and that CMs were an efficient adjuvant in nasal mucosal immunity for atrophic rhinitis vaccine.

Administration, Intranasal↗
PubMed1997

Transmission and protection in leprosy: indications of the role of mucosal immunity.

Recent advances in treatment have achieved a large drop in the prevalence of active leprosy cases, but the incidence is at best decreasing slowly. Most people within leprosy-endemic populations have been exposed to Mycobacterium leprae, but few develop disease and it seems likely that the majority of the population develops protective immunity. If the site of initial infection is in the nose, dissemination of bacilli around the body to skin and nerve implies that the initial infection is bacilliferous and it has been shown that nasal M. leprae are detectable by polymerase chain reaction (PCR) of nasal swabs. Since salivary anti-M. leprae IgA (sMLIgA) levels are correlated with protection, we have surveyed groups of leprosy patients, contacts and the general population for both their sMLIgA and nasal PCR positivity. A total of 304 subjects were enrolled in the study: PCR and mucosal challenge tests were performed in 204 of these individuals. sMLIgA was present in 66% of treated patients, 76% of leprosy workers and 72% of healthy contacts. However, only 33% of indigenous subjects were sMLIgA+, in contrast to the earlier studies showing 74% positivity. PCR for M. leprae was present in both household contacts (2%) and indigenous controls (5%). In a subsequent follow-up study, nasal swabs were taken from 97 of those studied in the first series: three PCR+ individuals followed up after one year became negative, while of the remaining 94 PCR- individuals retested, 2 became positive. Of 112 subjects retested with the mucosal challenge test for sMLIgA: 22 converted from positive to negative and 12 from negative to positive. These results suggest that there is widespread subclinical transmission of M. leprae with transient infection of the nose resulting in the development of a mucosal immune response, despite the fact that few individuals will develop clinical disease. This may explain the current lack of effect of multidrug therapy (MDT) control programmes on incidence, although the reduction in general population immunity is consistent with some effect of MDT on transmission.

Adolescent↗
PubMed2004

Odor from industrial hog farming operations and mucosal immune function in neighbors.

The authors evaluated whether exposure to malodor from industrial hog farming operations has a psychophysiologically mediated immunosuppressive effect on secretory immunoglobulin A (sIgA) in neighbors. Fifteen adults living within 2.4 km (1.5 mi) of at least one hog farming operation rated odor intensity on a 9-point scale and provided saliva samples twice daily for two weeks. The authors used hierarchical regression to model the association between reported odor and sIgA; study participants were their own controls. The natural log of slgA concentration and secretion rate declined, on average, 0.058 (0.032) and 0.116 (0.103), respectively, for each incremental 1-unit increase in reported odor from 4 to 9, adjusted for time of day, suggesting reduced levels of sIgA in response to moderate or high odor. Findings support the hypothesized immunosuppressive effect of malodor on mucosal immunity and provide preliminary data useful in understanding health effects related to malodor from industrial hog farming operations.

Adult↗
PubMed2005

Melanin: dietary mucosal immune modulator from Echinacea and other botanical supplements.

The agents responsible for the therapeutic effects of many botanical supplements have not been established in spite of their popularity. Here we show that melanin is a previously unrecognized immunostimulatory compound that is a major component of botanicals traditionally used to enhance immune function. While melanin is present in commonly consumed vegetables, its specific activity is several orders of magnitude less than melanin extracted from these botanicals. The major reason that this agent has eluded detection is its solvent-specific requirement for extraction/solubility. Melanin activates NF-kappa B in monocytes in vitro through a toll-like receptor 2-dependent process. Ingestion of melanin by mice for four days increases production ex vivo of interferon-gamma by spleen cells and IgA and interleukin-6 by Peyer's patch cells. The identification of this new class of mucosal immune stimulants will allow further characterization of botanical products and advances our understanding of the basis for their traditional use.

Animals↗
PubMed2004

Proximity between 5-HT secreting enteroendocrine cells and lymphocytes in the gut mucosa of rhesus macaques (Macaca mulatta) is suggestive of a role for enterochromaffin cell 5-HT in mucosal immunity.

The involvement of serotonin (5-hydroxytryptamine; 5-HT) in immunoregulation has been well documented. Gut mucosa is a large reservoir of 5-HT most of which is attributed to gut endocrine cells. In this study, we examined the anatomical relationship among 5-HT immunoreactive cells and T and B lymphocytes in the gut mucosa of rhesus monkeys (Macaca mulatta). 5-HT, CD3 and CD20 immunoreactive cells were immunofluorescently labeled and visualized by confocal microscopy. 5-HT immunoreactive cells were primarily found within the epithelium of the intestine and were present at all levels of the gastrointestinal tract. Many 5-HT immunoreactive cells were in contact with, or very close proximity to CD3(+) and CD20(+) lymphocytes. These results provide morphological evidence to suggest interactions between 5-HT secreting enteroendocrine cells and lymphocytes in the gut mucosa. This further supports a possible role of 5-HT in mucosal immune responses.

Animals↗
PubMed2005

The mucosal immune system: from control of inflammation to protection against infections.

The IV meeting of the European Mucosal Immunology Group, held October 8-10, 2004, in Lyon, gathered fundamental and clinical research scientists to discuss the most recent updates on basic and clinical aspects of mucosal immunology. The meeting was focused on innate and acquired immune mechanisms underlying handling and immune recognition of commensals, allergens, and pathogens by the mucosal immune system and its outcome in health and disease as well as for vaccine development. The scientific program featured five topics of growing interest for fundamental research scientists and clinicians, including the role of commensal bacteria in mucosal immunity; function of dendritic cells in infection, inflammation, and tolerance; control of mucosal inflammation by regulatory T cells; novel routes and adjuvants for mucosal vaccines; and mucosal immunity against HIV infection and vaccination strategies.

Animals↗
PubMed2001

RANTES potentiates antigen-specific mucosal immune responses.

RANTES is produced by lymphoid and epithelial cells of the mucosa in response to various external stimuli and is chemotactic for lymphocytes. The role of RANTES in adaptive mucosal immunity has not been studied. To better elucidate the role of this chemokine, we have characterized the effects of RANTES on mucosal and systemic immune responses to nasally coadministered OVA. RANTES enhanced Ag-specific serum Ab responses, inducing predominately anti-OVA IgG2a and IgG3 followed by IgG1 and IgG2b subclass Ab responses. RANTES also increased Ag-specific Ab titers in mucosal secretions and these Ab responses were associated with increased numbers of Ab-forming cells, derived from mucosal and systemic compartments. Splenic and mucosally derived CD4(+) T cells of RANTES-treated mice displayed higher Ag-specific proliferative responses and IFN-gamma, IL-2, IL-5, and IL-6 production than control groups receiving OVA alone. In vitro, RANTES up-regulated the expression of CD28, CD40 ligand, and IL-12R by Ag-activated primary T cells from DO11.10 (OVA-specific TCR-transgenic) mice and by resting T cells in a dose-dependent fashion. These studies suggest that RANTES can enhance mucosal and systemic humoral Ab responses through help provided by Th1- and select Th2-type cytokines as well as through the induction of costimulatory molecule and cytokine receptor expression on T lymphocytes. These effects could serve as a link between the initial innate signals of the host and the adaptive immune system.

Adjuvants, Immunologic↗
PubMed2001

Regulation of mucosal immune responses in effector sites.

In human disease and rodent models, immune responses in the intestinal mucosa can be damaging. Damage is characterised by villus atrophy, crypt hyperplasia and reduced ability to digest and absorb nutrients. In normal individuals active responses to harmless environmental antigens associated with food and commensal bacteria are controlled by the development of immunological tolerance. Similar pathological changes occur in piglets weaned early from their mothers. Active immune responses to food antigens are observed in these piglets, and we and others have hypothesised that the changes occur as a result of transient allergic immune responses to novel food or bacteria antigens. The normal mechanism for producing tolerance to food antigens may operate at induction (Peyer's patches and mesenteric lymph nodes) or at the effector stage (intestinal lamina propria). In our piglet studies immunological tolerance occurs despite the initial active response. Together with evidence from rodents, this observation suggests that active responses are likely to be controlled at the effector stage, within the intestinal lamina propria. Support for this mechanism comes from the observation that human and pig intestinal T-cells are susceptible to apoptosis, and that this process is accelerated by antigen. We suggest that the role of the normal mature intestinal lamina propria is a balance between immunological effector and regulatory function. In neonatal animals this balance develops slowly and is dependant on contact with antigen. Immunological insults such as weaning may tip the balance of the developing mucosal immune system into excessive effector or regulatory function resulting in transient or chronic allergy or disease susceptibility.

Animals↗
PubMed1992

The role of the mucosal immune system in inflammatory bowel disease.

Continued delineation of the major factors that lead to intestinal inflammation will provide critical insights into many of the pathophysiologic events leading to tissue destruction in IBD. The exploration of exciting and important new areas, such as the role of adhesion molecules, proinflammatory cytokines, and the activation of lymphocytes and phagocytes, will contribute significantly to a better understanding of the mechanisms that sustain the intestinal inflammatory process. Determining the mechanisms of amplification and perpetuation of intestinal inflammation as well as learning more about the natural suppression of intestinal inflammation by the normal cellular and cytokine networks of the mucosal immune system will open exciting new therapeutic approaches. It is encouraging to see realistic and testable working models emerge from the combined efforts of many committed investigators who have been engaged in studying the role of the mucosal immune system in the pathophysiology of IBD. A great deal more remains to be learned in this rapidly advancing area, and we can look forward with confidence to continued advances in the study of IBD.

Antibody Formation↗
PubMed2001

Nasal or intramuscular immunization of mice with influenza subunit antigen and the B subunit of Escherichia coli heat-labile toxin induces IgA- or IgG-mediated protective mucosal immunity.

Local mucosal IgA antibodies play a central role in protection of the respiratory tract against influenza virus infection. Therefore, new-generation influenza vaccines should aim at stimulating not only systemic, but also local antibody responses. Previously, we demonstrated that the recombinant B subunit of the Escherichia coli heat-labile toxin (LTB) is a potent adjuvant towards nasally administered influenza subunit antigen. Here, we investigated the protection conferred by LTB-supplemented influenza subunit antigen given intranasally (i.n.) or intramuscularly (i.m.) to mice. Both i.n. and i.m. immunization with subunit antigen and LTB completely protected the animals against viral infection. Protection upon i.n. immunization was associated with the induction of antigen-specific serum IgG and mucosal IgA, whereas protection upon i.m. immunization correlated with strong serum and mucosal IgG, but not IgA responses. We conclude that LTB-supplemented influenza subunit antigen, given either i.n. or i.m, induces protective antibody-mediated mucosal immunity and thus represents a promising novel flu vaccine candidate.

Adjuvants, Immunologic↗
PubMed2006

Mucosal immunization against hepatitis A: antibody responses are enhanced by co-administration of synthetic oligodeoxynucleotides and a novel cationic lipid.

Hepatitis A caused by hepatitis A virus (HAV) transmitted by the fecal-oral route, results in considerable morbidity and economic loss. Mucosal immunization can be more effective than conventional injection at inducing both local and systemic immunity to HAV. Here we show that co-administration of killed HAV with synthetic oligodeoxynucleotides (ODNs) containing CpG sequences, and a novel polycationic sphingolipid (CCS)/cholesterol liposomal delivery system, markedly enhances the HAV-specific antibody response at the intestinal interface, particularly when delivered intrarectally or intranasally, to Balb/c mice at low HAV doses. A mucosally delivered, antigen-sparing HAV vaccine that is easily administered without specialized equipment or personnel, is an attractive alternative for facilitating mass immunization in hepatitis A outbreaks.

Adjuvants, Immunologic↗
PubMed2000

Activation of intestinal mucosal immunity in tumor-bearing mice by lactoferrin.

We have previously demonstrated that oral administration of bovine lactoferrin (bLF) markedly increases CD4(+) and CD8(+) T cells and NK (asialoGM1(+) ) cells in the blood of tumor-bearing mice and enhances anti-metastatic activity. In this paper, we document that oral administration of bLF and bLF-hydrolysate (bLFH) is associated with strong increases in CD4(+) and CD8(+) T, as well as asialoGM1(+) cells in lymphoid tissues and lamina propria of the small intestine in mice, especially in tumor-bearing animals in which Co26Lu cells were implanted subcutaneously. Moreover, IgM(+) and IgA(+) B cells in lamina propria of the small intestine were also significantly increased by bLF and bLFH. Bovine apo-transferrin (bTF) did not exhibit such activity. In the colon, only CD8(+) cells were significantly increased by treatment with bLF, while asialoGM1(+) cells were significantly decreased. bLF and bLFH induced cytokines to activate T, B and asialoGM1(+) cells. Administration of bLF and bLFH, but not bTF, increased production of interleukin-18 (IL-18), interferon-gamma (IFN-gamma) and caspase-1 in the mucosa of the small intestine. Particularly high levels of IL-18 were found in the epithelial cells of the small intestine. Moreover, administration of bLF and bLFH, but not bTF, induced IFN-gamma presenting cells in the small intestine. Caspase-1, which processes proIL-18 to mature IL-18, was also induced in the epithelial cells of the small intestine following treatment with bLF and bLFH, but not with bTF. These results suggest that enhanced production of IL-18 and IFN-gamma and caspase-1 induction by treatment with bLF may be important for elevation of intestinal mucosal immunity.

Administration, Oral↗