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PubMed1997

An in vitro model to assess mucosal immune function and bacterial translocation.

The importance of secretory immunoglobulin A (IgA) on intestinal barrier function has gained increasing acceptance. However, due to the complexity of the intestinal microenvironment, the relative role of secretory IgA (sIgA) in mucosal defense has been difficult to study in vivo. Polarized Madin-Darby canine kidney (MDCK) epithelial cells expressing the complementary DNA (cDNA) for the polymeric Ig receptor were grown as monolayers in an in vitro two-chamber cell culture system to study the impact of sIgA on bacterial translocation (BT). Polymeric sIgA or media alone was added to the apical chambers of cell monolayers followed by apical inoculation with bacteria. The basal compartment was sampled at timed intervals thereafter to determine BT. Bacterial passage across the MDCK epithelial cell monolayers occurred in a time and bacterial inoculum concentration gradient. Addition of sIgA led to significant reductions in BT across the epithelial cell monolayers. This is a useful model for further investigation on the role of sIgA in intestinal barrier function.

Animals↗
PubMed2003

Mucosal immunization with PLGA-microencapsulated DNA primes a SIV-specific CTL response revealed by boosting with cognate recombinant modified vaccinia virus Ankara.

Systemically administered DNA encoding a recombinant human immunodeficiency virus (HIV) derived immunogen effectively primes a cytotoxic T lymphocyte (CTL) response in macaques. In this further pilot study we have evaluated mucosal delivery of DNA as an alternative priming strategy. Plasmid DNA, pTH.HW, encoding a multi-CTL epitope gene, was incorporated into poly(D,L-lactic-co-glycolic acid) microparticles of less than 10 microm in diameter. Five intrarectal immunizations failed to stimulate a circulating vaccine-specific CTL response in 2 Mamu-A*01(+) rhesus macaques. However, 1 week after intradermal immunization with a cognate modified vaccinia virus Ankara vaccine MVA.HW, CTL responses were detected in both animals that persisted until analysis postmortem, 12 weeks after the final boost. In contrast, a weaker and less durable response was seen in an animal vaccinated with the MVA construct alone. Analysis of lymphoid tissues revealed a disseminated CTL response in peripheral and regional lymph nodes but not the spleen of both mucosally primed animals.

AIDS Vaccines↗
PubMed1992

Liposomes and conjugate vaccines for antigen delivery and induction of mucosal immune responses.

In this brief review, emphasis was placed on the effectiveness of liposomes as carriers/vehicles of soluble antigens and as adjuvants for use in oral vaccine development. Evidence was provided that oral administration of antigen in liposomes resulted in a mucosal response which was higher than that obtained when the oral vaccine consisted of antigen alone. Specific mucosal responses were enhanced by incorporating lipophilic MDP into the antigen/liposome vaccines. Antigens shown to be effective in inducing a protective mucosal response when given in an oral liposome vaccine were anti-idiotypic antibodies, purified S. mutans GTF, CHO and Ag I/II. Evidence is also provided that CTB may be an effective oral adjuvant when coupled to proteins or peptides by either chemical or genetic methods. Further studies, however, will be required to characterize the effectiveness and safety of CTB in conjugate vaccines for inducing specific mucosal responses and to develop practical means to prepare oral liposome vaccines for use in humans.

Animals↗
PubMed2002

Regulation of mucosal immune responses by recombinant interleukin 10 produced by intestinal epithelial cells in mice.

BACKGROUND & AIMS: Interleukin (IL)-10 is a cytokine with anti-inflammatory properties. The aim of this study was to explore the effect of a site-specific delivery of IL-10 on intestinal immune responses. METHODS: Transgenic mice were created in which IL-10 is expressed by the intestinal epithelial cells. RESULTS: Transgenic mice showed a marked increase in the number of intraepithelial lymphocytes in the small intestine. Mucosal lymphocytes of transgenic animals produced fewer T helper type 1 cytokines than wild-type lymphocytes. By contrast, the production of transforming growth factor beta was increased. Moreover, the epithelial layer in transgenic mice was significantly enriched for CD4(+)CD25(+) T cells. Furthermore, transgenic mice had increased numbers of immunoglobulin A-producing B cells in the small intestine. These effects were local because splenic lymphocytes were not affected. Studies in models of inflammatory bowel disease showed that transgenic IL-10 was able to attenuate the acute colitis induced by dextran sodium sulfate administration or by adoptive transfer of CD4(+)CD45RB(high) splenocytes, with a modest effect on the chronic intestinal inflammation arising spontaneously in IL-10(-/-) mice. CONCLUSIONS: These observations provide evidence for an in vivo lymphoepithelial cross talk, by which cytokines locally produced by epithelial cells can regulate immune responses in the intestine without systemic modifications.

Animals↗
PubMed1989

Secretory immunoglobulin A response to Shiga toxin in rabbits: kinetics of the initial mucosal immune response and inhibition of toxicity in vitro and in vivo.

Although the role of Shiga toxin in dysentery is unknown, the toxin is cytotoxic to HeLa cells, causes fluid secretion in rabbit intestine, and is lethal to rabbits and mice when injected parenterally. In the present study, rabbits received three weekly doses of Shiga toxin directly into chronically isolated ileal loops. Within a week, secretions from these loops contained immunoglobulin A (IgA) anti-Shiga toxin. The titer of IgA anti-Shiga toxin increased after weekly doses 2 and 3. Little IgG anti-Shiga toxin was present in loop secretions, although high titers of IgG anti-Shiga toxin were found in the sera. These loop secretions were able to neutralize the cytotoxic effects of Shiga toxin in the HeLa cell assay. The capacity to neutralize the cytotoxicity of the toxin correlated strongly with the IgA anti-Shiga toxin titer in these same secretions. Pooled immune loop secretions were also able to significantly reduce fluid accumulation in acutely ligated loops in rabbits, while loop secretions from control rabbits could not. Shiga toxin elicited a strong secretory IgA response upon application to the intestine. Further, the mucosal antibodies produced functioned to prevent the toxic effects of Shiga toxin both in vitro and in vivo.

Animals↗
PubMed1988

Systemic and mucosal immune responses to rhesus rotavirus vaccine MMU 18006.

Thirty-four children 3 to 20 months of age ingested either 10(5), 10(4) or 10(3) plaque-forming units of rhesus rotavirus vaccine, MMU 18006, which possesses human rotavirus serotype 3 neutralization antigen. Immune responses were evaluated by a plaque reduction neutralization (PRN) assay to rotavirus serotypes 1, 2 and 3 and by a serum IgG, IgM and IgA and fecal IgA class-specific enzyme-linked immunosorbent assay. Homotypic PRN antibody seroconversions to serotype 3 rotavirus were detected in 31 of 34 children (91%), whereas rises in heterotypic PRN antibody to human rotavirus serotypes 1 or 2 were found in only 3 of 21 (14%) (p less than 0.00000001). Thirty of the 34 vaccinated children (88%) had at least one class of rotavirus-specific serum antibody detected by enzyme-linked immunosorbent assay. A rotavirus-specific IgA coproantibody response was seen in 11 of 16 children (69%) following vaccination. Two children who had no evidence of PRN antibody to serotype 3 after vaccination had evidence of both a fecal and a serum rotavirus-specific IgA response, suggesting that in these children the response to the vaccine was primarily mucosal. These data show that orally administered rhesus rotavirus vaccine MMU 18006 elicits local intestinal immunity but produces primarily a homotypic serum neutralization response as measured by plaque reduction neutralization assays.

Antibodies, Viral↗
PubMed1988

Normal flora and mucosal immunity of the head and neck.

The study of the human resident flora has grown from Antony van Leeuwenhoek's simple descriptions some 300 years ago to the sophisticated investigations being done today. The acquisition of organisms and the subsequent course of either stable colonization or invasion of the host involve complex host-parasite interactions. From one perspective, clearly host factors are operative that appear to select against certain species while being permissive for others. From another perspective, microbial species that are successful at colonization must overcome certain host factors to maintain a selective advantage and flourish within a particular body habitat. It is intriguing that whereas host mucosal defenses are a significant influence contributing to selection of the resident flora, it is this established flora that provides the host with perhaps its most important local defense system. In the head and neck areas, many of these mucosal surfaces are contiguous and thus for the most part share a common resident flora. These organisms are rarely involved in infection unless some breach of the mucosal surface or some upset in the balance of the normal flora occurs. On these occasions, the host is susceptible to infection from both newly acquired organisms and those previously present, which may now become invasive. In any event, it is clear that improved knowledge of the normal flora of the head and neck is essential for understanding and for effective treatment of infectious processes in this area. It is hoped that a better appreciation of the important role of the normal flora in maintaining the host mucosal defenses will further focus our attention on its preservation.

Head↗
PubMed2001

Homeostasis of the mucosal immune system: human milk and lactation.

External secretions, including milk, contain large amounts of immunoglobulins (Ig) and innate factors of humoral immunity The Ig isotype distribution, their origin, transport, and absorbability from the gut lumen differ greatly among various species. Milk of primates contains mainly secretory IgA (sIgA) which has unique biological properties. The functional advantages of sIgA compared with other Ig isotypes include its resistance to proteolysis, presence of 4 to 8 antigen-binding sites, carbohydrate moiety-mediated antiadherence properties, and inhibition of complement activation. Although IgA exhibits its protective effect mainly on mucosal surfaces, internalization by cells expressing various IgA receptors suggests additional protective functions.

Animals↗
PubMed1991

Prospective study of systemic and mucosal immune responses in dysenteric patients to specific Shigella invasion plasmid antigens and lipopolysaccharides.

Shigellosis is a major cause of infant morbidity and mortality in developing countries. To find immunological correlates of specific protection against shigellosis, we examined chronological samples of sera, stool extracts, duodenal aspirates, and saliva samples from 39 adults and 22 children with shigellosis from Peru for the presence of specific antibody to invasion plasmid antigens (Ipa) common to all virulent Shigella strains, by using both a whole-organism enzyme-linked immunosorbent assay (ELISA) and a Western blot (immunoblot) assay. Antibody responses to lipopolysaccharide (LPS) from Shigella serotypes both homologous and heterologous to the infecting strain were also determined by ELISA. ELISAs showed that the highest serum immunoglobulin G (IgG) antibody titers to Shigella whole organisms both with and without surface Ipa were found in adults and malnourished children, the two groups with the shortest and longest durations of disease, respectively. Mucosal IgA antibody titers to Shigella strains decreased over time to a much greater extent than serum IgG titers, and IgA to Ipa in mucosal secretions was found in adults and well-nourished children but not in malnourished children. The presence of mucosal antibody to Ipa may limit the spread and severity of the infection, as indicated by the prolonged illness observed in malnourished children who have no significant mucosal antibody to Shigella Ipa. Serum antibody titers to the Ipa antigens were high relative to anti-Shigella LPS antibody titers, especially in pediatric patients. In contrast to the anti-Ipa responses observed, no differences in antibody responses to LPS in children compared by nutritional status were found. High levels of serum and mucosal cross-reacting antibody to heterologous serotype LPS were found between Shigella flexneri serotypes 1a and 2a. Different patterns of immune response to Ipa proteins and LPS that may aid in the definition of Shigella antigens important in host protection were observed in adults, well-nourished children, and malnourished children.

Adult↗
PubMed1990

Whole cholera toxin and B subunit act synergistically as an adjuvant for the mucosal immune response of mice to keyhole limpet haemocyanin.

Cholera toxin (CT) is a potent stimulator of IgA responses when administered orally and has been shown to promote IgA responses to a second protein such as keyhole limpet haemocyanin (KLH) if this is fed simultaneously. In this paper we show that whilst feeding 5 mg KLH with either 0.5 micrograms CT or 10 micrograms B subunit fails to stimulate a mucosal IgA response to KLH, feeding 0.5 microgram CT and 10 micrograms B subunit together with 5 mg KLH produces a local IgA anti-KLH response as great as that produced by 10 micrograms of whole CT. In addition to stimulating IgA responses in the lamina propria, preliminary results indicate that cellular responses are also stimulated, as we have demonstrated KLH antigen-driven proliferation of cells isolated from groups of mice fed either 10 micrograms CT + 5 mg KLH or 0.5 micrograms CT + 10 micrograms CTB + 5 mg KLH but not mice fed KLH alone or with either 10 micrograms CTB or 0.5 micrograms CT. These results indicate that the mucosal adjuvant action of CT is due to a synergistic effect involving both the GM1 binding of the B subunit and adenylate cyclase activation by the A subunit.

Adenylyl Cyclases↗
PubMed1998

Increased intestinal permeability and altered mucosal immunity in cholestatic jaundice.

OBJECTIVE: To examine the effects of cholestatic jaundice on gut barrier function. SUMMARY BACKGROUND DATA: Gut barrier failure occurs in animal models of jaundice. In humans, the presence of endotoxemia indirectly implicates failure of this host defense, but this has not previously been investigated in jaundiced patients. METHODS: Twenty-seven patients with extrahepatic obstructive jaundice and 27 nonicteric subjects were studied. Intestinal permeability was measured using the lactulose-mannitol test. Small intestinal morphology and the presence of mucosal immunologic activation were examined in endoscopic biopsies of the second part of the duodenum. Systemic antiendotoxin core IgG antibodies and serum interleukin-6 and C-reactive protein were also quantified. Intestinal permeability was remeasured in 9 patients 5 weeks after internal biliary drainage. RESULTS: The median lactulose-mannitol ratio was significantly increased in the jaundiced patients. This was accompanied by upregulation of HLA-DR expression on enterocytes and gut-associated lymphoid tissue, suggesting immune activation. A significant increase in the acute phase response and circulating antiendotoxin core antibodies was also observed in the jaundiced patients. After internal biliary drainage, intestinal permeability returned toward normal levels. CONCLUSIONS: A reversible impairment in gut barrier function occurs in patients with cholestatic jaundice. Increased intestinal permeability is associated with local immune cell and enterocyte activation. In view of the role of gut defenses in the modern paradigm of sepsis, these data may directly identify an important underlying mechanism contributing to the high risk of sepsis in jaundiced patients.

Acute-Phase Reaction↗
PubMed1978

Concept of the local and common mucosal immune response.

The available information concerning the origin of IgA-producing plasma cells and the spectrum of IgA-associated antibodies found in external secretions provide arguments that support two pathways of stimulation for a secretory humoral immune response. In addition to an explicitly local immune response induced by a topical antigen application, a second mechanism of induction operating through the sensitization of GALT, and possibly BALT, emerges. The latter pathway of stimulation leads to the appearance of specific IgA-associated antibodies in secretions of mammary, salivary, and lacrymal glands (and perhaps other sites), all of which suggests the existence of a common mucosal secretory system. Not yet explained are the mechanisms involved in the homing to secretory glands of cells sensitized in the remote lymphoid tissues (GALT and BALT), the differentiation patterns of these cells, and the regulation of selective IgA expression.

Animals↗
PubMed2006

Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation.

The gastrointestinal (GI) tract is the main interface where the body encounters exogenous antigens. It is crucial that the local response here is tightly regulated to avoid an immune reaction against dietary antigens and commensal flora while still mounting an efficient defense against pathogens. Faults in establishing intestinal tolerance can lead to disease, inducing local and often also systemic inflammation. Studies in human as well as in animal models suggest a role for regulatory T cells (Tregs) in maintaining intestinal homeostasis. Transfer of Tregs can not only prevent the development of colitis in animal models but also cure established disease, acting both systemically and at the site of inflammation. In this review, we discuss the major regulatory pathways, including transforming growth factor-beta (TGF-beta), interleukin-10 (IL-10), and cytotoxic T-lymphocyte antigen-4 (CTLA-4), and their role in Treg-mediated control of systemic and mucosal responses. In addition, we give an overview of the known mechanisms of lymphocyte migration to the intestine and discuss how CD103 expression can influence the balance between regulatory and effector T cells. Further understanding of the factors that control the activity of Tregs in different immune compartments may facilitate the design of strategies to target regulation in a tissue-specific way.

Animals↗
PubMed1992

Effects of IL6 on B cells in mucosal immune response and inflammation.

Freshly isolated surface IgA+ (sIgA+) B cells from human gut-associated lymphoreticular tissues (GALT), e.g. the appendix, express high levels of IL6 receptor (IL6R) and respond to IL6 with significant increases in the number of IgA-secreting cells. On the other hand, neither sIgM+ nor sIgG+ B cells from appendix express IL6R. When the effect of IL6 on IgA subclass antibody synthesis was examined, the numbers of both IgA1- and IgA2-producing cells were increased upon incubation of GALT B cells with IL6; however, 60-70% of IgA-secreting cells were IgA2 subclass. Aberrant local production of IL6 can contribute to increased B-cell responses that occur in mucosal inflammation such as gingiva of patients with adult periodontitis (AP). When gingival mononuclear cells (GMC) isolated from AP patients were cultured without any stimulus, GMC spontaneously produced biologically active IL6 which induced peripheral blood mononuclear cells (PBMC) from the same patients to become IgG- and IgA-producing cells. Further, mRNA extracted from GMC possessed high message for IL6. When the expression of IL6R was compared between GMC and PBMC isolated from AP patients, IL6R-bearing cells were only seen in the former population. Thus, a high production of IL6, which have the ability to regulate later stages of IL6R+ B-cell development and to induce them to become Ig-secreting plasma cells and to support plasmacytoma growth, are important immunopathological elements for the induction of the increased B-cell response region in inflamed mucosal tissues.

Appendix↗
PubMed2000

Mucosal immunity and primary biliary cirrhosis: presence of antimitochondrial antibodies in urine.

We have shown that IgA-class antimitochondrial autoantibodies (AMA) can be detected in the bile and saliva of patients with PBC, suggesting that AMA are secreted into the luminal fluid across bile ducts and salivary glands. These data prompted us to determine whether AMA of the IgA isotype may be transported across other epithelial mucosa. Therefore, we tested for the presence of AMA in the urine specimens of 83 patients with PBC and 58 non-PBC controls including healthy individuals and patients with other liver diseases. Patients enrolled in this study had no history of renal disease, and we confirmed there was less than 50 microgram/mL of protein in each of the urine specimens. Interestingly, we found that AMA were present in the urine of 71/83 (86%) of all patients with PBC and in 71/78 (91%) of patients with PBC that were serum AMA positive. In contrast, AMA were not detected in any of the 58 control urine specimens. Of particular interest, AMA of the IgA isotype was present in 57/83 (69%) of patients with PBC, and in 52 of these 57, we found secretory-type IgA. In a nested random subgroup of urine samples, the prevalence of the IgA2 AMA was 6/18 (33%), significantly lower than in matched serum samples, 13/16 (81%, P =.007). These data show that AMA of the IgA isotype is secreted into urine from the uroepithelium of patients with PBC, and support the thesis that PBC originated from either a mucosal challenge or a loss of mucosal tolerance.

Autoantibodies↗
PubMed2000

Social class, sex, and age differences in mucosal immunity in a large community sample.

There have been very few reports addressing levels and distribution of commonly used PNI measures in large community samples. In this study, we report such data for secretion rates of secretory immunoglobulin A (sIgA), as determined from saliva samples taken from 1971 subjects interviewed as part of the West of Scotland Twenty-07 survey of health in West Central Scotland. Univariate analyses of demographic variables found lower sIgA and salivary flow to be significantly related to poorer social class, increased age, and being female. Smokers also had lower sIgA but not lower salivary flow. Multivariate analysis showed that demographic variables were significant predictors of sIgA independently of each other and assay variation. Adding smoking status to the equation confirmed it as an independent predictor and also indicated that social class differences in sIgA are partly explicable in terms of smoking status. In view of reported associations between sIgA levels and stress, its role as a first line of mucosal defense, and its relevance to health, these first results from a large survey are of interest. Further work is now needed to explore which factors, including psychosocial ones, may be contributing to subgroup differences.

Adolescent↗
PubMed1988

Modulation of systemic and mucosal immune responses to inhaled ragweed antigen in experimentally induced infection with respiratory syncytial virus implication in virally induced allergy.

Groups of BALB/c mice were either sham-infected or infected intranasally with respiratory syncytial virus (RSV). On the third day following intranasal inoculation, all groups of mice were exposed by inhalation to ragweed antigen for 5 consecutive days and rechallenged with ragweed on day 31. Development of antibody activity to ragweed antigen was examined in serum and bronchial washings at regular intervals employing an ELISA assay for IgG and IgA antibody activity and passive cutaneous anaphylaxis for IgE-specific responses. The serum IgG and IgE antibody response to ragweed following primary exposure developed at significantly higher levels in mice previously infected with RSV, compared to sham-infected controls. In addition, an earlier rise in serum IgE response to ragweed occurred in the RSV-infected animals. IgG and IgA anti-ragweed antibody activity in bronchial washings was also observed with significantly higher levels in the RSV-infected animals when compared to the controls, although a similar increase in antigen-specific IgE activity in bronchial washings was found in both groups of animals. These findings support the possibility that mucosally restricted virus infections of the respiratory tract may enhance the development of sensitization and the magnitude of antibody responses to other inhaled allergens found concomitantly in the respiratory tract during acute infection.

Administration, Inhalation↗
PubMed1996

Direct assessment of gastrointestinal inflammation and mucosal immunity in children with cystic fibrosis.

Fibrosing colonopathy is a recently described complication of cystic fibrosis, of unknown aetiology but possibly related to treatment with high-dose pancreatic enzyme supplements. We have used a whole gut perfusion technique to study subclinical gut inflammation in cystic fibrosis patients; concentrations of haemoglobin, IgG, albumin, alpha-1-antitrypsin, granulocyte elastase, IL1 beta, and IL8 were measured in whole gut lavage fluid: 23 tests were performed in 17 children with cystic fibrosis (20 elective tests, three lavages to treat distal intestinal obstruction syndrome (DIOS)). None has had fibrosing or haemorrhagic colitis. There were 12 tests in control children with constipation or precolonoscopy. Moderately abnormal results were obtained for many of the parameters studied, in specimens from all the cystic fibrosis children; however there were no significant differences between tests on high-dose and low-dose enzyme supplements of the same brand in the five children who had duplicate tests performed electively. The lavage fluid specimens from two cystic fibrosis children were strikingly abnormal in all tests apart from haemoglobin and alpha-1-antitrypsin. These were two of the three children with DIOS, and were also the only cases in the series taking Nutrizym 22. These data suggest that the majority of cystic fibrosis children, including those on high-dose enzyme supplements, do not have clinically significant colitis, but that there is subclinical mucosal inflammation in a minority (two of 17 in this series), for which DIOS and/or Nutrizym 22 treatment may be risk factors. Alternatively, inflammation and dysmotility in the proximal colon may be directly produced by a drug or other agent, producing a clinical syndrome indistinguishable from DIOS. Tests for indices of inflammation in gut lavage fluid offer a new approach to the detection and measurement of iatrogenic intestinal and colonic injury.

Adolescent↗