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PubMed1997

Class I-restricted CTL induction by mucosal immunization with naked DNA encoding measles virus haemagglutinin.

We have investigated the class I-restricted CTL response specific for measles virus haemagglutinin (HA) in the spleens of mice immunized by various mucosal routes with a DNA plasmid carrying the HA gene (pV1j-HA). A single immunization with recombinant DNA injected in the buccal mucosa induced an HA-specific CTL response. Similarly, nasal immunization with the DNA vaccine induced primary CTLs against measles virus HA. Booster immunization did not enhance the CTL activity. Oral or intrajejunal immunization with the plasmid induced a CTL response of lower magnitude. However, this could be potentiated by co-administration of the mucosal adjuvant cholera toxin or cationic lipids (DOTAP). These data show that a CTL response can be generated by mucosal vaccination using DNA vaccines.

Animals↗
PubMed1999

Hemorrhagic shock impairs mucosal immunity to gut-derived antigens.

Secretory immunoglobulin A (sIgA) is the principal antibody protecting against pathogens in the respiratory tract and other mucosal surfaces. Nosocomial pneumonias are frequent after injury and critical illness and are often due to enteric pathogens. The aim of this study was to assess the relative effect of hemorrhagic shock (HS) on mucosal immunity at intestinal and respiratory mucosal sites. Fisher rats were immunized intragastrically with dinitrophenylated (DNP) Pneumococcus (Pn). Three weeks later, animals were subjected to sham treatment or HS. The animals were then rechallenged with DNP-Pn 1 or 3 days later. Animals were sacrificed 7 days later, and bronchoalveolar and gastric lavage was performed. Total and anti-DNP-specific sIgA were quantitated from these secretions by enzyme-linked immunosorbent assay. There was a significant decrease in DNP-Pn-specific sIgA at 72 hours after HS, which was not present in animals at 24 hours after HS. This was most profound in bronchoalveolar lavage specimens. We conclude that impaired mucosal defense against gut-derived antigens after HS may be important mechanistically for the development of posttraumatic pneumonia and other mucosally related infectious complications.

Animals↗
PubMed2003

[Specific mucosal immunity in the female reproductive tract: protection against infectious diseases and regulation of fertility (part 2)].

Immune mediated defense against pathogenic microorganisms and maintenance of immune tolerance to allogeneic antigens of sperm and fetus are main function of female reproductive tract mucosal immune system. Specific mechanisms concerning development of mucosal vaccines to sexually transmitted diseases and the immune regulation of fertility are reviewed in this article.

Animals↗
PubMed1986

Duct-associated lymphoid tissue (DALT) of minor salivary glands and mucosal immunity.

Minor salivary glands (MSG) play a substantial role in the secretory immunoglobulin A (sIgA)-mediated immunity of the oral cavity. There are two possibilities for the induction of this immunity: (i) an explicitly local antigenic stimulus, or (ii) a remote stimulus as part of the so-called 'common mucosal immune system'. This communication is an attempt to consolidate available evidence in support of both possibilities and to address the former in detail. Although there is strong circumstantial evidence supporting the feasibility of MSG functioning as a part of the common mucosal immune system, direct experimental evidence is yet to emerge. On the other hand, there is increasing structural and physiological evidence in support of MSG serving as a local immunological organ. The purely local response is attributed to the presence of MSG duct-associated lymphoid tissue (DALT), which is comparable to gut- or bronchial-associated lymphoid tissue (GALT or BALT) in origin, tissue organization and function. DALT is accessible to oral antigens by retrograde passage through MSG ducts. Repeated topical antigenic challenging via the oral mucosa may result in the appearance of interacinar plasma cells carrying specific homologous antibodies in MSG. Gut or enteric priming of the same antigen, by passing the oral mucosa by gastric intubation, need not evoke a remote immune response in MSG. Since DALT is more likely to occur in healthy, young growing individuals, who are less likely to undergo bioptic examination of MSG, it has not yet been documented in humans. The physiologically induced DALT is apt to be confused with focal accumulations of lymphoid tissue in pathologically altered MSG, as a consequence of local and some systemic autoimmune diseases. An attempt is made to demarcaate healthy and pathological MSG on the basis of currently available clinical, serological, immunological and genetic evidence.

Aging↗
PubMed1991

Ontogeny of the mucosal immune system and IgA deficiency.

Studies of ontogenesis contribute to better understanding of regulatory events underlying the striking heterogeneity in B-cell differentiation pathways employed in the human mucosal immune system. This disparity is probably explained by exogenous environmental factors, although regional differences probably also exist in accessory cells and cytokines involved in local immune responses. IgA deficiency signifies a heterogeneous syndrome but is basically a manifestation of a defect in B-cell differentiation. The immaturity of the IgA system revealed in this disorder bears a striking resemblance to that seen in newborn infants. It may therefore be worthwhile to consider IgA deficiency in relation to the ontogeny of mucosal immunity.

Breast Feeding↗
PubMed2004

Intranasal immunization with outer membrane protein P6 and cholera toxin induces specific sinus mucosal immunity and enhances sinus clearance of nontypeable Haemophilus influenzae.

Nontypeable Haemophilus influenzae (NTHi) is one of the leading pathogens in sinusitis. One of the outer membrane proteins of NTHi, P6, is a common antigen to all strains and is an attractive candidate for a subunit bacterial vaccine. In this study, we characterized normal sinus mucosa (SM) and investigated the potential of intranasal immunization with P6 and cholera toxin (CT) for induction of mucosal protective immunity against NTHi in the maxillary sinuses of rats. Intranasal immunization induced P6-specific sinus mucosal and systemic immunological responses, mainly of the IgA and IgG isotype. The protective effect of intranasal immunization was demonstrated by enhancement of sinus clearance of NTHi. The present study showed that unilateral intranasal immunization has a capacity to induce protective immunity against NTHi in the bilateral maxillary sinuses. Systemic administration of the vaccine did not affect sinus clearance of NTHi. These findings suggest that a nasal vaccine might be useful for preventing sinusitis.

Administration, Intranasal↗
PubMed1994

Exploration of mucosal immunity in humans: relevance to vaccine development.

Although the immune system is remarkably diverse, there is evidence that certain types of immune responses take place and are restricted to certain anatomic locations within the body. The concept of a common mucosal immune system that provides immune reactivity not only at the site of antigen deposition but also at remote mucosal sites may be explained by the utilization of organ-specific recognition molecules by circulating precursors of mucosal immunoblasts and by the production of certain maturation factors (e.g. cytokines, hormones) produced preferentially in certain organs or parts of a given organ. This notion may explain the unification of immune responses in diverse mucosal sites and the physiologic segregation of mucosal from systemic immune mechanisms. Novel methods have been developed to enable studies of antigen specific B and T cell responses in various mucosal and extramucosal tissues in primates and rodents, using cholera toxin or its B subunit as prototype immunogens and mucosal carrier-delivery systems. The tissue localization and isotype commitment of antibody-secreting cells (ASC) and the homing potential of their circulating precursors have also been examined after oral, nasal, intra-tonsillar, rectal and/or genital immunization(s). The anatomical distribution of T- and accessory cell-derived cytokines has also been examined. These tools and approaches are being employed in studies attempting to induce optimal mucosal immune responses to several mucosal pathogens including HIV-1, in certain organs such as the lower gastrointestinal tract and the female urogenital tract.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2003

Maintaining mucosal immunity during parenteral feeding with surrogates to enteral nutrition.

Pneumonia and intra-abdominal abscesses are significantly lower in trauma patients receiving enteral feeding compared with those receiving parenteral feeding. Extensive experimental evidence suggests that this is related to maintenance of the mucosal-associated lymphoid tissue, which provides immunologic protection for both the gastrointestinal and respiratory tracts against microbial flora and infectious pathogens. This system is exquisitely sensitive to the route and type of nutrition delivery that affects its functional effectiveness. Although parenteral nutrition decreases the effectiveness of this extraintestinal mucosal immunity, specialty nutrients like glutamine and neuropeptides such as gastrin-releasing peptide and cholecystokinin are capable of preventing some of the immune defects associated with parenteral nutrition. This review examines the mechanisms associated with the mucosal immunity and role of both glutamine and neuropeptides in normalizing defects induced by parenteral feeding. Based upon evolving data, specific nutrients and products of the enteric nervous system show promise as adjuncts to parenteral feeding that are capable of maintaining immune function in patients unable to be fed via the gastrointestinal tract.

Journal Article↗
PubMed2000

Unique characteristics of lacrimal glands as a part of mucosal immune network: high frequency of IgA-committed B-1 cells and NK1.1+ alphabeta T cells.

PURPOSE: Immunologic characterization of IgA-committed B-1 and B-2 cells, and unique subsets of T cells isolated from the murine lacrimal gland (LG), the primary exocrine tissue for the ocular surface, which is considered to be a part of the mucosal immune system. METHODS: Single cells were obtained from LGs of C57BL/6 mice by the enzyme dissociation method using collagenase type IV. Samples underwent flow cytometric analysis to characterize the unique subsets of T and B cells. To test the effectiveness of ocular vaccination, mice were immunized ocularly or nasally with cholera toxin (CT; 10 microg/mouse) suspended in phosphate-buffered saline. Antigen-specific immune responses were determined by isotype and CT-specific enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunospot (ELISPOT) assay. RESULTS: When mononuclear cells (MC) isolated from LG samples were examined by flow cytometry, approximately 28% of cells were characterized as B220+ B cells. Because surface IgA+ (sIgA+) B cells develop from B-1 and B-2 lineages, it was important to examine which subset of B cells gives rise to LG sIgA+ B cells. Examination of the MC isolated from LG samples showed that approximately 4% of cells were sIgA+ B cells. Furthermore, nearly all these sIgA+ B cells (97.5%) belonged to the B-1 lineage, especially the B-1a cell line (B220low, CD5+). Of the isolated CD3+ T cells, 75% were alpha(beta) and 25% were gamma(delta)T-cell receptor positive. The proportion of NK1.1+ alpha(beta) T cells was higher (3%) in LG samples than in submandibular gland samples (0.5%). Ocular immunization with CT-induced antigen-specific mucosal (e.g., found in tear-wash and saliva samples) and systemic (e.g., serum) immune responses. The magnitude of antigen-specific antibody responses was comparable to those induced by nasal immunization. CONCLUSIONS: These results show that LG contains unique subsets of B (e.g., sIgA+ B-1 cells) and T (e.g., NK1.1+ alpha(beta)T cells) cells. Furthermore, as a part of the mucosal immune barrier, the LG is an important immunologic tissue for the ocular surface.

Animals↗
PubMed2004

In vivo effects of bifidobacteria and lactoferrin on gut endotoxin concentration and mucosal immunity in Balb/c mice.

The aim of the present study was to examine the effects of oral supplementation of newborn Balb/c mice with bifidobacteria (B. infantis, B. bifidum) and iron-free apo-lactoferrin (bovine, human) on gut endotoxin concentration and mucosal immunity. Endotoxin concentration was measured in ileocecal filtrates at 7, 14, 21, and 28 days postdelivery by a quantitative limulus amebocyte lysate test. While endotoxin levels in bifidobacteria-fed mice showed a steady rise over time, they were consistently lower than that observed in control animals. Results of lactoferrin supplementation varied depending on the specific time point, but overall by day 28, all treatment groups showed lower intestinal endotoxin concentrations compared to saline fed animals. Neither bifidobacteria nor lactoferrin stimulated an increase in B or T cells, or in cytokine production (IL-6, TNF-alpha, INF-gamma), in Peyer's patches as measured by flow cytometry. Bifidobacteria and lactoferrin were well tolerated as dietary supplements and showed promising potential to reduce gut endotoxin levels.

Administration, Oral↗
PubMed2005

Mucosa-associated lymphoid tissues in the aerodigestive tract: their shared and divergent traits and their importance to the orchestration of the mucosal immune system.

As inductive tissues for the initiation of antigen-specific T and B cell responses, the various mucosa-associated lymphoid tissues (MALT) of the aerodigestive tract, which include gut-associated lymphoid tissue (GALT), nasopharynx-associated lymphoid tissue (NALT) and bronchus-associated lymphoid tissue (BALT), share many histological and immunological characteristics. However, recent advances in our molecular and cellular understanding of immunological development have revealed that the various types of MALT also exhibit different molecular and cellular interactions for their organogenesis. In this review, we delineate the distinctive features of GALT, NALT and BALT and seek to show the role played by those features in the regulation of mucosal tissue organogenesis, the mucosal immune system, and mucosal homeostasis, all in an attempt to provide insights which might lead to a prospective mucosal vaccine.

Gastrointestinal Tract↗
PubMed1988

Characterization of the mucosal immune response to dietary antigens in patients with dermatitis herpetiformis.

The association of dermatitis herpetiformis (DH) with granular IgA deposits at the dermal-epidermal junction and a gluten sensitive enteropathy (GSE) suggests that a mucosal immune response may play an important role in the pathogenesis of DH. The degree of antigenic restriction, the immunoglobulin class and subclass response to dietary antigens, and the relationship of antibodies against dietary antigens to IgA-containing circulating immune complexes (CIC) in patients with DH, however, are not known. We have examined the serum of 33 patients with DH for IgG and IgA antibodies against gliadin, and against 3 dietary proteins not thought to be related to GSE, beta-lactoglobulin (beta-lacto), bovine gamma globulin (BGG), and casein. Eleven of 33 (33%) patients with DH had IgA anti-gliadin antibodies, whereas IgA antibodies against beta-lacto were found in 11 of 33 patients (33%), against BGG in 15 of 32 (47%), and against casein in 6 of 33 (18%); 17 of 32 (53%) patients had IgA antibodies against one or more of these dietary antigens. Significantly higher levels of IgA antibodies were detected against beta-lacto (2,500 +/- 2,320 ng/ml, mean +/- SEM) and BGG (2,340 +/- 1,890 ng/ml) than gliadin (1,250 +/- 851 ng/ml) in this group of antibody positive patients (p less than 0.05, Wilcoxon signed ranks test). Eleven of 17 patients with IgA antibodies against dietary antigens were found to have IgA-containing CIC, whereas only one of the 15 antibody negative patients had IgA-containing CIC (p = 0.0008, Fisher's exact test). IgA anti-gliadin antibodies were found to contain both IgA1 and IgA2 with a significantly increased proportion of IgA2 when compared with the IgA2 composition of the total serum IgA (IgA2: anti-gliadin antibodies = 34 +/- 4.2%; total serum IgA = 19 +/- 4.8%, p = 0.02, Students paired t test). IgG antibodies against these antigens were found to occur slightly more frequently in amounts not significantly greater than IgA antibodies. This data demonstrates that a serum IgA and IgG antibody response to dietary antigens occurs in approximately 50% of DH patients with a higher proportion of IgA2 than total serum IgA and does not appear to be restricted to gliadin. This is significantly different from the pattern of cutaneous immunoreactants in patients with DH, and suggests that the deposition of IgA in DH skin may be the result of an atypical mucosal immune response, a non-immunologic interaction of IgA1 and DH skin, or arise from a non-mucosal source.

Antibodies, Anti-Idiotypic↗
PubMed1998

Microbial translocation and impairment of mucosal immunity induced by an elemental diet in rats is prevented by selective decontamination of the digestive tract.

OBJECTIVE: To assess the effect of selective decontamination of the digestive tract (SDD) on intestinal secretory immunoglobulin A (sIgA) concentrations in a model of intestinal bacterial overgrowth and bacterial translocation induced by an elemental diet in rats. DESIGN: Laboratory study. SETTING: University hospital, Germany. MATERIAL: 45 specific pathogen free female Crl:CD(R) BR rats. INTERVENTIONS: For 7 days, 3 groups of rats were fed orally with standard chow (n = 15), total parenteral nutrition solution (ORAL-TPN, n = 15), or ORAL-TPN plus tobramycin (20 mg/L) and polymyxin E (25 mg/L) (ORAL-TPN + SDD). MAIN OUTCOME MEASURES: Bacterial translocation to mesenteric lymph nodes (MLN), numbers of gram negative enterobacteria and total aerobic bacteria in the caecum, and intestinal concentrations of sIgA. RESULTS: The incidence of bacterial translocation was significantly increased in the group given ORAL-TPN (8/15, 53%) compared with the group given chow (1/15, 7%, p < 0.01). Supplementation of ORAL-TPN with SDD reduced translocation to 0/15. The ORAL-TPN group had a pronounced overgrowth of aerobic bacteria in the caecum, mainly by gram negative enterobacteria, which was prevented by the SDD. The concentrations of intestinal sIgA were significantly reduced in the ORAL-TPN group. SDD resulted in both the soluble and insoluble sIgA fractions in the gut being within the reference ranges. CONCLUSION: SDD prevents gram negative caecal overgrowth and translocation to MLN in rodents fed on ORAL-TPN. The significantly reduced mucosal immunity caused by ORAL-TPN alone is restored by SDD, although one might have expected a further reduction in sIgA concentrations with lower microbial populations than in the ORAL-TPN group. Not only does SDD not seem to affect the mucosa associated immune system adversely, but also depressed mucosal immunity was restored.

Administration, Oral↗
PubMed2004

Mucosal immunity in asthma and chronic obstructive pulmonary disease: a role for immunoglobulin A?

Despite our knowledge on the role of IgA in mucosal homeostasis and host defense and clinical evidence suggesting deficient first-line defense mechanisms in chronic airway disorders, little is known regarding its role in asthma and chronic obstructive pulmonary disease (COPD). Studies suggest that the mucosal IgA response is impaired in COPD, and a deficient transport of IgA across the bronchial epithelium in COPD has been identified, possibly involving neutrophil proteinases, which may degrade the Ig receptor mediating this transepithelial routing. In contrast, the IgA response to allergens in patients with asthma may play a pathogenic role through eosinophil activation. Thus, secretory IgA can induce eosinophil degranulation in vitro, a feature in keeping with the correlations observed in vivo between airway IgA levels and eosinophil cationic protein during late asthmatic responses. Selective IgA deficiency is associated with an increased prevalence of atopy, and a protective role of IgA has been seen in murine models of asthma, delineating the complexity of the IgA system in the airway mucosa. Future studies will hopefully yield better knowledge of IgA biology and lung mucosal immunity and help to use more efficiently the mucosal route for immunotherapy or target specific genes in inflamed airways.

Asthma↗
PubMed2003

Deoxynivalenol-induced IgA production and IgA nephropathy-aberrant mucosal immune response with systemic repercussions.

Dietary exposure to the common foodborne mycotoxin deoxynivalenol (DON) selectively upregulates serum immunoglobulin A (IgA) in the mouse, most of which is polymeric, thus suggesting that the mucosal immune system is a primary target. When ingested, DON has no adjuvant or antigen properties but, rather, induces polyclonal IgA synthesis and serum elevation in an isotype-specific fashion. Resultant hyperelevated IgA is polyspecific, autoreactive and is likely to be involved in immune complex formation as well as kidney mesangial deposition. These latter effects mimic IgA nephropathy, the most common human glomerulonephritis. At the cellular level, DON upregulates production of T helper cytokines and enhances T cell help for IgA secretion. Analogous effects are observed in the macrophage with IL-6 being of particular importance based on ex vivo reconstitution and antibody ablation studies as well as experiments with IL-6 deficient mice. Upregulation of cytokines by DON involves both increased transcriptional activation and mRNA stability which are mediated by activation of mitogen-activated protein kinases. Interestingly, dietary omega-3 fatty acids can downregulate these processes and ameliorate DON-induced IgA nephropathy. From the perspective of gut mucosal immunotoxicology, these studies demonstrate that the capacity of a chemical to affect mucosal immune response can have systemic repercussions and, further, that these effects can be modulated by an appropriate nutritional intervention.

Animals↗
PubMed2006

Stimulating effect of Japanese herbal (kampo) medicine, hochuekkito on upper respiratory mucosal immune system.

Japanese herbal (Kampo) medicine, Hochuekkito (Bu-Zhong-Yi-Qi-Tang in Chinese, TJ-41) and Juzentaihoto (Shi-Quan-Da-Bu-Tang in Chinese, TJ-48) are well-known Kampo formulas used as tonic. Although these medicines have separately been applied to the patients clinically depending on their symptoms, the differences of the pharmacological activities for these medicines have not been fully understood. TJ-48 and TJ-41 were compared for their effects on antibody response in upper respiratory mucosal immune system in vivo. Oral administration of TJ-41 (100 mg kg(-1) per day) to early aged BALB/c mice, which were nasally sensitized with influenza hemagglutinin vaccine, significantly enhanced influenza virus-specific IgA and IgG antibody titers in nasal cavity and sera, respectively. However, oral administration of TJ-48 (100 mg kg(-1) per day) failed to show the enhancing activity. TJ-41 increased not only influenza virus-specific IgA antibody titer but also total IgA antibody titer in nasal cavity. The stimulating activity of TJ-41 disappeared after treatment with methotrexate. The present study strongly suggests that TJ-41 can stimulate the mucosal immune system of upper respiratory tract, and results in enhancement of antigen-specific antibody response in upper respiratory mucosal and systemic immune systems.

Journal Article↗
PubMed1997

Nasal lymphoid tissue (NALT) as a mucosal immune inductive site.

Intranasal (i.n.) immunization is a very effective route for inducing mucosal immunity, but the cellular mechanism responsible for regulating and disseminating these responses is not fully understood. The authors studied the role of nasal lymphoid tissue (NALT) as a mucosal inductive site by using highly purified NALT cells obtained by a new method of mechanical isolation. The NALT cells, like Peyer's patch (PP) cells, were smaller in size and less granular than lymphocytes from salivary glands (SG) and small intestinal lamina propria (LP). The NALT cells isolated from i.n. immunized mice contained antigen-specific antibody-secreting cells (ASC) predominantly of immunoglobulin (Ig)A isotype, similar to those also recovered from salivary glands in a time course study. However, the higher proportion of smaller sized sports formed by NALT cells in ELISPOT assays suggested that these cells were less differentiated precursors of those found in salivary glands. This was supported by the fact that after i.n. immunization, IgA ASC appeared in NALT, as well as in mucosal effector sites SG and LP, but none or very few in another mucosal inductive site, PP. In contrast, after intragastric (i.g.) immunization, IgA ASC were detected in PP, along with the SG and LP, but none or very few in NALT. Furthermore, after i.n. immunization, lymphocytes from NALT but not PP proliferated in response to the specific antigen in culture. These findings imply that NALT served as an inductive site for IgA antibody responses at mucosal effector sites.

Administration, Intranasal↗