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PubMedDate not supplied

Mucosal immune network in the gut for the control of infectious diseases.

The common mucosal immune system (CMIS) consists of an integrated cross-communication pathway of lymphoid tissues made up of inductive and effector sites for host protection against pathogenic microorganisms. Major effector molecules of the CMIS include IgA antibodies and cytokines, chemokines and their corresponding receptors. Secretory IgA (S-IgA), the major immunoglobulin, is induced by gut-associated lymphoreticular tissue (GALT)-derived B cells with the help of Th1- and Th2-type CD4(+) T lymphocytes. Cytotoxic T lymphocytes (CTLs) in the mucosal epithelium, a subpopulation of intraepithelial lymphocytes (IELs), also help maintain the mucosal barrier. The CMIS is unique in that it can provide both positive and negative signals for the induction and regulation of immune responses in both the mucosal and systemic compartments after oral or nasal antigen exposure. Prevention of infection through mucosal surfaces can be achieved by the CMIS through connections between inductive (e.g. GALT) and effector tissues. When vaccine antigens are enterically administered together with mucosal adjuvants [e.g. cholera toxin (CT), heat-labile toxin produced by Escherichia coli (LT) and IL-12], antigen-specific Th1/Th2 and IgA B cell responses are induced simultaneously in the mucosal effector compartment. Since these antigen-specific immune responses are not generated by oral vaccine without mucosal adjuvant, safe and effective adjuvants for the induction of antigen-specific S-IgA and CTL responses are essential for the development of mucosal vaccines for protection against infectious diseases. Finally, recent findings suggest the presence of a CMIS-independent IgA induction pathway, which also must be considered in the development of mucosal vaccines.

Animals↗
PubMed1998

Induction of gut mucosal immune responses: importance of genetic background and Th1/Th2 cross-regulation.

The reciprocal regulation of T-helper cell (Th) subsets is widely documented in various animal models of infectious diseases. In this study IFN-gamma/IL-4 double knockout (DKO) mice were used to analyse the role of Th subsets in mucosal immune responses. We found that the DKO mice had normal IgA differentiation but impaired induction of specific gut mucosal antibody responses after oral immunization using cholera toxin adjuvant. Both Th1 and Th2 responses were reduced compared with wild-type mice. Despite the absence of both IFN-gamma and IL-4 in the DKO mice the overall results were similar to previous observations in IFN-gamma receptor-knockout (IFN-gammaR-/-) mice and did not suggest a strict cross-regulation of the two Th subsets in the gut mucosa. To further examine the role of IFN-gamma in mucosal immunity we compared two different mouse strains lacking IFN-gamma, i.e. IFN-gamma-/- (C57BL/6) and IFN-gammaR-/- mice (129/Sv). We found that IFN-gammaR-/- mice exhibited reduced mucosal antibody responses and decreased Th1 and Th2 activity after oral immunization, while IFN-gamma-/- mice had intact antibody responses and increased Th2 responses. Thus, genetic differences were found to critically affect the development of a specific gut mucosal immune response. An enhanced Th2 activity in the Peyer's patches following oral immunization was associated with an ability to mount strong intestinal IgA immunity.

Animals↗
PubMed2004

Participation of the intestinal epithelium and mast cells in local mucosal immune responses in commercial poultry.

The intestinal mucosa of commercial poultry is continually subjected to invasion or colonization by a wide array of potentially hostile enteric pathogens. Although, recent investigations have focused on lymphocyte involvement in immune responses in the intestine, lymphocyte-mediated immunity alone will not explain the barrier nature of mucosal membranes associated with rejection of many enteric pathogens upon secondary homologous challenge. Our laboratories have focused on nontraditional elements of mucosal immunity in poultry to better understand host-pathogen interactions in the intestine. Following classical and novel immunization procedures, we have identified an antigen-specific mechanism of immediate responsiveness of the mucosal epithelium characterized by epithelial chloride secretion. This mechanism, characteristic of intestinal anaphylaxis, is mediated by local immune elements. Similar mechanisms in mammals contribute to the barrier nature of mucosal membranes during pathogen challenge. To identify cells participating in these and similar responses, additional studies have described a role for mast cells in acute phase responses in the intestines of chickens experimentally challenged with Eimeria. To a more practical end, other experiments in our laboratories have characterized drinking water administration of BSA for elicitation of local and systemic antibody responses. These experiments have shown ad libitum drinking water administration of BSA to be as effective as i.p. administration of BSA; they present a novel approach to immunization of commercial poultry with protein vaccines. These investigations support continued research on host-pathogen interactions within the intestine of commercial poultry to better understand and control enteric pathogens through vaccination or immunomodulation.

Anaphylaxis↗
PubMed2002

Intranasal immunization with SIV virus-like particles (VLPs) elicits systemic and mucosal immunity.

By using a baculovirus expression system, we have successfully produced simian immunodeficiency virus (SIV)-like particles (VLPs) with high levels of biologically active SIV envelope (Env) incorporated on their surfaces. To study whether SIV VLPs represent effective mucosal immunogens, we immunized groups of mice with VLPs alone or VLPs plus the mucosal adjuvant cholera toxin (CT) by the intranasal (i.n.) route. High levels of serum IgG antibody production were achieved in mice immunized intranasally with SIV VLPs, and the antibody response was found to be antigen dose-dependent. The IgG1 and IgG2a ratio indicates that immune responses induced by SIV VLPs are Th1 oriented. Mice immunized with VLPs plus CT were found to exhibit higher serum antibody responses than those immunized with VLPs alone (P<0.001). Furthermore, IgA antibody production was detected in both saliva and vaginal fluid from mice mucosally immunized with SIV VLPs. Higher levels of IgA were found in vaginal fluid than in saliva in animals immunized with SIV VLPs plus CT (P<0.05). Higher neutralizing activity to SIV 1A11 was also found in serum of animals immunized with SIV VLPs plus CT. Moreover, increased numbers of MHC I-restricted peptide-specific IFN-gamma and IL-4 producing T cells were detected in both splenocytes and lymph nodes by intranasal immunization of SIV VLP plus CT. These results suggest that VLPs are effective mucosal antigens that can induce both humoral and cellular immune responses at systemic and mucosal sites.

Administration, Intranasal↗
PubMed1995

Commensal enteric bacteria engender a self-limiting humoral mucosal immune response while permanently colonizing the gut.

We have employed a germfree mouse model to study the development and persistence of a humoral mucosal immune response to a gram-negative murine commensal organism, Morganella morganii. M. morganii bacteria rapidly colonize the gut, resulting in hypertrophy of Peyer's patches (PP), including germinal center reactions (GCR), and the development of specific immunoglobulin A (IgA) responses detected in vitro in PP fragment cultures and by ELISPOT assays of lamina propria cells. The GCR peaks 14 days after infection and begins to wane thereafter. Upon colonization, the organisms successfully translocate to the mesenteric lymph node and spleen, but the number of translocating bacteria begins to drop with the onset of a specific IgA response. A clonal B-cell microculture technique was used to determine the frequency of specific IgA plasmablasts and IgA memory cells. The frequencies of preplasmablasts were seen to be higher in the earlier stages of germinal center development, whereas the frequencies of antigen-specific memory cells appeared to remain at a relatively constant level even after 193 days postmonoassociation. We suggest that a successful secretory IgA response can attenuate chronic stimulation of GCR even though the bacteria persist in the gut. The observed developing hyporesponsiveness to a chronically present commensal organism may be relevant to the use of bacterial vectors for mucosal immunization.

Animals↗
PubMed2006

1,25-dihydroxyvitamin d3 enhances systemic and mucosal immune responses to inactivated poliovirus vaccine in mice.

1,25-Dihydroxyvitamin D3 (DHVD3) coadministered with monovalent inactivated poliovirus vaccine (IPV) of all 3 serotypes significantly enhances antipoliovirus systemic and mucosal immunity in mice. Although serum immunoglobulin G antibodies are significantly higher in serotypes 2 and 3, and although salivary immunoglobulin A is significantly increased in serotypes 1 and 3, DHVD3 had the most dramatic effect on the level of neutralizing serum antibodies of all 3 IPV serotypes. These findings suggest a possible use of vitamin D3 as an adjuvant for currently used and proposed new Sabin IPVs.

Animals↗
PubMed2006

Systemic and mucosal immunity to respiratory syncytial virus induced by recombinant Streptococcus gordonii surface-displaying a domain of viral glycoprotein G.

A conserved fragment comprising amino acid residues 130-230 of the G glycoprotein of human respiratory syncytial virus subtype A was expressed in the commensal bacterium Streptococcus gordonii. Recombinant streptococci displaying the G domain at the cell surface were used to immunize mice via both parenteral and mucosal routes. Subcutaneous immunization induced respiratory syncytial virus-specific serum immunoglobin G (IgG) capable of partially controlling virus replication in the lungs. Intranasal immunization with live bacteria stimulated the production of IgA against both the whole virus and the G domain in serum and bronchoalveolar fluid. Upon challenge, immunized animals had significantly lower virus titres in the lungs than the controls. Our results show for the first time that the G domain-expressing S. gordonii strain elicits both systemic and mucosal immunity that reduced respiratory syncytial virus replication in the lungs of mice.

Animals↗
PubMed1988

The IgA mucosal immune system.

This report reviews the immunophysiology of the mucosal immune system, the principal antibody of which is a special form of IgA, termed secretory IgA. This IgA is produced locally by mucosal plasma cells that are descended from precursors initially stimulated in organized, mucosal lymphoid organs designed for antigen sampling. After the initial triggering, the precursor cells pass via regional lymph nodes, lymph, and blood to disseminate widely among mucosal sites. After secretion from a local plasma cell, IgA binds to an epithelial cell surface receptor and the complex passes through the epithelial cell into the secretions where it serves as a nonphlogistic immunologic barrier to inhibit uptake of antigens. The production of IgA is facilitated by particular regulatory T cells. At the same time, the synthesis of other classes of antibody, such as the phlogistic IgG, is dampened. This differential regulation of individual antibody classes after exposure to mucosal antigen plus the interrelatedness of the various mucous membranes of the body have important implications for host defense, pathogenesis of a variety of diseases including IgA nephropathy, and strategies of immunization.

Antigen-Antibody Complex↗
PubMed2005

Mucosal immunization of CD4+ T cell-deficient mice with an inactivated virus induces IgG and IgA responses in serum and mucosal secretions.

Immunoglobulin (Ig) class switching can occur in the absence of alphabeta+ or gammadelta+ T cells when mice are infected with certain live viruses, although CD4 T helper cells are believed to be essential for induction of a high-affinity antibody response and for efficient isotype switching from IgM to IgG and IgA production. However, little information is available about the immune responses after mucosal immunization of CD4+ T cell-deficient mice with inactivated virus. In this study, we show that intranasal immunization with formalin-inactivated influenza A/PR8/34 virus induces IgG and IgA responses in serum and IgA responses in mucosal secretions in CD4+ T cell-deficient mice. All four subclasses of IgG were produced. IgG1/IgG2a ratios were found to be from 1 to 1.75, indicating that both Th1 and Th2 immune responses are induced by the inactivated influenza virus. The sera and mucosal secretions were found to have neutralizing activity against influenza virus in vitro. In addition, the mucosally immunized CD4+ T cell-deficient mice were protected completely from challenge with a lethal dose of live, pathogenic influenza virus. To our knowledge, this is the first demonstration that mucosal immunization with an inactivated virus induces immune responses in serum and mucosal secretions in CD4+ T cell-deficient mice.

Animals↗
PubMed2001

Serum and mucosal immune responses to an inactivated influenza virus vaccine induced by epidermal powder immunization.

Both circulating and mucosal antibodies are considered important for protection against infection by influenza virus in humans and animals. However, current inactivated vaccines administered by intramuscular injection using a syringe and needle elicit primarily circulating antibodies. In this study, we report that epidermal powder immunization (EPI) via a unique powder delivery system elicits both serum and mucosal antibodies to an inactivated influenza virus vaccine. Serum antibody responses to influenza vaccine following EPI were enhanced by codelivery of cholera toxin (CT), a synthetic oligodeoxynucleotide containing immunostimulatory CpG motifs (CpG DNA), or the combination of these two adjuvants. In addition, secretory immunoglobulin A (sIgA) antibodies were detected in the saliva and mucosal lavages of the small intestine, trachea, and vaginal tract, although the titers were much lower than the IgG titers. The local origin of the sIgA antibodies was further shown by measuring antibodies released from cultured tracheal and small intestinal fragments and by detecting antigen-specific IgA-secreting cells in the lamina propria using ELISPOT assays. EPI with a single dose of influenza vaccine containing CT or CT and CpG DNA conferred complete protection against lethal challenges with an influenza virus isolated 30 years ago, whereas a prime and boost immunizations were required for protection in the absence of an adjuvant. The ability to elicit augmented circulating antibody and mucosal antibody responses makes EPI a promising alternative to needle injection for administering vaccines against influenza and other diseases.

Adjuvants, Immunologic↗
PubMed1993

New perspectives in mucosal immunity with emphasis on vaccine development.

In this review, we have purposely focused on five areas that are currently receiving extensive research attention and will be of major importance for development of mucosal and systemic immunity to oral vaccines. These five areas include the following: (1) helper T-cell (Th) subsets and cytokines for mucosal IgA responses; (2) Th1- and Th2-type subsets in regulation of mucosal IgA responses; (3) antigen uptake and presentation in the mucosal immune system; (4) the importance of memory in mucosal immunity to vaccines; and (5) the determination of whether oral immunization alone induces immunity in all mucosal effector tissues. It is now established that the mucosal immune system can be divided into discrete mucosal inductive sites where vaccines/antigens are encountered and taken up, processed, and presented to B and T cells, and separate areas where immune cells actually function (mucosal effector tissues). Further, through the help provided by Th cells and cytokines, the B cells respond to antigen and undergo expansion including memory cell formation. Following the migration of memory B cells to mucosal effector tissues, the cells rapidly develop into IgA plasma cells, and the prevalence of the latter cell type represents a major characteristic of mucosal effector tissues. It also appears that antigen-specific Th cells and perhaps even CD8+ cytotoxic T lymphocytes can make this circular journey (along with memory/activated B cells) from inductive to mucosal effector sites, and this is termed the common mucosal immune system (CMIS). The major implications of the CMIS for development of vaccines would include each of the five components that are discussed.

Administration, Oral↗
PubMed2001

Apoptosis: one of the mechanisms that maintains unresponsiveness of the intestinal mucosal immune system.

Intestinal mucosa is constantly exposed to environmental AGS: Activation of lamina propria (LP) T cells by luminal Ags may lead to the production of inflammatory cytokines and subsequent mucosal inflammation and tissue damage. However, in normal circumstances, LP T cells do not respond to antigenic stimulation. The mechanisms of this unresponsiveness in healthy subjects are not fully understood. In this study, we found by in vivo analysis that, except for T cells in lymph nodules of the mucosa, 15% of LP T cells underwent apoptosis in normal individuals. In contrast, there was a marked reduction in apoptosis of LP T cells in patients with inflammatory bowel disease (Crohn's disease and ulcerative colitis) and those with specific colitis. Our findings suggest that apoptosis might be a mechanism that turns off mucosal T cell responses to environmental Ags in healthy subjects, and resistance to apoptosis could be an important cause of mucosal immune dysregulation and tissue inflammation in colitis.

Apoptosis↗
PubMed1985

Effect of protein deprivation on immunoregulatory cells in the rat mucosal immune response.

Secretory IgA antibody responses such as those directed against respiratory and enteric pathogens, may be impaired in protein-calorie malnutrition. In previous studies using a rat model of the mucosal immune response to cholera toxin, as little as 2 weeks of severe protein deprivation markedly impaired mucosal anti-toxin production. The present studies examined the effect of protein deprivation on lymphocyte populations which adoptively transfer either priming or suppression of a mucosal anti-toxin response from malnourished donor rats to syngeneic well nourished recipients. Either 2 or 8 weeks of protein deprivation severely impaired the development of thoracic duct lymphocytes which could transfer priming or suppression after intraduodenal priming, and impaired splenic suppressor cell development after s.c. priming. The abrogation of suppression by protein deprivation was dependent on the dose of s.c. antigen used to induce suppression. Refeeding rats after two months of protein deprivation led to recovery of both priming cell and suppressor cell function. Severe protein deprivation induces a reversible defect in both priming and suppressor cell populations; the net effect is an impaired mucosal immune response.

Animals↗
PubMed2006

Strong systemic and mucosal immune responses to surface-modified PLGA microspheres containing recombinant hepatitis B antigen administered intranasally.

Surface-modified DL-lactide/glycolide copolymer (PLGA) microspheres with chitosan (CS) were developed for nasal immunization using recombinant Hepatitis B (HBsAg) surface protein for the induction of humoral, cellular and mucosal immunity. Modified PLGA microspheres were characterized in vitro for their size, shape, entrapment efficiency and zeta potential. The nasal clearance rate was evaluated by gamma scintigraphy in rabbits. The antigen integrity, in vitro release and its stability at 37 degrees C were also evaluated. The designed cationic microspheres possessed 27.2 mV zeta potential and an average size less than 10 microm with antigen loading efficiency of 80+/-5%. However, zeta potential of unmodified PLGA microspheres was measured to be negative (-8.7 mV). The modified PLGA microspheres showed the lowest nasal clearance rate when compared with unmodified PLGA microspheres and lactose powder. The antigen integrity was retained intact in encapsulated form as well as on release. The immune-stimulating activity was studied by measuring anti-HBsAg titre, secretory IgA level in serum, vaginal, nasal and salivary secretions (mucosal secretions) and cytokine level (interleukin-2 (IL-2) and interferon-gamma (IFN-gamma)) in spleen homogenates following nasal administration of modified PLGA microspheres in Balb/c mice and compared with alum-HBsAg vaccine injected subcutaneously. The serum anti-HBsAg titre obtained after nasal administration of modified PLGA microspheres was comparable with titre recorded after alum-HBsAg was administered subcutaneously. Moreover, alum-HBsAg vaccine did not elicit sIgA in mucosal secretions as it was induced and measured in the case of nasal administration of modified PLGA microspheres. Similarly, there was no cellular response (cytokine level) in case of alum-HBsAg vaccine. Modified PLGA microspheres (cationic microspheres) thus produced humoral (both systemic and mucosal) and cellular immune responses upon nasal administration. These data demonstrate high potential of modified PLGA microspheres for their use as a carrier adjuvant for nasal subunit vaccines.

Administration, Intranasal↗
PubMed2006

Effects of cyadox and olaquindox on intestinal mucosal immunity and on fecal shedding of Escherichia coli in piglets.

A 2 x 3 factorial arrangement of treatments was used to determine the effects of olaquindox and cyadox on the intestinal mucosal immune response and on fecal shedding of Escherichia coli in Landrace x Large White barrows that had been orally given 10(10) cfu of E. coli (O139:K88). Factors included 1) E. coli inoculation or no inoculation, and 2) no antimicrobial, 100 mg of olaquindox/kg, and 100 mg of cyadox/kg in the basal diet, respectively. The effects of cyadox and olaquindox were assessed in terms of fecal shedding of E. coli, the number of intraepithelial lymphocytes (IEL), immunoglobulin A-positive cells (APC) in the intestinal lamina propria, and ADG. There was no difference in the fecal shedding of total E. coli or the inoculated E. coli between olaquindox-supplemented pigs and cyadox-supplemented pigs during the experiment. However, fecal shedding of the inoculated E. coli in olaquindox- or cyadox-supplemented pigs was less (P < 0.05) than that in nonsupplemented pigs. Escherichia coli inoculation increased IEL and APC in the jejunum and ileum, but olaquindox or cyadox decreased IEL and APC (P < 0.05). Jejunal APC in cyadox-supplemented pigs was less (P < 0.05) than that in olaquindox-supplemented pigs. Escherichia coli inoculation reduced (P < 0.05) ADG, whereas the supplementations improved ADG (P < 0.01) during the experiment. Average daily gain in cyadox-supplemented pigs was greater (P < 0.05) than that in olaquindox-supplemented pigs. The data indicated that olaquindox and cyadox reduced the number of intestinal E. coli and suppressed E. coli-induced immune activation, which might be responsible for the enhanced growth that was observed.

Animals↗
PubMed1996

Antigen sampling across epithelial barriers and induction of mucosal immune responses.

Epithelial barriers on mucosal surfaces at different sites in the body differ dramatically in their cellular organization, and antigen sampling strategies at diverse mucosal sites are adapted accordingly. In stratified and pseudostratified epithelia, dendritic cells migrate to the outer limit of the epithelium, where they sample antigens for subsequent presentation in local or distant organized lymphoid tissues. In simple epithelia, specialized epithelial M cells (a phenotype that occurs only in the epithelium over organized lymphoid follicles) deliver samples of foreign material by transepithelial transport from the lumen to organized lymphoid tissues within the mucosa. Certain pathogens exploit the M cell transport process to cross the epithelial barrier and invade the mucosa. Here we review the features of M cells that determine antigen and pathogen adherence and transport into mucosal lymphoid tissues.

Animals↗
PubMedDate not supplied

Peyer's patches: organized lymphoid structures for the induction of mucosal immune responses in the intestine.

Peyer's patches (PP) comprise transmucosal clusters of lymphoid follicles overlaid with a specialized lympho-epithelium and consequently play a central role in the induction of mucosal immune responses in the gut. Despite considerable achievements in the last 3 decades, in our understanding of how PP are involved in the induction of immune responses, much remains to be learned about these major organized lymphoid organs. The history and current status of PP termed 'the major inductive site of immune responses' is reviewed. The present understanding of PP biology and function, taking into account their preferential and unique retention of immune competent cells at specific sites, is discussed.

Animals↗