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PubMed2001

Highly purified mutant E112K of cholera toxin elicits protective lung mucosal immunity to diphtheria toxin.

We demonstrated that the mutant of cholera toxin (mCT) E112K which was LPS-free supported the induction of protective immunity in mucosal (e.g. lung lavage) and systemic (e.g. serum) compartments when given nasally with vaccine-grade diphtheria toxoid (DT) to mice. Significant DT-specific mucosal IgA antibody (Ab) and serum IgG, IgA and IgM Ab responses were induced when LPS-depleted mCT E112K or native CT (nCT) was co-administered nasally with DT. The analysis of DT-specific Ab-forming cell (AFC) responses supported the Ab titers and significant numbers of DT-specific IgA AFC were present in the lungs, nasal passages and submandibular glands. Furthermore, DT-specific IgG AFC in cervical lymph nodes (CLN) and the spleen were induced in mice administered with DT nasally with either mCT or nCT. The analysis of antigen-specific T cell responses revealed that increased DT-specific CD4+ T cell proliferative and Th2-type cytokine responses were induced in mice nasally-immunized with DT and the LPS-free form of mCT. The neutralization of diphtheria toxin by Abs showed that DT-specific IgG Ab responses in serum and lung lavages of mice immunized with DT and mCT were protective. Furthermore, it was shown that an IgA-enriched fraction of lung lavages possessed diphtheria toxin-specific neutralizing activity. These results are the first demonstration that nasally co-administered mCT E112K can induce DT-specific protective Ab responses in mucosal compartments (e.g. lung lavages and the lungs).

Administration, Intranasal↗

PubMed2005

[Regulative action of acupuncture and moxibustion on mucosal immunity].

OBJECTIVE: To explore the regulative action of acupuncture and moxibustion on mucosal immunity and its curative effect on mucosal relative diseases. METHODS: Review the recent 10 years' achievements of studies on mucosal immunity and analyze the regulative action of acupuncture and moxibustion on the mucosal immunological system in treatment of mucosal relative diseases. CONCLUSION: Acupuncture and moxibustion has a good regulative action on local mucosal immunological system, which is one of the mechanisms of acupuncture and moxibustion in prevention and treatment of mucosal relative diseases. This proves a more reliable basis for treatment of mucosal relative diseases with acupuncture and moxibustion.

Acupuncture↗

PubMed1993

Mucosal immune response in a case of sudden infant death syndrome.

A prospective study to define the normal patterns of development of mucosal immunity in 263 children provided a unique opportunity to study the mucosal immune response in an infant who unexpectedly died from sudden infant death syndrome. The subject initially had a normal pattern of mucosal immune function, which was perturbed after a transient mild upper respiratory tract infection at 3 1/2 wk of age. After the upper respiratory tract infection, there was an increase in mucosal permeability and the appearance of IgA and IgM in saliva. The unusual features in this case were the degree and the duration of the increases in salivary IgA and IgM after resolution of the illness. The marked abnormalities suggested a persistent stimulation of the mucosal immune response. The case provides informative data on potential mechanisms of sudden infant death syndrome and supports a role for involvement of upper respiratory tract infection.

Albumins↗

PubMed1995

Induction of systemic and mucosal immune responses following immunization with somatostatin-avidin complexes incorporated into ISCOMS.

Synthetic, biotinylated somatostatin-14 (Somatotropin Release-Inhibiting Factor; SRIF) was conjugated to avidin, and the resulting complex incorporated into immune-stimulating complexes (ISCOMS). The ISCOMS were used to study the systemic and mucosal immune responses induced by parenteral and gastrointestinal vaccination. Mice were immunized by intraperitoneal (IP) and intragastric (IG) routes and subsequently by either IP or IG secondary immunizations (groups-IP/IP; IP/IG; IG/IG). Antigen specific IgG and IgA antibody secreting cells (ASC) from the spleen, mesenteric lymph nodes (MLN) and Peyer's patches (PP's) were studied by an enzyme-linked immunospot assay (ELISPOT). Specific proliferative responses of spleen cells to avidin and to SRIF were measured. Immunization IP/IP evoked the highest serum IgG levels to avidin and to SRIF as well as the highest numbers of splenic IgG isotype ASC. The greatest IgA response in MLN and PP's was induced by IP/IG immunization. Only marginal mucosal immunity and no splenic cell specific proliferative responses were found by IG/IG immunization. These results indicate that ISCOMS are an effective delivery system for protein-peptide antigens. The ISCOMS system described elicited systemic and mucosal antibody immune responses, and primed specific proliferative response when administered IP/IG. This offers another approach for the design and delivery of mucosally administered peptide vaccines.

Administration, Oral↗

PubMed2003

Evidence for immune-mediated reduction of viral replication in Macaca nemestrina mucosally immunized with inactivated SHIV(89.6).

Although most HIV-1 infections worldwide result from heterosexual transmission, most vaccine candidates have focused on induction of systemic immunity and protection. We hypothesized that combining systemic priming with mucosal boosting would induce mucosal immunity that would protect from intravaginal challenge. Macaques were primed systemically with recombinant vaccinia viruses and boosted mucosally using inactivated SHIV(89.6) plus adjuvant. Other animals received protein boosts with adjuvant alone. Priming and boosting induced antiviral IgG and IgA antibodies. Such antibodies were induced to a lesser degree in animals receiving boosts alone. Anti-SHIV T cell responses were induced only in the prime-boost animals. Immunized animals and controls were challenged intravaginally with SHIV(89.6) and significant reductions in proviral and viral RNA loads were observed in the prime-boost animals. The boost-only animals did not have significant viral load reductions. These data suggest that cellular immunity was required for protection from intravaginal challenge. This immunization regimen provides a promising lead for vaccine development.

AIDS Vaccines↗

PubMed1995

Intranasal immunization with liposomes induces strong mucosal immune responses in mice.

BALB/c mice were immunized intranasally with either soluble ovalbumin (OVA) or OVA entrapped in liposomes. The effect of adding Sigma cholera toxin B subunit (sCT-B), which contained low amounts of cholera holotoxin (CT), or recombinant CT-B (rCT-B) which was free from CT, as mucosal adjuvants was also investigated. The mucosal [lung enzyme-linked immunospot assay (ELISPOT), lung washing] and systemic (serum antibody and spleen ELISPOT) responses of immunized mice to OVA and CT-B were determined. Results showed that soluble OVA and liposome-entrapped OVA were poor inducers of mucosal or systemic responses unless CT-B was added as adjuvant. The types of responses augmented by sCT-B and rCT-B were different. CT-B containing low levels of CT (i.e. sCT-B) boosted both mucosal and systemic IgA and IgG responses, whereas rCT-B only increased IgG responses, unless antigen was entrapped in liposomes. Although rCT-B was unable to adjuvant IgA responses against soluble OVA, it was able to induce IgA responses against itself. These data show that mucosal responses can be increased by addition of CT-B containing low levels of CT to antigen preparations given intranasally, suggesting a direct role for CT-A in isotype switching. Furthermore, the ability of CT-B to adjuvant IgA responses against added antigens and its ability to induce responses against itself appear to be separate phenomena. The results from this study should assist the rational formulation of mucosal vaccines which induce potent mucosal and systemic immune responses.

Administration, Intranasal↗

PubMed1992

Trichinella spiralis: dose dependence and kinetics of the mucosal immune response in mice.

The role of the mucosal immune response in helminth infections is not clear. In this study, the dose dependence and kinetics of the mucosal immune response to Trichinella spiralis were determined in experimentally infected Swiss Webster and BALB/c mice. The primary mucosal isotype was sIgA, although IgG was also detected, and primary infections with 10 and 150 larvae produced an anamnestic response on challenge. The mucosal and systemic immunoglobulin responses were dose dependent in both primary and challenge infections. The fecundity and length of worms and the rate of expulsion from the gut were determined on Day 6 postchallenge in Swiss Webster mice. Adult worm recovery and fecundity were reduced by greater than 50% and worm length by 28% in mice infected and challenged with 10 larvae and by 90, 85, and 35%, respectively, in mice infected and challenged with 150 larvae. The rate of expulsion was correlated with the size of both primary and challenge doses and a reduction in fecundity was correlated with the size of the primary dose only. The reduction in worm length did not differ significantly between the infection doses, but the trend was similar to that for expulsion. In BALB/c mice the expulsion response was dissociated from a reduction in fecundity and worm length, the latter two being positively correlated with sIgA levels, supporting a role for sIgA and/or IgG in these effects. However, expulsion does not appear to be dependent on the mucosal immunoglobulin response.

Animals↗

PubMed2006

Mucosal immunity and optimizing protection with meningococcal serogroup B vaccines.

Candidate Neisseria meningitidis serogroup B vaccines that are based on outer-membrane vesicles induce protective immunity in adults but provide neither crossprotection for infants nor long-lasting immunity. We suggest that this lack of vaccine efficacy is not solely because the best antigens are yet to be identified but also results from inappropriate programming of the immune response. Natural carriage of N. meningitidis and related bacteria leads to the development of protective immunity both at the mucosal surface and in the circulation. We propose that vaccine strategies that mimic this natural immunization process would better-optimize vaccine-induced protective immunity. Thus, mucosal immunization before a systemic booster vaccination could provide the solution and reduce the necessity for multiple injections to achieve immunity.

Administration, Intranasal↗

PubMed1998

Induction of apoptosis of lymphocytes in rat mucosal immune system.

AIM:To undergo apoptosis during negative and positive selection processes in rat mucosal immune system which are implicated in the pathogenesis of various mucosal diseases.METHODS: Female Sprague-Dawley rats were given protein synthesis inhibitor, cycloheximide, intravenously or intraperitoneally, an apoptosis was recognized by morphological hallmark under light and electronmicroscopy, and the expression of proliferating cell nuclear antigen was visualized immunohisto-chemically.RESULTS: The apoptosis of mucosal lymphocytes in the digestive tract, as well as in trachea, uterus and lacrimal gland was induced by cycloheximide (>1.0mg·kg(-1) body weight), which were located mainly in lamina propria and germinal centers of lymphoid nodules. At the same time, a portion of crypt epithelial cells of proliferating zone in small and large intestine, and the epithelial cells in genital tract were also found to undergo apoptosis. Immunostainings showed that apoptotic cells expressed proliferating cell nuclearantigen.CONCLUSION: Apo-ptosis of lymphocytes in mucosal immune system can be induced by cycloheximide. This model will facilitate the understanding of normal mucosal immune system and its role in the pathogenesis of related diseases such as inflammatory bowel diseases.

Journal Article↗

PubMed2003

A murine model of enterohemorrhagic Escherichia coli O157:H7 infection to assess immunopotentiating activity of drugs on mucosal immunity: effect of drugs.

An enterohemorrhagic Escherichia coli (EHEC) O157 oral infection murine model was established to examine the potentiating activity of drugs on mucosal immune responses. Groups of ICR mice inoculated intragastrically with 10(11) CFU/kg EHEC O157 showed chronic intestinal infection with the pathogen that persisted over 3 weeks and resulted in the synthesis of relatively high levels of antigen specific fecal IgA antibody. Intraperitoneal administration of 80 NU/kg Neurotropin, an immunopotentiator, augmented the antigen specific mucosal immune responses to EHEC O157. On the other hand, FK506 clearly suppressed the response. To further document the augmenting effect of Neurotropin on mucosal immune responses, mice were immunized intranasally with a mixture of ovalbumin and cholera toxin. Co-administration of 80 NU/kg Neurotropin significantly potentiated the synthesis of fecal IgA and serum IgG antibodies. These results suggest that Neurotropin has potential as a mucosal adjuvant to promote secretory IgA antibody production and that the mice model of oral infection with EHEC O157 is useful for immunopharmacological studies of bacterial infection-defensive mucosal immune responses.

Adjuvants, Immunologic↗

PubMed1999

Mucosal immunity.

Advances have been made in understanding specialized aspects of acquired mucosal immunity and the importance of cross-talk between host innate and acquired immune responses in host mucosal defense. These advances include elucidation of a molecular basis for the coordinated trafficking and retention of lymphocytes in intestinal sites, new insights into the possible extrathymic origin of mucosal T cells in the intestine, and the description of ligands that may be the targets of intraepithelial T-cell recognition. The past year has witnessed the characterization of an array of regulated epithelial cell mediators and responses important for host mucosal defense against enteric microbial pathogens and firmly establishes epithelial cells as an integral component of the mucosal immune network. Animal models continued to further understanding of intestinal inflammatory disease, and studies on tissue transglutaminase have generated significant new insights into the immunopathogenesis of human celiac disease.

Journal Article↗

PubMed2002

The induction of systemic and mucosal immunity to protein vaccines delivered through skin sites exposed to UVB.

It has been reported that common mucosal immunity can be efficiently induced in mice following immunization through the skin with vaccine formulations containing either the active form of vitamin D, or chemical agents capable of locally enhancing cyclic adenosine monophosphate levels. Herein, we report that exposure of skin to ultraviolet radiation B (UVB) can be employed as a means to alter systemic humoral immune responses and to promote the induction of mucosal immunity to protein antigens delivered into UVB-exposed skin sites. Our data indicates that the skin, as a vaccination site, can be manipulated to allow efficient induction of common mucosal and systemic immune responses.

Administration, Cutaneous↗

PubMed1999

The mammary gland and neonate mucosal immunity.

The passive mucosal protection of neonate mammals is dependent on the continuous supply until weaning of maternally dimeric IgA (monogastric) and IgG1 (ruminants). This lactogenic (humoral) immunity is linked to the gut, the so-called entero-mammary link, because of the translocation of Ig (IgA and IgG1) or the emigration of IgA lymphoblasts from the gut into the mammary gland (MG); on the other hand, studies on the lymphocyte subsets in the MG of artiodactyls sustained the view of a true local immune response, depending on the MG stage development. Accordingly, the increase of the lactogenic immunity may focus on (1) inductor sites (gut and, possibly, the MG), (2) increase in cell traffic from the gut into the MG, and (3) enhancement at the effector site of the Ig production and excretion in milk. A specific mucosal environment (interleukins and hormones) is responsible for IgM/IgA switch, the induction of mucosal homing receptor onto lymphoblasts and mucosal vascular addressins; very few data are available for the mechanism of lymphoblasts recruitment, either IgA or IgG1, although lactogenic hormones have been implicated in the IgA-blasts homing into the mice MG. After weaning, the neonate is able to mount a gut immune response, but the shortage of the suckling period did not seem to be detrimental for its onset. In soyabean allergy, both piglet and calf exhibited gut villus atrophy, gut accumulation of IgA (swine) and IgG1 (cattle) immunocytes, sustaining the view that a specific environment in ruminant is responsible for both IgA and IgG1 production.

Animals↗

PubMed1997

Interferon-gamma receptor-deficient mice exhibit impaired gut mucosal immune responses but intact oral tolerance.

Interferon-gamma (IFN-gamma) receptor knock-out (IFN-gamma R -/-) mice were used to analyse the role of IFN-gamma in mucosal immune responses following oral immunization. We found that the IFN-gamma R -/- mice demonstrated 50% reduced spot-forming cell (SFC) responses in the gut lamina propria and spleen after oral immunization with keyhold limpet haemocyanin (KLH) plus cholera toxin (CT) adjuvant. The IFN-gamma R -/- mice exhibited 10-fold reduced total serum KLH-specific antibody levels compared with wild-type mice after oral immunization, while after intravenous immunization, no such difference was seen, suggesting a selective impairment of mucosal immune responses. Moreover, oral immunizations resulted in impaired interleukin-4 (IL-4), IL-10 and IFN-gamma production by spleen T cells from IFN-gamma R -/- mice, indicating that no reciprocal up-regulation of Th2-activities had occurred despite the lack of IFN-gamma R function. No reduction in Th1 or Th2 cytokines was observed following systemic immunizations. Despite potentially strong modulating effects of IFN-gamma on epithelial cell IgA transcytosis and electrolyte barrier functions, CT-immunized IFN-gamma R -/- mice demonstrated unaltered protection against CT in ligated intestinal loops together with normal anti-CT IgA and total IgA levels in gut lavage. Oral feeding with KLH followed by parenteral immunization resulted in strongly suppressed SFC numbers and reduced cell-mediated immunity in both wild-type and IFN-gamma R -/- mice. CT-adjuvant abrogated induction of oral tolerance in both IFN-gamma R -/- and wild-type mice. Collectively, our data argue that the two major response patterns induced by oral administration of protein antigen, i.e. active IgA immunity and oral tolerance, are differently regulated. Thus, IFN-gamma R -/- mice have impaired mucosal immune responses while induction of oral tolerance appears to be unaffected by the lack of IFN-gamma functions.

Administration, Oral↗

PubMed1999

Characterization of the mucosal immune response in breast milk after peroral immunization of chimpanzees (Pan troglodytes) with Streptococcus mutans.

The characteristics of the mucosal immune response to Streptococcus mutans cells, antigen A, antigen B, glucosyltransferases and glucan-binding proteins were examined in four pregnant chimpanzees that had been immunized perorally with Strep. mutans. Six pregnant chimpanzees served as non-immunized controls. None of the chimpanzees harbored S. mutans. Samples of milk were collected from all animals throughout the experiment. Peroral immunization resulted in an overall 17-fold median increase in SIgA in milk. Although SIgA1 comprised almost two-thirds of milk SIgA, Strep. mutans whole-cell antibody activity was contained predominantly in the SIgA2 subclass. The difference between the specific activities of anti-Strep. mutans SIgA1 and SIgA2 antibodies compared over time reached the borderline of statistical significance (p = 0.08). The avidity of anti-Strep. mutans antibodies was low in three of four chimpanzees and there was no evidence of affinity maturation. SIgA antibodies from the milk of all four immunized chimpanzees recognized antigen A. In three animals these antibodies were restricted to the SIgA1 subclass and, in one animal, anti-A antibodies were confined to SIgA2. Antibodies from all of the immunized chimpanzees recognized degradation products of antigen B in both the SIgA1 and the SIgA2 subclasses. Only two of four immunized chimpanzees responded to glucosyltransferases and these antibodies were restricted to the SIgA1 subclass. None of the chimpanzees responded to the 74-kDa glucan-binding protein. However, three animals produced SIgA1 antibodies against the 59-kDa glucan-binding protein and two of these also produced SIgA2 antibodies against this protein.

Analysis of Variance↗

PubMed1999

Mucosal immunity and inflammation. III. The mucosal antigen barrier: cross talk with mucosal cytokines.

We have known for many years that mucosal responses to antigens are regulated by immune cells and their molecular signals. More recently, it has become clear that epithelial cells also synthesize and secrete chemokines and cytokines. A sophisticated system of bidirectional cytokine signals is responsible for immune activation in the case of enteropathogens vs. immune suppression to food and commensal microbial antigens. A key factor in determining antigen handling is the route taken by antigens across the epithelial barrier. Cytokines and other mucosal messenger molecules play a critical role in the regulation of transepithelial antigen transport.

Animals↗

PubMed1998

Novel mucosal immunization with polysaccharide-protein conjugates entrapped in alginate microspheres.

A novel mucosal immunization was examined using biocompatible and biodegradable alginate microspheres containing a conjugate of polysaccharide antigen and cholera toxin B subunit (CTB). In order to prepare the alginate microspheres with diameters of less than 5 microm, a new diffusion-controlled interfacial gelation technique was developed. Also, in order to improve the mucosal immune response, a pneumococcal capsular polysaccharide type 19 (PS19) was conjugated to the CTB (PS19-CTB). This conjugate was subsequently encapsulated into the alginate microspheres. The loading content of PS19-CTB to the alginate microspheres was 60%. An in vitro sustained release pattern was observed with the antigen-loaded microspheres, showing 80% antigen release within one day. Mucosal and systemic immunities following oral immunization with the alginate microspheres were studied. Balb/c mice were immunized perorally three times at intervals of two weeks. Peroral immunization with 25 microg of PS19-CTB entrapped in the alginate microspheres evoked both the mucosal IgA and systemic IgM responses to PS19 in small intestine and in sera, respectively. The results suggest that both the mucosal and systemic antibody responses could be induced by oral administration of the PS19-CTB antigen entrapped in alginate microspheres.

Alginates↗

PubMed2006

Parenteral nutrition impairs gut-associated lymphoid tissue and mucosal immunity by reducing lymphotoxin Beta receptor expression.

OBJECTIVE: To determine the effects of parenteral nutrition (PN) on LTbetaR in gut-associated lymphoid tissue (GALT), particularly the intestine and Peyer's patches (PP). SUMMARY BACKGROUND DATA: Lack of enteral stimulation with PN impairs mucosal immunity and reduces IgA levels through depression of GALT cytokines (IL-4 and IL-10) and GALT specific adhesion molecules. We have shown that each is critical to intact mucosal immunity through effects on lymphocyte homing, IgA production, and resistance to antibacterial and antiviral immunity. IgA is the principal specific immunologic mucosal defense. LTbetaR stimulation controls production of IL-4, the adhesion molecule MAdCAM-1, and other key components of GALT, all of which are important in increasing IgA levels and maintaining mucosal defenses. METHODS: Experiment 1: LTbetaR expression in intestine and PP was analyzed by Western blot after 5 days of chow, a complex enteral diet (CED), or PN. Diets were isocaloric and isonitrogenous except for chow. Experiment 2: After completing pilot experiments to determine the appropriate dose of the LTbetaR agonistic antibody, mice received chow, PN + 5 mug of anti-LTbetaR mAb (2 times/d, i.v.) or PN + isotype control antibody. PP lymphocytes and intestinal IgA levels were measured after 2 days. RESULTS: Lack of enteral stimulation with PN significantly decreased LTbetaR expression in intestine and PP compared with chow and CED. LTbetaR stimulation with an agonistic anti-LTbetaR mAb significantly increased PP lymphocyte counts and intestinal IgA in PN fed-mice. CONCLUSIONS: LTbetaR expression is critical for GALT control mechanisms and intact mucosal immunity. PN reduces LTbetaR expression, PP lymphocytes, and intestinal IgA production. Exogenous LTbetaR stimulation reverses PN-induced depression of gut mucosal immunity.

Animals↗