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PubMed1998

Mucosal immunity of the gastrointestinal tract and oral tolerance.

To guard against disease, mucosal surfaces of the intestinal, respiratory and urogenital tracts are protected by a carefully regulated system of defenses known as the mucosal immune system. The hallmark of mucosal immunity is secretory IgA which can prevent infection and remove antigen crossing the mucosal barrier. IgE responses are also associated with mucosal immunity. In addition, a lymphocyte population resides within the mucosal epithelium, possibly forming a 'first line of defense' against infections. Oral administration of antigen can also induce antigen-specific peripheral immune tolerance, known as oral tolerance. Oral tolerance may prevent allergies, inflammation and other problems due to responses against food antigens or gut flora. It also has a tremendous potential in treating autoimmune and inflammatory diseases. The aim of this article is to present an overview of mucosal immunity. Specifically, the focus is on immunity along the gastrointestinal tract; however, similar principles are active in other mucosal tissues.

Journal Article↗
PubMed2003

Mucosal immunity.

Food allergy is the manifestation of an abnormal immune response to antigen delivered by the oral route. Normal mucosal immune responses are generally associated with suppression of immunity. A normal mucosal immune response relies heavily on a number of factors: strong physical barriers, luminal digestion of potential antigens, selective antigen sampling sites, and unique T-cell subpopulations that effect suppression. In the newborn, several of these pathways are not matured, allowing for sensitization rather than suppression. With age, the mucosa associated lymphoid tissue matures, and in most individuals this allows for generation of the normal suppressed tone of the mucosa associated lymphoid tissue. As a consequence, food allergies are largely outgrown. This article deals with the normal facets of mucosal immune responses and postulates how the different processes may be defective in food-allergic patients.

Animals↗
PubMed1994

Comparison of systemic and mucosal priming for mucosal immune responses to a bacterial protein antigen given with or coupled to cholera toxin (CT) B subunit, and effects of pre-existing anti-CT immunity.

Intraperitoneal immunization with a bacterial protein antigen conjugated to cholera toxin B subunit (CTB) was generally less effective than intragastric or intranasal immunization in generating mucosal IgA antibodies, and in priming the mucosal immune system to respond to intragastric or intranasal boosting. Previous intragastric or intranasal immunization which generated high levels of mucosal and circulating antibodies to CTB did not suppress mucosal IgA responses induced by intragastric or intranasal immunization with bacterial antigen conjugated to or mixed with CTB, but serum antibody responses were inhibited depending on the route of immunization and whether CTB was conjugated to or mixed with the antigen.

Administration, Intranasal↗
PubMed1999

Ileal and jejunal Peyer's patches play distinct roles in mucosal immunity of sheep.

The majority of pathogens enter the body through mucosal surfaces and it is now evident that mucosal immunity can provide effective disease protection. However, the induction of mucosal immunity will require efficient targeting of mucosal vaccines to appropriate mucosa-associated lymphoid tissue. An animal model, based upon the surgical preparation of sterile intestinal 'loops' (blind-ended segments of intestine), was developed to evaluate mucosal and systemic immune responses to enteric vaccines in ruminants. The effectiveness of end-to-end intestinal anastomoses was evaluated and fetal surgery did not disrupt normal intestinal function in lambs up to 6-7 months after birth. The immunological competence of Peyer's patches (PP) within the intestinal 'loops' was evaluated with a human adenovirus 5 vector expressing the gD gene of bovine herpesvirus-1. This vaccine vector induced both mucosal and systemic immune responses when injected into intestinal 'loops' of 5-6-week-old lambs. Antibodies to the gD protein were detected in the lumen of intestinal 'loops' and serum and PP lymphocytes proliferated in response to gD protein. The immune competence of ileal and jejunal PP was compared and these analyses confirmed that jejunal PP are an efficient site for the induction of mucosal immune responses. This was confirmed by the presence of gD-specific antibody-secreting cells in jejunal but not ileal PP. Systemic but not mucosal immune responses were detected when the vaccine vector was delivered to the ileal PP. In conclusion, this model provided an effective means to evaluate the immunogenicity of potential oral vaccines and to assess the immunological competence of ileal and jejunal Peyer's patches.

Adenoviruses, Human↗
PubMed2000

Genetic immunization with lung-targeting macroaggregated polyethyleneimine-albumin conjugates elicits combined systemic and mucosal immune responses.

Genetic immunization is a novel form of vaccination in which transgenes are delivered into the host to produce the foreign protein within host cells. Although systemic immune responses have been relatively easy to induce by genetic immunization, the induction of regional and mucosal immunity has often been more challenging. To address the problem of eliciting mucosal immunity in the lung, we utilized macroaggregated albumin to target plasmid DNA to the lung. Macroaggregated albumin is trapped in the lung after i. v. injection, and it is routinely used in radiolabeled form as an imaging modality to evaluate pulmonary blood flow. To couple DNA to this targeting agent, polyethyleneimine (a polycation that binds DNA and enhances transfection) was conjugated to serum albumin, and the conjugate was aggregated by heating to produce particles of 25-100 microm. The resulting particles bound plasmid DNA avidly, and when injected i.v. in mice, the particles distributed in the peripheral lung tissue in the alveolar interstitium. Particle-bound luciferase plasmid transfected a variety of cell lines in vitro, and after i.v. injection, gene expression was detected exclusively in the lung. Using human growth hormone as the encoded foreign Ag for immunization, i.v. injection of the particle-bound plasmid elicited both pulmonary mucosal and systemic immune responses, whereas naked DNA injected either i.v. or i.m. elicited only systemic responses. Thus, particle-bound plasmid DNA may have utility for genetic immunization by intravascular delivery to the lung and potentially to other organs and tissues.

Amino Acid Sequence↗
PubMed1995

FK-506 and cyclosporine A (CsA) immunomodulation of the human gut mucosal immune system.

FK-506 and cyclosporine A (CsA) are two immunosuppressive drugs used in the treatment of patients after liver and small intestine transplantation. A clinical advantage of FK-506 over CsA has been observed in these patients. Although the immunomodulation of both drugs has been well documented in the circulatory immune system, their effect on the mucosal immune system is not well established. In this study, the effect of FK-506 on the human gut mucosal immune system was compared to CsA. Proliferation of human colonic lamina propria lymphocytes (LPL) was measured by DNA synthesis and ornithine decarboxylase (ODC) activity. Results show that FK-506 and CsA suppress LPL DNA proliferation in a dose-dependent manner. FK-506 had a stronger antiproliferative effect compared to CsA. Moreover, the antiproliferative effect of both drugs was not dependent on monocytes or monocyte-associated factors (IL-1 beta, IL-6). In addition, exogenous addition of IL-2 did not restore the suppressive effect of either drug on LPL DNA synthesis. We conclude that: (1) both drugs have an antiproliferative effect on the human mucosal immune system; and (2) the stronger effect of FK-506 on human LPL compared to CsA may explain its superior clinical response observed in patients after liver/small intestine transplantation.

Cell Division↗
PubMed1998

Differences in immune responses induced by oral and rectal immunizations with Salmonella typhi Ty21a: evidence for compartmentalization within the common mucosal immune system in humans.

Based on the concept of the common mucosal immune system, immunization at various inductive sites can induce an immune response at other, remote mucosal surfaces. The immune responses elicited through rectal and oral routes of antigen delivery were compared with respect to (i) measurement of antibody responses in serum and various external secretions of the vaccinees and (ii) characterization of the nature and homing potentials of circulating antibody-secreting cells (ASC). Specific ASC appeared in the circulation in 4 of 5 volunteers after oral and 9 of 11 volunteers after rectal immunization with Salmonella typhi Ty21a. The kinetics, magnitude, and immunoglobulin isotype distribution of the ASC responses were similar in the two groups. In both groups, almost all ASC (99 or 95% after oral or rectal immunization, respectively) expressed alpha4 beta7, the gut homing receptor (HR), whereas L-selectin, the peripheral lymph node HR, was expressed only on 22 or 38% of ASC, respectively. Oral immunization elicited a more pronounced immune response in saliva and vaginal secretion, while rectal immunization was more potent in inducing a response in nasal secretion, rectum, and tears. No major differences were found in the abilities of the two immunization routes to induce a response in serum or intestinal secretion. Thus, the rectal antigen delivery should be considered as an alternative to the oral immunization route. The different immune response profiles found in various secretions after oral versus rectal antigen administration provide evidence for a compartmentalization within the common mucosal immune system in humans.

Administration, Oral↗
PubMed1998

Human vaginal mucosal immune system: characterization and function.

OBJECTIVE: The mucosal immune system has been recognized as the first line of defense against foreign antigens. The limited information available on the mucosal immunity of the lower reproductive organs have restricted our ability to fight infections, especially, the sexually transmitted disease. The aim of this study was to characterize in-vitro the human vaginal lamina propria lymphocytes (VLPL), their cell surface phenotypes, and cellular function. METHODS: VLPL were isolated from human vaginal mucosa by enzymatic techniques. Cell surface characteristics were investigated by immunohistochemistry and flow cytometric analysis. Cellular immune function was evaluated by 3H-thymidine incorporation studies and ornithine decarboxylase (ODC) activity. RESULTS: Immunohistochemistry and flow cytometric analysis showed that the CD4/CD8 ratio of the human vaginal mucosa is reversed compared to the gut lamina propria lymphocytes (0.55 +/- 0.17). PHA and ConA mitogens enhanced VLPL thymidine incorporation, while PWM did not have any significant effect. Very high level of ODC activity was observed in VLPL after PHA stimulation. CONCLUSIONS: The human VLPL can be isolated, characterized, and respond to a mitogenic stimulus. We postulate that further analysis of the vaginal immune system will enhance our understanding of local defence mechanisms which will help in the development of new therapeutic modalities against vaginal infections.

CD4-CD8 Ratio↗
PubMed1999

The induction of systemic and mucosal immune responses following the subcutaneous immunization of mature adult mice: characterization of the antibodies in mucosal secretions of animals immunized with antigen formulations containing a vitamin D3 adjuvant.

Systemic and mucosal immune responses were effectively induced following the subcutaneous administration of Haemophilus influenzae type b oligosaccharide conjugated to diphtheria toxoid vaccine in a formulation containing the active form of vitamin D3. IgA and IgG antibodies with specificity for both the protein and oligosaccharide components of the vaccine were detectable in mucosal secretions following immunization. The IgA and IgG mucosal antibodies were produced locally, and were functional as demonstrated by their diphtheria toxin neutralizing activity. Our data suggests that subcutaneous tissues can effectively serve as effective antigen presenting sites for both mucosal and systemic immune responses to antigens administered in combination with vitamin D3.

Adjuvants, Immunologic↗
PubMed1999

Regional specialization in the mucosal immune system: what happens in the microcompartments?

Mucosal immunity is an important arm of the immune system because it operates in tissues involved in everyday infectious defence as well as in tolerance against innocuous environmental and dietary antigens. Here, Per Brandtzaeg and colleagues discuss compartmentalized regulation of mucosal B cells and mechanisms that might explain the strikingly regionalized effector disparity of the human mucosal immune system.

B-Lymphocytes↗
PubMed1990

Mucosal immunity of the mammary gland and immunology of mother/newborn interrelation.

Mammary gland is assumed to function as a part of the common mucosal immune system. Lymphocytes observed in the mammary gland derived their origin from precursor immunocompetent cells presented in BALT and GALT. In relation to local immunity of the other sites of the mucosal membranes, lymphocytes homing to the mammary gland are regulated by lactogenic hormones. The other peculiarity of the mammary gland mucosal immunity is a direction of the milk protective factors. The secretory products of lactating mammary gland provide a protection not for own organism, but for newborn infant. The human neonates are essentially devoid of differentiated mechanisms of the secretory immunity. The low IgA level and high free Sc level in newborn secretions reflect the immaturity of the mucosal immunity in the neonatal period. But some evidences suggest the activation and fast maturation of newborn mucosal immunity. There were shown the sharp rises of IgA levels in different newborn's secretions during the neonatal period. Using as an object for the study on the neonatal mucosal immunity the newborn mammary gland, we detected the higher level of Ia-positive cells in neonatal milk in relation to maternal milk, in spite of the low level of Ia-positive cells in newborn's blood. Local immunity seems to function, at least partially, independently on systemic functions in neonates. Significant influence on the development of newborn mucosal immunity exerts maternal milk. The circumstantial evidences support the promoting effect of the human milk on the SIgA synthesis by newborn mucosal membranes. It is impossible to exclude the feasibility of antiidiotypic antibodies presented in human milk actively immunize offspring. At the same time, numerous immunosuppressive factors were found in colostrum. It seems that these factors can protect the newborn immune system against overstimulation by large number of environmental antigens. Human colostrum and milk provide also to neonate numerous soluble and cellular factors of passive immunization. Thus, we can say that human milk serve as a connection link between maternal and newborn immune system, and the main role in mother/newborn interrelations plays the local immunity.

Animals↗
PubMed2002

Role for mucosal immune responses and cell-mediated immune functions in protection from airborne challenge with Venezuelan equine encephalitis virus.

Venezuelan equine encephalitis virus (VEEV) replicates in lymphoid tissues following peripheral inoculation and a high titre viraemia develops. Encephalitis develops after the virus enters the central nervous system from the blood, with the earliest neuronal involvement being via the olfactory nerve. Following aerosol challenge with virulent VEEV, the virus is thought to replicate in the nasal mucosa and there could be direct entry into the olfactory nerve via infected neuroepithelial cells. Protection from VEEV infection is believed to be primarily mediated by virus specific antibody. The correlation between protection and neutralising serum antibody titres is, however, inconsistent when the virulent virus is administered by the airborne route. This study demonstrates a link between antibody in serum and the nasal mucosa and protection by means of passive immunisation studies. Intra-nasal administration of antibody increased protection against airborne virus in Balb/c mice. Vaccination of mu MT strain mice that do not have functional B cells and cannot produce antibody revealed normal proliferation of spleen cells in vitro and robust cytokine production. Aerosol challenge of mu MT mice demonstrated that complete protection was only achieved when passive immunisation with antibody was supplemented with active immunisation with the TC-83 vaccine strain of the virus. This implies that cell-mediated immune functions are required for protection against airborne challenge with virulent VEEV.

Administration, Intranasal↗
PubMed2003

Serotype-specific mucosal immune response and subsequent poliovirus replication in vaccinated children.

A total of 32 unimmunized children (median age 5 months) living in an orphanage in Minsk, Belarus, were vaccinated with three doses of oral poliovirus vaccine (OPV) with a 60-day interval between the doses. Blood samples were drawn before the immunizations and 45-50 days after each vaccine dose. Excretion of the vaccine viruses was followed by examining fecal specimens collected weekly after each vaccine dose. All children seroconverted by the second dose of OPV at the latest to all three serotypes of poliovirus but differences were seen regarding the intestinal responses. The strongest responses in both neutralizing antibodies and virus-binding IgA in fecal suspensions were seen toward poliovirus Type 2. Consistent with this, relatively little poliovirus Type 2 excretion was seen after the second and third doses of OPV as compared to that of poliovirus Type 1 or Type 3. The delayed development of functional intestinal immunity against the latter serotypes was associated with relatively weaker intestinal antibody responses compared to poliovirus Type 2. In the case of poliovirus Type 3, about 10% of children were still excreting the vaccine virus 9 weeks after administering the third dose. These results are consistent with epidemiological observations of the serotype-specific efficacy of OPV immunizations. The proportion of specimens showing nonpolio enteric viruses gradually increased through the 6-month study period. This may reflect the possibility that after the first dose of OPV, intensive replication of the vaccine viruses may out compete the nonpolio viruses in the intestines of the vaccinees or, alternatively, mask nonpolio viruses during the cell culture isolation procedure.

Antibodies, Viral↗
PubMed1997

Neonatal appendectomy impairs mucosal immunity in rabbits.

We compared the effects of neonatal appendectomy in rabbits on total Ig and antigen (Ag)-specific Ig levels in the serum and gut, and on plasma cell numbers in the small intestine in response to intraperitoneal (i.p.) and intraduodenal (i.d.) immunizations with ovalbumin (OVA). Animals were sacrificed after 9 weeks. Antibodies (Abs) in the duodenum were collected and quantified by enzyme-linked immunosorbent assay (ELISA) while plasma cells were quantified by double immunofluorescent staining. Appendectomy markedly reduced total intestinal IgA (P < 0.0006), IgM (P < 0.003), and IgG (P < 0.05) relative to controls, whereas total serum Ig levels were not lowered significantly. Moreover, appendectomy nearly ablated OVA-specific IgA (P < 0.007) in the gut and severely depleted OVA-specific IgG in the gut (P < 0.03) and serum (P < 0.007). The sharp decreases in total IgA and anti-OVA IgA were paralleled by decreases in total IgA+ plasma cells (P < 0.0005) and OVA-reactive IgA+ plasma cells (P < 0.05). These results support a major role of the rabbit appendix in seeding the intestinal lamina propria with plasma cell precursors, especially those producing IgA.

Animals↗
PubMed1999

Antibody-independent protective mucosal immunity to gastric helicobacter infection in mice.

Helicobacter pylori infection of the gastric mucosa can result in gastritis and peptic ulcer disease. Although vaccination can induce protective immunity in animal models of Helicobacter infection, the mechanism(s) of protective immunity has not been fully elucidated. This study was designed to determine whether humoral immune responses are required for protective Helicobacter immunity. IgA-deficient or immunoglobulin-deficient mice were orally immunized against Helicobacter felis and then challenged with live H. felis. Both groups were protected at levels comparable to that of wild-type mice. Additionally, inflammation was equivalent in extent and character between wild-type and antibody-deficient mice. Therefore antibody-independent mechanisms of immunity can protect mice against gastric Helicobacter infection.

Animals↗
PubMed1996

Induction of systemic and mucosal immune responses in cotton rats immunized with human adenovirus type 5 recombinants expressing the full and truncated forms of bovine herpesvirus type 1 glycoprotein gD.

We generated both replication-incompetent (HAd5-gD-E1 and HAd5-tgD-E1) and replication-competent (HAd5-gD-E3 and HAd5-tgD-E3) human adenovirus type 5 (HAd5) recombinants expressing the full (gD) or truncated form (tgD) of the glycoprotein gD gene of bovine herpevirus type 1 (BHV-1). Recombinant gD and tgD expressed by HAd5-gD-E1 and HAd5-gD-E3 and by HAd5-tgD-E1 and HAd5-tgD-E3, respectively, were recognized by gD-specific monoclonal antibodies (MAbs) directed against linear and conformational epitopes, suggesting that antigenicity of recombinant gD and tgD was similar to that of the native gD expressed in BHV-1 infected cells. In HAd5-gD-E1- or HAd5-gD-E3-inoculated cotton rats there was a strong gD- and HAd5-specific IgG and IgA antibody response. The immune response was significantly lower in animals similarly immunized with HAd5-tgD-E1 or HAd5-tgD-E3, indicating that live adenovirus vaccine vectors may be better suited to the full-length form of glycoprotein gD than its truncated form. After a BHV-1 challenge, no infectious BHV-1 virions were isolated from the trachea of cotton rats previously immunized with HAd5-gD-E1 or HAd5-gD-E3. These results suggest that adenovirus E1 insertion (replication-incompetent) and E3 insertion (replication-competent) vectors have excellent potential for use in developing live recombinant virus vaccines and provide evidence that the cotton rat model can be used in BHV-1 vaccination-challenge trials.

Adenoviruses, Human↗
PubMed2004

Production of antibodies in murine mucosal immunization with Toxoplasma gondii excreted/secreted antigens.

Toxoplasmagondii RH strain excreted/secreted antigens (ESA) were administrated weekly by the oral route, to two groups of 40 OF1 mice for 4 weeks. One group received ESA associated with cholera toxin (CT+) and the other, ESA only (CT-). Five animals from each group were sacrificed from day 4 (D4) to D49 following the first immunization and their feces and sera were collected and tested by ELISA for IgA, IgG and IgM antibody detection. In feces, IgA antibodies were detected on D4 and on D12 in the CT+ and CT- groups, respectively, and they persisted up to D49. IgG antibodies were detected from D12 to D41 in the CT+ group and on D12 only in the CT- group. No IgM antibodies were detected. In sera, IgA antibodies were detected on D27, D41 and D49 only in the CT+ group. IgG and IgM antibodies were found on D12 and D4, respectively, in the CT+ group and starting from D27 in the CT- group. To our knowledge, this is the first demonstration that ESA, with or without CT, are immunogenic when administrated by the oral route.

Adjuvants, Immunologic↗