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PubMed1998

Current concepts in mucosal immunity. I. Antigen presentation in the intestine: new rules and regulations.

The recognition that immune responses in the intestine differ from those seen systemically has led to a search for novel pathways involved in mucosal immunoregulation. One cell type that has surfaced as a prime candidate for such a regulatory role is the intestinal epithelial cell. A number of laboratories have documented that intestinal epithelial cells sample luminal antigens and process and present these to primed T cells. However, several unique features have emerged, making their potential role as antigen-presenting cells a critical part of mucosal homeostasis.

Animals↗
PubMed2001

Impaired mucosal immunity in L-selectin-deficient mice orally immunized with a Salmonella vaccine vector.

Lymphocyte trafficking in the gastrointestinal tract is primarily mediated by interactions with the mucosal addressin cell adhesion molecule 1 and its lymphocyte ligand, alpha(4)beta(7), and partly by L-selectin (L-Sel) interactions with peripheral node addressin coexpressed on some mucosal addressin cell adhesion molecule 1. We inquired whether intestinal responses in mice lacking L-Sel would be enhanced. L-Sel-deficient (L-Sel(-/-)) mice were orally immunized with either Salmonella vaccine vector or Salmonella vector-expressing colonization factor Ag I (CFA/I) from enterotoxigenic Escherichia coli. In L-Sel(-/-) mice, mucosal IgA anti-CFA/I fimbrial responses were greatly reduced, and systemic IgG2a anti-CFA/I fimbrial responses were 26-fold greater compared with C57BL/6 (L-Sel(+/+)) mice. L-Sel(-/-) Peyer's patch (PP) CD4(+) Th cells revealed IFN-gamma-dominated responses and an unprecedented absence of IL-4, whereas the expected mixed Th cell phenotype developed in L-Sel(+/+) mice. PP CD4(+) Th cell anti-Salmonella responses were nearly nonexistent in L-Sel(-/-) mice immunized with either Salmonella vaccine. Splenic CD4(+) Th cell anti-Salmonella responses were reduced but did show cytokine production in Ag restimulation assays. Increased colonization of PP and spleen was noted only with the Salmonella vector in L-Sel(-/-) mice, resulting in increased splenomegaly, suggesting that the Salmonella-CFA/I vaccine was not as infectious or that the presence of the fimbriae improved clearance, possibly because of reduced neutrophil recruitment. However, sufficient anti-Salmonella immunity was induced, because Salmonella vector-immunized L-Sel(-/-) mice showed complete protection against wild-type Salmonella challenge, unlike L-Sel(+/+) mice. This evidence shows that L-Sel is important for development of mucosal immunity, and absence of L-Sel is protective against salmonellosis.

Administration, Oral↗
PubMed1999

Induction of mucosal immunity with a replication-defective adenoviral recombinant.

A replication-defective adenoviral recombinant expressing the rabies virus glycoprotein was tested for induction of transgene specific central and mucosal antibodies upon systemic inoculation or upon application to the mucosa of the airways, the rectum or the female genital tract. Mice developed serum and mucosal antibody titers to rabies virus upon subcutaneous or intranasal immunization with the latter route favoring induction of genital and intestinal secretion of antibodies of the IgA isotype. Immunization through the mucosa of the genital tract or the rectum was inefficient. Mucosal and systemic antibody titers could be increased by intranasal priming followed by a booster immunization with the same construct.

Adenoviruses, Human↗
PubMed2006

Helminths and mucosal immune modulation.

Geographic and ethnic variations in ulcerative colitis and Crohn's disease frequency suggest that environmental factors affect disease risk. Prevention of parasitic worms (helminths) through improved hygiene may be one factor leading to the increased disease prevalence. Helminths alter host mucosal and systemic immunity. Animals exposed to helminths are protected from experimental colitis and other immunological diseases, and helminthic colonization can be used to treat ongoing murine and human disease. Helminths induce mucosal T cells to make Th2 and regulatory cytokines. Helminth-induced mucosal IL4, TGFbeta, and IL10 likely are part of the protective process. Helminths affect pathways of innate immunity like TLR4 expression and function. Worms also induce various regulatory-type T-cell subsets in the gut that limit effector T-cell growth and function. These effects of once ever-present helminths may have protected people from immune-mediated illnesses like inflammatory bowel disease.

Animals↗
PubMed2005

Mucosal immune responses are related to reduction of bacterial colonization in the stomach after therapeutic Helicobacter pylori immunization in mice.

The aim of this study was to investigate the capacity of oral and parenteral therapeutic immunization to reduce the bacterial colonization in the stomach after experimental Helicobacter pylori infection, and to evaluate whether any specific immune responses are related to such reduction. C57BL/6 mice were infected with H. pylori and thereafter immunized with H. pylori lysate either orally together with cholera toxin or intraperitoneally (i.p.) together with alum using immunization protocols that previously have provided prophylactic protection. The effect of the immunizations on H. pylori infection was determined by quantitative culture of H. pylori from the mouse stomach. Mucosal and systemic antibody responses were analyzed by ELISA in saponin extracted gastric tissue and serum, respectively, and mucosal CD4+ T cell responses by an antigen specific proliferation assay. Supernatants from the proliferating CD4+ T cells were analyzed for Th1 and Th2 cytokines. The oral, but not the parenteral therapeutic immunization induced significant decrease in H. pylori colonization compared to control infected mice. The oral immunization resulted in markedly elevated levels of serum IgG+M as well as gastric IgA antibodies against H. pylori antigen and also increased H. pylori specific mucosal CD4+ T cell proliferation with a Th1 cytokine profile. Although the parenteral immunization induced dramatic increases in H. pylori specific serum antibody titers, no increases in mucosal antibody or cellular immune responses were observed after the i.p. immunization compared to control infected mice. These findings suggest that H. pylori specific mucosal immune responses with a Th1 profile may provide therapeutic protection against H. pylori.

Animals↗
PubMed2004

Mucosal immunity and tolerance in the elderly.

Age-associated dysregulation of the immune system of the gastrointestinal (GI) tract has been well documented for both secretory (S)-IgA immunity and oral tolerance. Thus, impaired antigen-specific Ab responses in aged animals and the elderly have been reported. Further, it has been shown that gut-associated lymphoreticular tissue (GALT) mediated immune responses are more susceptible to aging than are lymphoid tissues involved in peripheral immunity. Aging also impairs oral tolerance, which may be of central importance for maintaining GI homeostasis. Thus, as early as 6-8-month-old mice failed to establish systemic unresponsiveness to orally introduced antigens. Despite these studies, the precise mechanisms for impaired GI tract immune system responses remain unclear. The evidence of reduced sizes of Peyer's patches through aging suggests that age-associated mucosal dysregulation may be the result of mucosal inductive tissue dysfunction. Indeed, the frequencies of naive CD4+ T cells and dendritic cells (DCs) in Peyer's patches of aged mice were reduced and this led to a lack of essential cytokine synthesis for the induction of either S-IgA immunity or oral tolerance.

Aging↗
PubMed2001

Mucosal immune responses and protection against tetanus toxin after intranasal immunization with recombinant Lactobacillus plantarum.

The use of live microorganisms as an antigen delivery system is an effective means to elicit local immune responses and thus represents a promising strategy for mucosal vaccination. In this respect, lactic acid bacteria represent an original and attractive approach, as they are safe organisms that are used as food starters and probiotics. To determine whether an immune response could be elicited by intranasal delivery of recombinant lactobacilli, a Lactobacillus plantarum strain of human origin (NCIMB8826) was selected as the expression host. Cytoplasmic production of the 47-kDa fragment C of tetanus toxin (TTFC) was achieved at different levels depending on the plasmid construct. All recombinant strains proved to be immunogenic by the intranasal route in mice and able to elicit very high systemic immunoglobulin G (IgG1, IgG2b, and IgG2a) responses which correlated to the antigen dose. No significant differences in enzyme-linked immunosorbent assay IgG titers were observed when mice were immunized with live or mitomycin C-treated recombinant lactobacilli. Nevertheless, protection against the lethal effect of tetanus toxin was obtained only with the strains producing the highest dose of antigen and was greater following immunization with live bacteria. Significant TTFC-specific mucosal IgA responses were measured in bronchoalveolar lavage fluids, and antigen-specific T-cell responses were detected in cervical lymph nodes, both responses being higher in mice receiving a double dose of bacteria (at a 24-h interval) at each administration. These results demonstrate that recombinant lactobacilli can induce specific humoral (protective) and mucosal antibodies and cellular immune response against protective antigens upon nasal administration.

Administration, Intranasal↗
PubMed2000

Mucosal immune responses to meningococcal group C conjugate and group A and C polysaccharide vaccines in adolescents.

Previous studies in children have shown that Haemophilus influenzae type b (Hib) polysaccharide conjugate vaccines can reduce nasopharyngeal carriage of H. influenzae and provide herd immunity and suggest that this effect is mediated through mucosal antibodies. As this phenomenon may operate in other invasive bacterial infections which are propagated by nasopharyngeal carriage, mucosal antibody responses to meningococcal C conjugate and A/C polysaccharide vaccines were investigated. A total of 106 school children aged 11 to 17 years were randomized to receive a single dose of either conjugate or polysaccharide vaccine in an observer-blind study. Before and at 1, 6, and 12 months after immunization, samples of unstimulated saliva were collected and assayed by enzyme-linked immunosorbent assay for group C polysaccharide-specific immunoglobulin A (IgA), IgA1, IgA2 and secretory component, IgG antibodies, and total IgG and IgA. A subset of serum samples were also assayed for specific IgA and IgG antibodies. The concentrations of specific IgA and IgG in saliva were expressed both as nanograms per milliliter and as nanograms per microgram of total IgA or IgG. One month after immunization, significant increases in antibody titers (both IgA and IgG) were observed in saliva in both groups. There were significant subsequent falls in antibody titers by 6 months. Anti-meningococcal C-specific secretory component and IgA antibody titers were closely correlated (r = 0.85, P < 0.001), but there was no significant correlation between salivary and serum IgA titers, suggesting that IgA antibodies are locally produced. Significant correlation was found between salivary and serum IgG titers (r = 0.52, P < 0.01), suggesting that salivary IgG may be serum derived. Compared with polysaccharide vaccine, the conjugate vaccine induced significantly higher salivary IgG responses (P < 0.05), although there were no significant differences between salivary IgA responses to the two vaccines. The conjugate vaccine induced greater salivary IgG responses than a polysaccharide vaccine. Both vaccines induced significant salivary IgA antibodies. Further studies are needed to establish the functional significance of these mucosal responses.

Adolescent↗
PubMed2002

Helicobacter pylori-specific immunoglobulin synthesis in gnotobiotic piglets: evidence for the induction of mucosal immunity in the stomach.

Short term tissue biopsy cultures and paired, sera, bile and gastric and intestinal contents from Helicobacter pylori-infected gnotobiotic piglets were tested for the synthesis of H. pylori-specific immunoglobulin (Ig) isotype production by antigen-specific ELISA from post-infection days (PIDs) 2-28. Serum antibody levels in all three Ig isotypes were elevated from baseline values by PID 14, serum IgM levels reached peak levels on PID 14 and by PID 28 bile was strongly positive for IgA and IgG.Intestinal, but not gastric contents from infected piglets, contained IgA-specific antibody from PID 14 onward. Gastric mucosal epithelia adjacent to areas of inflammation in infected but not uninfected control piglets produced readily detectable amounts of porcine secretory component (SC); IgA-positive plasma cells were identified in gastric submucosa and lamina propria in these areas. Culture fluid supernatants, collected from explanted gastric cardia and antra and intestinal ilea of H. pylori-infected piglets had trace amounts of IgA as early as PID 2 in some animals, and strong IgA reactivity in all by PID 28. Supernatants also contained H. pylori-specific IgG by PID 14. A strong gastric lymph node IgA response contrasted with moderate IgA production in mesenteric lymph nodes and spleen. Mucosal biopsy production of H. pylori-specific IgG was more evenly distributed throughout the lymphoid system. These data support the contention that the Ig response to H. pylori is initiated within the gastric compartment and matures over time to a generalized IgA-dominated mucosal and IgG-dominated nonmucosal humoral immune response.

Animals↗
PubMed2000

Effective mucosal immunization against respiratory syncytial virus using purified F protein and a genetically detoxified cholera holotoxin, CT-E29H.

We exploited the powerful adjuvant properties of cholera holotoxin (CT) to create a mucosally administered subunit vaccine against respiratory syncytial virus (RSV). A genetically detoxified mutant CT with an E to H substitution at amino acid 29 of the CT-A1 subunit (CT-E29H) was compared to wild type CT for toxicity and potential use as an intranasal (IN) adjuvant for the natural fusion (F) protein of RSV. When compared to CT the results demonstrated that: (1) CT-E29H binding to GM1 ganglioside was equivalent, (2) ADP-ribosylation of agmatine was 11.7%, and (3) toxicity was attenuated in both Y-1 adrenal (1.2%) and patent mouse gut weight assays. IN vaccination with F protein formulated with CT-E29H induced serum anti-CT and anti-F protein antibodies that were comparable to those obtained after vaccination with equivalent doses of CT. Vaccinations containing CT-E29H at doses of 0.1 microg were statistically equivalent to 1.0 microg in enhancing responses to F protein. Antigen-specific mucosal IgA and anti-RSV neutralizing antibodies were detected in nasal washes and sera, respectively, of mice that had received F protein and 0.1 or 1.0 microg of CT-E29H. Anti-F protein IgA was not detected in the nasal washes from mice IN vaccinated with 0.01 microg CT-E29H or IM with F protein adsorbed to AlOH adjuvant. In addition, the formulation of purified F protein and CT-E29H (0.1 and 1.0 microg) facilitated protection of both mouse lung and nose from live RSV challenge. Collectively, the data have important implications for vaccine strategies that use genetically detoxified mutant cholera holotoxins for the mucosal delivery of highly purified RSV antigens.

Animals↗
PubMed2001

Hyperattenuated recombinant influenza A virus nonstructural-protein-encoding vectors induce human immunodeficiency virus type 1 Nef-specific systemic and mucosal immune responses in mice.

We have generated recombinant influenza A viruses belonging to the H1N1 and H3N2 virus subtypes containing an insertion of the 137 C-terminal amino acid residues of the human immunodeficiency virus type 1 (HIV-1) Nef protein into the influenza A virus nonstructural-protein (NS1) reading frame. These viral vectors were found to be genetically stable and capable of growing efficiently in embryonated chicken eggs and tissue culture cells but did not replicate in the murine respiratory tract. Despite the hyperattenuated phenotype of influenza/NS-Nef viruses, a Nef and influenza virus (nucleoprotein)-specific CD8(+)-T-cell response was detected in spleens and the lymph nodes draining the respiratory tract after a single intranasal immunization of mice. Compared to the primary response, a marked enhancement of the CD8(+)-T-cell response was detected in the systemic and mucosal compartments, including mouse urogenital tracts, if mice were primed with the H1N1 subtype vector and subsequently boosted with the H3N2 subtype vector. In addition, Nef-specific serum IgG was detected in mice which were immunized twice with the recombinant H1N1 and then boosted with the recombinant H3N2 subtype virus. These findings may contribute to the development of alternative immunization strategies utilizing hyperattenuated live recombinant influenza virus vectors to prevent or control infectious diseases, e.g., HIV-1 infection.

AIDS Vaccines↗
PubMed2001

Protective mucosal immunity to ocular herpes simplex virus type 1 infection in mice by using Escherichia coli heat-labile enterotoxin B subunit as an adjuvant.

The potential of nontoxic recombinant B subunits of cholera toxin (rCtxB) and its close relative Escherichia coli heat-labile enterotoxin (rEtxB) to act as mucosal adjuvants for intranasal immunization with herpes simplex virus type 1 (HSV-1) glycoproteins was assessed. Doses of 10 microg of rEtxB or above with 10 microg of HSV-1 glycoproteins elicited high serum and mucosal anti-HSV-1 titers comparable with that obtained using CtxB (10 microg) with a trace (0.5 microg) of whole toxin (Ctx-CtxB). By contrast, doses of rCtxB up to 100 microg elicited only meager anti-HSV-1 responses. As for Ctx-CtxB, rEtxB resulted in a Th2-biased immune response with high immunoglobulin G1 (IgG1)/IgG2a antibody ratios and production of interleukin 4 (IL-4) and IL-10 as well as gamma interferon by proliferating T cells. The protective efficacy of the immune response induced using rEtxB as an adjuvant was assessed following ocular challenge of immunized and mock-immunized mice. Epithelial disease was observed in both groups, but the immunized mice recovered by day 6 whereas mock-immunized mice developed more severe corneal disease leading to stromal keratitis. In addition, a significant reduction in the incidence of lid disease and zosteriform spread was observed in immunized animals and there was no encephalitis compared with 95% encephalitis in mock-immunized mice. The potential of such mucosal adjuvants for use in human vaccines against pathogens such as HSV-1 is discussed.

Adjuvants, Immunologic↗
PubMed2001

Oral administration of hepatitis E virus-like particles induces a systemic and mucosal immune response in mice.

We evaluated the potential of recombinant hepatitis E virus (rHEV) virus-like particles (VLPs) as an oral immunogen by analyzing the response of serum IgM, IgG, and IgA and fecal IgA in mice after oral administration. The capsid proteins of HEV with its N-terminal 111 amino acids truncated were expressed with a recombinant baculovirus in insect cells, where the capsid proteins self-assembled into VLPs. Mice were orally inoculated four times with purified rHEV VLPs in concentrations ranging from 10 to 100 microg without adjuvant. Serum IgM response was obtained with as little as 10 microg of the VLPs, and the level reached its maximum in all mice groups within 2 weeks after the first administration. Serum IgG was detected by 4 weeks post-immunization (p.i.) in the majority of mice given doses of 50 and 100 microg and continuously increased at least until the 10 week mark. Serum IgA was also detected by 4 weeks p.i. in the majority of mice given doses of 50 and 100 microg, and the level reached the maximum at 8 weeks p.i. Furthermore, the maximum level of intestinal IgA responses was detected in the groups of mice receiving 50 and 100 microg rHEV VLPs at 8 weeks p.i. All these antibody responses were obtained without a mucosal adjuvant. We therefore concluded that oral immunization of rHEV VLPs is capable of inducing systemic as well as intestinal antibody responses. Furthermore, serum IgG and fecal IgA thus induced were reactive to the native HEV antigen, as determined by Western blot assays and antigen-capture ELISA.

Administration, Oral↗
PubMed2006

Serological and mucosal immune responses after vaccination and infection with FMDV in pigs.

The aim of this study was to determine a possible correlation between humoral immune responses shortly after vaccination and protection against foot-and-mouth disease virus (FMDV) infection and to study the serological and mucosal antibody responses after vaccination and infection. We used three groups of ten pigs, one non-vaccinated group, one group vaccinated with a single dose vaccine and one group vaccinated with a four-fold dose vaccine. At 7 days post vaccination, five pigs per group were challenged intra-dermally with FMDV O TAW 3/97 and the remaining pigs of each group were contact-exposed to the inoculated pigs. In each group, virus excretion and number of contact infections were quantified. The serological and mucosal antibody responses were evaluated until 116 days post infection. Vaccination resulted in a significant decrease of virus excretion. Stepwise linear regression analysis of variables from individual vaccinated pigs revealed the virus excretion after challenge to be correlated with neutralising antibody titres at the day of challenge (p<0.01). In serum and OPF samples comparable isotype-specific antibody responses (IgM, IgG and IgA), could be detected after vaccination as well as after infection. Remarkably, the pigs with the highest IgA responses after vaccination were protected against contact exposure. After infection, a long lasting (up to 116dpi) IgA response was seen in the non-vaccinated and to a lesser extent in the single dose vaccinated pigs. The induction of NSP antibodies in the vaccinated pigs after infection was lower and of shorter duration as compared to the non-vaccinated infected pigs. This experiment shows that vaccination can reduce virus excretion in pigs, which will contribute to reduced transmission of FMDV in the field, even if the pigs are not fully protected. Moreover, vaccines that induce local IgA responses may be more effective, which merits further investigation.

Animals↗
PubMed1999

Regional specialization in the mucosal immune system: primed cells do not always home along the same track.

According to the current paradigm of lymphocyte trafficking, primed B and T cells extravasate in the intestinal lamina propria chiefly by means of the mucosal homing receptor alpha4beta7, which interacts with the vascular addressin MAdCAM-1. However, as discussed here, this mechanism cannot explain the preferential homing of B cells with a high level of J-chain expression to mucosal effector sites outside the gut.

Animals↗
PubMed2000

IL-15 and IL-15 receptor selectively regulate differentiation of common mucosal immune system-independent B-1 cells for IgA responses.

We show in this report a new regulatory role for IL-15 and IL-15R in the development of B-1 cells and their differentiation into IgA-producing cells. Mucosal IgA levels were found to be inhibited by anti-IL-15 mAb treatment in vivo, but enhanced by administration of rIL-15, while serum IgA levels remained unaffected. Mucosal B-1 cells preferentially proliferated in response to IL-15 in vitro. When mucosal B-1 and B-2 cells were separated into surface (s)IgM(+)sIgA(-) and sIgM(-)sIgA(+) fractions, IL-15R-specific mRNA was found to be predominant in both sIgM(+)sIgA(-) and sIgM(-)sIgA(+) B-1 cells at a much higher level than B-2 cells. Further, incubation of these different subsets of B-1 and B-2 cells with IL-15 resulted in greater enhancement of the corresponding receptor expression by B-1 subset when compared with B-2 fraction. Interestingly, de novo isolated sIgM(+)sIgA(-) B-1, but not sIgM(+)sIgA(-) B-2, cells were already class-switched cells because the germline Calpha transcript was detected and was then further enhanced by IL-15. IL-15 also supported differentiation of both sIgM(+)sIgA(-) and sIgM(-)sIgA(+) B-1 cells into IgA-producing cells. Taken together, these findings suggest that IL-15 is a critically important cytokine for the differentiation of both sIgM(+),IgA(-) and sIgM(-)sIgA(+) B-1 cells expressing IL-15R into IgA-producing cells in mucosal tissues.

Animals↗
PubMed1987

Enteric immunization reveals a T cell network for IgA responses and suggests that humans possess a common mucosal immune system.

The local IgA response is a result of two related events, the induction of sensitized T and B cells in gut- or bronchial-associated lymphoreticular tissues (GALT or BALT) and the final differentiation of IgA plasma cells in mucosal tissues where IgA is produced and transported to become secretory IgA (S-IgA) antibodies into external secretions. Oral administration of various types of antigens/vaccines may result in two types of response, i.e., S-IgA antibodies at mucosa and systemic unresponsiveness to antigen, a state termed oral tolerance. Regulatory T cells in GALT help account for both S-IgA responses and oral tolerance and thus serve to fine tune responses to orally encountered antigens. Studies in animal models and humans have shown that oral administration of antigens sensitize lymphoid cells in GALT which subsequently home to mucosa and result in S-IgA responses in several external secretions. The significant promise of oral vaccines for prevention of microbial diseases including neisserial diseases is discussed.

Animals↗
PubMed1998

Contribution of plasma-derived molecules to mucosal immune defence, disease and repair in the airways.

This review discusses recent observations, in health and disease, on the release and distribution of plasma-derived molecules in the airway mucosa. Briefly, the new data on airway mucosal exudation mechanisms suggest that the protein systems of plasma contribute significantly to the mucosal biology, not only in injured airways but also in such mildly inflamed airways that lack oedema and exhibit no sign of epithelial derangement. Plasma as a source of pluripotent growth factor, adhesive, leucocyte-activating, etc., molecules may deserve a prominent position in schemes that claim to illustrate immunological and inflammatory mechanisms of the airway mucosa in vivo.

Absorption↗