Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “mucosal immunization”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,027 records · Page 57Linked to original sources

Novel approaches for the induction of T helper 1 (Th1)- or Th2-type mucosal and parenteral immune responses.

Mucosal surfaces are constantly challenged by micro-organisms and are protected by an integrated component of the immune system called mucosa-associated lymphoreticular tissue (MALT). The immune responses elicited at the mucosal level are regulated by T-helper (Th) cells and involve secretory IgA (S-IgA) antibodies (Abs) and cytotoxic T-lymphocytes (CTLs). Mucosal immunisation has the advantage over parenteral immunisation, of inducing S-IgA Abs and of conferring protection at both the mucosal and parenteral levels; however, administration of soluble antigens through a mucosal route very seldom results in significant mucosal and systemic immune responses. Therefore, appropriate mucosal adjuvants, recombinant bacterial and viral vectors and delivery systems have been developed to increase the immunogenicity of vaccine antigens and to preferentially induce antigen-specific T-helper (Th)1- or Th2-type responses, which in turn result in polarised effector immune responses. Understanding the mechanisms underlying Th1- and Th2-type developmental pathways and the ability of novel mucosal adjuvants and delivery systems to target the desired Th1- or Th2-type immune response would help to design effective mucosal vaccines, inducing predominant cell-mediated or humoral responses.

Journal Article↗

Towards targeting strategies for oral immunization--identification of marker antigens in rat M cells.

Specialized M cells of the follicle-associated epithelium (FAE) of Peyer's patches in the gastrointestinal and respiratory tracts play a crucial role in the immune surveillance of mucosal surfaces and are essential for the induction of mucosal immune responses. These cells transport luminal antigens to the underlying germinal centers and thereby initiate an immune response or induce tolerance. Mucosal immune responses could be significantly enhanced if oral antigens could be directly targeted to the apical surface of M cells. However, thus far M cells have not been isolated and suitable surface markers have not been described. For the characterization and identification of potential molecular markers of M cells the follicle associated epithelium of Peyer's patches from the small intestine of rats was analyzed by indirect immunofluorescence and immunogold electronmicroscopy. The expression of intermediate filament proteins in the FAE was found to be heterogeneous. Immunoreactivity of a specific monoclonal cytokeratin 8 antibody (clone 4.1.18) was selectively found in cells which were additionally characterized by the lack of staining for alkaline phosphatase in their apical membranes. In the FAE this property is an accepted criterium for the presence of M cells. The antigen recognized by the clone 4.1.18 is expressed in substantially higher amounts in M cells of Peyer's patches as compared to neighbouring epithelial cells or "normal" enterocytes and thus can be employed as an intracellular molecular marker for M cells of Peyer's patches in rats. It is expected, that this marker will be very helpful for the isolation of M cells.

Administration, Oral↗

Oral administration of second-generation immunomodulatory oligonucleotides induces mucosal Th1 immune responses and adjuvant activity.

CpG DNA induces potent Th1 immune responses through Toll-like receptor 9. In the present study, we used oligonucleotides consisting of a novel 3'-3'-linked structure and synthetic stimulatory motifs, referred as second-generation immunomodulatory oligonucleotides (IMOs). The stimulatory motifs included: CpR, YpG, or R'pG (R = 2'-deoxy-7-deazaguanosine, Y = 2'-deoxy-5-hydroxy-cytidine, and R' = 1-[2'-deoxy-beta-d-ribofuranosyl]-2-oxo-7-deaza-8-methyl-purine). We evaluated the stability of orally administered IMOs in the gastrointestinal (GI) environment and their ability to induce mucosal immune responses in mice, and compared these characteristics with those of a conventional CpG DNA. The IMOs were significantly more stable than CpG DNA following oral administration, and IMOs induced stronger local and systemic immune responses as determined by MIP-1beta, MCP-1, IP-10, and IL-12 production. Mice orally immunized with ovalbumin (OVA) and IMO had higher levels of IgG2a antibodies in serum and IgA antibodies in intestinal mucosa than did mice immunized with OVA and CpG DNA. These studies demonstrate that IMOs are more stable than CpG DNA in the GI tract and can induce more potent mucosal Th1 adjuvant responses. IMOs may prove to be effective oral adjuvants, able to promote strong systemic and mucosal immune responses to oral vaccines and antigens for therapeutic and prophylactic applications.

Administration, Oral↗

The enteric immune response to shigella antigens.

Mucosal immunity to some enteropathogens occurs naturally following infection. By learning how to optimize initiation of the mucosal immune response it will be possible to develop vaccines against a wide variety of enteropathogens and their toxic products. In the past few years, we have examined stimulation of the mucosal response to Shigella antigens. We have found that the mucosal memory response to Shigella LPS can be stimulated by oral immunization with live, but not with killed Shigella. This primes specific B lymphocytes which, following rechallenge, quickly migrate from the Peyer's patches to mesenteric lymph nodes, the spleen, and back to the Peyer's patches. We have found that the uptake of S. flexneri is the initial step in developing a mucosal immune response to Shigella. Whereas there is little difference between the initial uptake of virulent and avirulent bacteria by M cells, pathogenic strains of Shigella are able to replicate following their uptake by the specialized M cells located in the follicle-associated epithelium of the gut. This likely serves as the source of the ulcerative lesions found in dysentery. Lastly, we have detected a vigorous secretory IgA response to Shiga toxin. The titer of IgA activity to Shiga toxin from these loop secretions correlated well with the ability to prevent Shiga toxin cytotoxin effects in vitro. The extremely vigorous mucosal immune response to Shiga toxin makes this an attractive alternative to cholera toxin to potentiate the secretory IgA immune response.

Administration, Oral↗

Vaccination of puppies born to immune dams with a canine adenovirus-based vaccine protects against a canine distemper virus challenge.

None of the currently available distemper vaccines provides a satisfactory solution for the immunization of very young carnivores in the face of maternal-derived immunity. Since mucosal immunization with replication-competent adenovirus-based vaccines has been proven effective in the face of passive immunity against the vector, it has the potential to provide a solution for the vaccination of young puppies born to canine distemper virus (CDV)-immune dams. We report the engineering and the characterization of two replication-competent canine adenovirus type 2 (CAV2)-based vaccines expressing, respectively, the CDV hemagglutinin (HA) and fusion (F) antigens. We first demonstrated that the intranasal vaccination with a mixture of both recombinant CAV2s provides an excellent level of protection in seronegative puppies, confirming the value of replication-competent adenovirus-based vectors for mucosal vaccination. In contrast, intranasal immunization with the same vaccine of puppies born to CDV- and CAV2-immune dams, failed to activate specific and protective immune responses. We hypothesized that an active CAV2 infection occurred while puppies were in close contact with the vaccinated dams in the breeding units and that the resulting active mucosal immunity interfered with the intranasal administration of CAV2-based CDV vaccine. However, when puppies born to CDV- and CAV2-immune dams were vaccinated subcutaneously with the CAV2-based CDV vaccine, significant seroconversion and solid protective immunity were triggered despite pre-existing systemic immunity to the vector. This latter result is surprising and suggests that subcutaneous vaccination with a replication-competent recombinant CAV2 may be an efficient strategy to overcome both passive and active adenovirus specific immunity in the dog. From a practical point of view, this could pave the way for an original strategy to vaccinate young puppies in the face of maternal-derived immunity.

Adenoviruses, Canine↗

Intestinal drug delivery systems with biodegradable microspheres targeting mucosal immune-regulating cells for chronic inflammatory colitis.

We developed two kinds of delivery systems targeting mucosal immune regulating cells with poly (D,L-lactic acid) microspheres containing dexamethasone and dichloromethylene diphosphonate, and gelatine microspheres containing interleukin-10. To estimate the efficacy of these drug delivery systems, we studied the effects on experimental colitis induced by dextran sodium sulfate, 2,4,6-trinitrobenzene sulfonic acid, and interleukin-10-deficient mice. Intestinal administration of these microspheres significantly improved colitis with decreased histological score, myeloperoxidase activity, and nitric oxide production compared with mice treated with free agents. Gene expressions of tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma were down-regulated in treated animals. Serum Dx, IL-10 levels, and systemic macrophages were unchanged after treatment. Our findings suggest that local macrophages in the intestine play a critical role in the initiation of chronic colitis in the animal model of inflammatory bowel disease (IBD). Intestinal drug delivery systems with biodegradable microspheres targeting mucosal immune-regulating cells may become a therapeutic approach to human IBD.

Animals↗

Mucosal humoral immunity to experimental Salmonella enteritidis infection in the chicken crop.

In this report, we show that chickens, infected with Salmonella enteritidis (SE) by oral gavage, produce secretory immunoglobulin As (sIgAs) that specifically bind to numerous SE antigens. Chickens infected with SE showed strong sIgA response against flagella in both bile and crop. The optical density values of enzyme-linked immunosorbent assay (ELISA) tests in positive bile and crop were 1.17 and 0.38, respectively, and were significantly different from those of negative samples. Western immunoblotting revealed that approximately 13.5-, approximately 56-, approximately 62-, approximately 80-, and approximately 143-kD polypeptides were immunodominant proteins in bile, whereas approximately 56-, approximately 62-, and approximately 80-kD polypeptides were found to be strong antigens in crop. These results indicate that the crop may function as another site for mucosal immunity, and the SE flagella-based ELISA of crop samples can provide a useful screening test of SE exposure in chickens.

Animals↗

HIV vaccine and genital secretory immune response.

This review will summarize the function of the normal mucosal immune system and will highlight its role in the heterosexual transmission of HIV. The discussion of reproductive system mucosal immunity will be limited to the female genital tract with the understanding that this is only half of the story. An excellent review of the mucosal immune system in the male genital tract and its implications on the transmission of HIV has recently been published. As emphasized in recent editorials, a better understanding of genital mucosal immunity will ultimately allow us to manipulate the mucosal immune system and, hopefully, design vaccines to prevent the sexual transmission of HIV.

AIDS Vaccines↗

The functions of mucosal T cells in containing the indigenous commensal flora of the intestine.

There is an immense load of non-pathogenic commensal bacteria in the distal small intestine and the colon of mammals. The physical barrier that prevents penetration (translocation) of these organisms into the body is a simple epithelium comprised of the single enterocyte/colonocyte cell layer with its overlying mucus. In this review, we discuss the roles of intestinal T cells in initiating and regulating innate and adaptive mucosal immune responses of the mucosal immune system that avoid or limit penetration of the commensal intestinal bacteria.

Animals↗

A Phase I safety and immunogenicity trial of UBI microparticulate monovalent HIV-1 MN oral peptide immunogen with parenteral boost in HIV-1 seronegative human subjects.

Thirty-three HIV-seronegative adults were recruited into a Phase I safety and immunogenicity HIV-1 vaccine trial. The immunogens were as follows: a synthetic, monovalent, octameric HIV-1 MN V3 peptide in aluminum hydroxide (alum) adjuvant administered by intramuscular delivery; and a similar product encapsulated in biodegradable micro-spheres composed of co-polymers of lactic and glycolic acids, administered by the oral route. These were administered in three sequential oral doses, followed by a parenteral boost. No serious adverse experiences were observed. Oral administration of this vaccine, alone or in combination with parenteral boosting, resulted in no significant humoral, cellular, or mucosal immune responses.

AIDS Vaccines↗

Simultaneous induction of specific immunoglobulin A--producing cells in major and minor salivary glands after tonsillar application of antigen in rabbits.

The immunoglobulin A (IgA)-producing cells in the stroma of major salivary glands are induced by antigenic stimulation of the mucosal immune system. Whether such cells also are induced in minor salivary glands by this stimulation remains to be determined. After application of sheep red blood cells to the palatine tonsils every 3 days for 6 weeks, anti-sheep red blood cell IgA was detected in saliva both by agglutination tests and by enzyme-linked immunosorbent assay. Using enzyme-linked immunospot assay, an increase in the number of anti-sheep red blood cell IgA-producing cells was found in minor as well as in major salivary glands of the sixth week of application; such cells constituted 4.9% to 5.9% of the total number of IgA-producing cells in these tissues. Tonsillar application of whole cells of formalin-killed Streptococcus sobrinus induced anti-S. sobrinus IgA in saliva. The number of anti-S. sobrinus IgA-producing cells in the above glands simultaneously increased over 6 weeks, and reached 5.2-5.6% of the total number of IgA-producing cells.

Animals↗

Kinetics of inflammatory cytokines in the clearance of non-typeable Haemophilus influenzae from the lung.

Levels of the pro-inflammatory cytokines TNF-alpha and IFN-gamma were measured from the time of infection to the time of complete clearance of non-typeable Haemophilus influenzae (NTHi) from the lung in immune and non-immune rats. Mucosal immunization facilitated production of significant levels of TNF-alpha as early as 30 min post-pulmonary challenge with NTHi in immune animals. Following the peak at 2 h, rapid decline of TNF-alpha levels occurred from the alveolar spaces. Levels of TNF-alpha in non-immunized animals increased at a slower rate, peaked at a lower concentration and were slower to decline. The significantly larger number of macrophages seen in the immune animals at 1 h after bacterial challenge could partially account for the higher levels of TNF-alpha. Interferon-gamma was not detected in immune or non-immune rats at any time point before NTHi clearance after pulmonary challenge. Study of the kinetics of TNF-alpha release demonstrates that immunized animals control the release of pro-inflammatory cytokines more effectively than non-immunized animals for enhanced clearance of bacterial infection from the lungs.

Animals↗

Studies on the generation and maintenance of mucosal cytotoxic T lymphocytes against human immunodeficiency virus type 1 Gag in mice.

Aspects of the generation and maintenance of mucosal immunity against human immunodeficiency virus type 1 (HIV-1) were examined. Mice were immunized either intranasally or intrarectally with recombinant HIV-1 Gag p24 protein plus cholera toxin. Nasal immunization generated strong nasal IgA responses but low vaginal IgA, whereas rectal immunization yielded good vaginal IgA responses but poor nasal responses. Nasal immunization resulted in strong Gag-specific cytotoxic T lymphocyte (CTL) activity in nasal-associated lymphoid tissue (NALT), posterior cervical lymph nodes (pCLNs), and the spleen, but not in mesenteric lymph nodes (MLNs). Rectal immunization induced weak Gag-specific CTLs in the MLNs only, indicating distinct compartmentalization of the upper and lower mucosa. Combining nasal and rectal immunizations overcame their respective deficiencies. CTL memory after the third nasal immunization was found to persist for up to 6 months in the draining pCLNs, but was gradually lost from the NALT induction site. Analysis of the T cell receptor Vbeta usage of Gag-specific CD8(+) T cells in lymphoid tissues of intranasally immunized mice indicated that the memory CTLs in the pCLNs are generated from a few clones in NALT. The memory CTL clones also appear to be poor killers whereas the NALT clones from which the pCLN clones appear to originate are potent killers. Our results support the view that CTL activity is determined by the level and duration of antigen stimulation and that in NALT, CTLs develop as effector memory T cells with high avidity, whereas the pCLNs sequester the memory T cells with low avidity but longer survival.

AIDS Vaccines↗

Mucosal immunisation with Clostridium botulinum type C 16 S toxoid and its non-toxic component.

Clostridium botulinum types C and D produce a 16 S (500 kDa) toxin that is formed by conjugation of neurotoxin with a non-toxic component (nonTox). The amino acid sequences of type C and D nonTox components are almost identical. In a previous report it was proposed that nonTox is necessary for the effective absorption of the toxin from the small intestine. This suggested the hypothesis that mucosal immunity against nonTox in the small intestine might prevent the absorption of both C- and D-16 S toxins. The nonTox was purified from a mutant strain, (C)-N71, that does not produce neurotoxin. This nonTox or detoxified C-16 S toxin were mixed with adjuvant (a mutant form of heat-labile toxin of Escherichia coli), and inoculated into mice via the nasal or oral route, or both. The mice inoculated nasally four times with nonTox or toxoid produced high levels of antibodies (including IgA) against the immunogens, both in intestinal fluids and sera. When these nonTox-immunised mice were challenged orally with 2 and 20 oral minimum lethal doses (MLD) of C- or D-16 S toxins, the same results were obtained with both C and D; the mice survived after challenge with 2 MLD of either C or D but were killed by 20 MLD of either toxin although the time to death was significantly longer than in the control non-immunised mice. These results indicate that the local anti-nonTox antibodies reduce absorption of both C- and D-16 S toxins from the small intestine. The C-16 S toxoid-immunised mice showed similar behaviour with type D toxin challenge, probably due to the same mechanism, but were protected against 20 MLD of C-16 S toxin.

Administration, Intranasal↗

The pathogenesis of gluten-sensitive enteropathy.

Gluten-sensitive enteropathy is characterized by flattening of intestinal villi and malabsorption caused by the toxic effect of gluten, a wheat protein. Gluten activates an endogenous mechanism of toxicity that may be the local mucosal immune system: local mucosal immunoglobulin and antigluten antibody production occur soon after gluten ingestion. Approximately 80% of patients with this disease possess HL-A8, a second segregant series antigen. This association also occurs in dermatitis herpetiformis, a disease with vesicular skin lesions and gluten-sensitive flattening of intestinal villi. The association suggests that the fundamental abnormality in enteropathy is a binding reaction involving gluten protein and a binding site on a cell surface, determined in part by the histocompatibility gene; this reaction then results in a local mucosal immune response to gluten. Alternatively, the fundamental abnormality may be the presence of an abnormal immune-response gene linked to the HL-A8 gene or acting in concert with it; this immune-response gene results in local mucosal production of antigluten antibody.

Adult↗

Absorption and imagery locate immune responses in the body.

Imagery instructions specifying mucosal immunity should alter mucosal immunoglobulin A (m-IgA) levels in high absorbers, whose intent concentration evokes intense physiological responses. After screening for health status, 121 high or low absorbers were randomly assigned to either Relaxation Alone (R), Relaxation with Mucosal Immune Imagery (RI), or Vigilance Task control (VT). Before and after one 60-min intervention, subjects reported theory-relevant psychological variables and provided 5 ml whole saliva, which was immediately frozen and assayed later en masse with enzyme-linked immunoabsorbence (ELISA). MANOVA analysis of psychological variables replicated past research. ANOVA on residualized m-IgA found Time x Absorption interaction and Condition main effects. High more than low absorbers responded to relaxation with mucosal immune imagery by producing higher m-IgA. High absorbers appear able to locate where their immune systems will respond. Individual differences like absorption level need to be emphasized in diagnosis and treatment responsiveness.

Absorption↗

Induction of specific immunity at mucosal surfaces: prospects for vaccine development.

We have demonstrated the feasibility of studying antigen-specific immune responses in a variety of mucosal tissues in humans after vaccination and during infection. In this respect, we have documented the usefulness of both oral cholera and ETEC vaccines for assessing in functional terms specific subpopulations of B- and T-cell immunocytes during an immune response initiated and/or expressed in human mucosal tissues. Circulating specific IgA antibody-secreting cells in blood appear to reflect recent or ongoing antigen exposure of mucosal surfaces. This implies that the detection of such cells in blood, the most accessible lymphoid compartment in humans, represents the simplest way to assess the immunogenicity of mucosal vaccines and to supplement the diagnostic and monitoring of active mucosal infections. Our studies indicate that while the concept of an integrated mucosal immune network is clearly operational in humans (at least in regards to induction of secretory antibody responses), its generalization appears somewhat simplistic as illustrated by the compartmentalization of immune responses initiated in certain mucosal organs such as the small intestine and the tonsils. Finally, the potential of the cholera toxin B subunit as a carrier for delivery of chemically or genetically linked foreign epitopes for induction of disseminated mucosal immune responses raises hope for the development of broadly applicable vaccines to control mucosal infections.

Animals↗

Mucosal and systemic adjuvant activity of alphavirus replicon particles.

Vaccination represents the most effective control measure in the fight against infectious diseases. Local mucosal immune responses are critical for protection from, and resolution of, infection by numerous mucosal pathogens. Antigen processing across mucosal surfaces is the natural route by which mucosal immunity is generated, as peripheral antigen delivery typically fails to induce mucosal immune responses. However, we demonstrate in this article that mucosal immune responses are evident at multiple mucosal surfaces after parenteral delivery of Venezuelan equine encephalitis virus replicon particles (VRP). Moreover, coinoculation of null VRP (not expressing any transgene) with inactivated influenza virions, or ovalbumin, resulted in a significant increase in antigen-specific systemic IgG and fecal IgA antibodies, compared with antigen alone. Pretreatment of VRP with UV light largely abrogated this adjuvant effect. These results demonstrate that alphavirus replicon particles possess intrinsic systemic and mucosal adjuvant activity and suggest that VRP RNA replication is the trigger for this activity. We feel that these observations and the continued experimentation they stimulate will ultimately define the specific components of an alternative pathway for the induction of mucosal immunity, and if the activity is evident in humans, will enable new possibilities for safe and inexpensive subunit and inactivated vaccines.

Adjuvants, Immunologic↗