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Results for “mucosal immunization”

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PubMed2003

Protective levels of diphtheria-neutralizing antibody induced in healthy volunteers by unilateral priming-boosting intranasal immunization associated with restricted ipsilateral mucosal secretory immunoglobulin a.

Subunit intranasal vaccines offer the prospect of inducing combined systemic-mucosal immunity against mucosally transmitted infections such as human immunodeficiency virus. However, although human studies have demonstrated the induction of active immunity, secretory immunoglobulin A (sIgA) responses are variable, and no study has demonstrated protection by accepted vaccine-licensing criteria as measured by direct toxin-neutralizing activity. Using the genetically inactivated mutant diphtheria toxoid CRM(197) in a bioadhesive polycationic polysaccharide chitosan delivery system, we found that a single nasal immunization was well tolerated and boosted antitoxin neutralizing activity in healthy volunteers, which could be further boosted by a second immunization. The neutralizing activity far exceeded accepted protective levels and was equivalent to that induced by standard intramuscular vaccine and significantly greater than intranasal immunization with CRM(197) in the absence of chitosan. A striking but unexpected observation was that although unilateral intranasal immunization induced circulating antitoxin antibody-secreting cells, a nasal antitoxin sIgA response was seen only after the second immunization and only in the vaccinated nostril. If these data are reproduced in larger studies, an intranasal diphtheria vaccine based on CRM(197)-chitosan could be rapidly licensed for human use. However, a restricted sIgA response suggests that care must be taken in the priming-boosting strategy and clinical sampling techniques when evaluating such vaccines for the induction of local mucosal immunity.

Administration, Intranasal↗
PubMed2003

B- and T-cell responses to the mycobacterium surface antigen PstS-1 in the respiratory tract and adjacent tissues. Role of adjuvants and routes of immunization.

Induction of mucosal immunity in the respiratory tract is crucial for protection against respiratory infections. Here, we have investigated the effects of the routes of immunization as well as of three different adjuvants on the induction of mucosal immune responses. Mice were immunized using intranasal (i.n.) or intraperitoneal (i.p.) routes with the mycobacterium PstS-1 antigen. Cholera toxin (CT), detoxified pertussis toxin (detPT) and RU 41.740 from Klebsiella pneumoniae were compared as mucosal adjuvants. Our data showed that i.n. route of immunization induced the most favorable stimulation of mucosal antigen-specific IgA responses supported by mixed Th cells producing IL-4, IL-5, IFN-gamma. In contrast, i.p. immunizations elicited only enhancement of systemic responses, predominantly of the Th2 type. Furthermore, the use of CT as mucosal adjuvant resulted in the stimulation of a mixed Th cell response whereas detPT evoked mainly Th2 type of responses. Likewise CT, the RU 41.740 adjuvant elicited a mixed Th cell response, albeit supported by much lower numbers of CD4(+) T-cells. Thus, i.n. route of immunization favors the induction of mucosal and systemic immune responses, while the Th cell development at mucosal inductive site is influenced by the adjuvant used for immunizations.

Adjuvants, Immunologic↗
PubMed2005

Bacterial modulation of mucosal innate immunity.

The human gut harbours a diverse population of non-pathogenic, commensal bacteria whose contribution to gastrointestinal health and disease is now recognised. This microflora plays an important role in the development and expansion of lymphoid tissues and in the maintenance and regulation of gut immunity. A critical feature of the mucosal immune system is the ability to discriminate between harmful pathogens and the harmless members of the commensal flora. This is achieved in part, by an evolutionary-conserved family of cell surface and cytosolic receptors, referred to as toll-like receptors (TLRs), which function in microbial recognition. Appropriate activation of TLRs has been demonstrated as an essential component of host immunity against pathogens but is also vital for immune homeostasis. The ability of TLRs to discriminate between pathogens and commensals is not clear cut, however, and hence complex regulatory systems, derived both from host and bacterial origin, appear to reinforce and support this system. Host factors that modulate and alter TLR-mediated signaling have recently been defined and are thought to control the level of immune activation. Similarly, certain gut bacteria are also recognised to suppress unnecessary inflammatory responses, thereby helping to maintain immune homeostasis. Their relative contribution to these regulatory processes is currently unknown. The host transcription factor, nuclear factor kappa B (NF-kappaB) has been consistently identified as an important target molecule for bacterial regulation. NF-kappaB, which is also essential for immune activation, is an important therapeutic target for the treatment of inflammatory bowel diseases. Hence, the possibility exists that bacterially derived effector molecules, with defined modes of action, may have clinical relevance and application.

Animals↗
PubMed2000

Correlations between antibody immune responses at different mucosal effector sites are controlled by antigen type and dosage.

Monitoring specific secretory immunoglobulin A (IgA) responses in the intestines after mucosal immunization or infection is impeded by the fact that sampling of small intestinal secretions requires invasive methods not feasible for routine diagnostics. Since IgA plasma cells generated after intragastric immunization are known to populate remote mucosal sites as well, secretory IgA responses at other mucosal surfaces may correlate to those in the intestines and could serve as proxy measures for IgA secretion in the gut. To evaluate the practicability of this approach, mice were immunized intragastrically with 0.2, 2, and 20 mg of ovalbumin plus 10 microg of cholera toxin, and the antigen-specific local secretory IgA responses in duodenal, ileal, jejunal, rectal, and vaginal secretions, saliva, urine, and feces, as well as serum IgG and IgA responses were analyzed by enzyme-linked immunosorbent assay. Correlation analysis revealed significant relationships between serum IgG and IgA, urinary IgA, salivary IgA, and secretory IgA in duodenal, jejunal, ileal, and rectal secretions for the 0.2-mg but not for the 20-mg ovalbumin dose. Fecal samples were poor predictors for intestinal antiovalbumin IgA responses, and no correlations could be established for cholera toxin, neither between local anti-cholera toxin levels nor to the antiovalbumin responses. Thus, specific IgA in serum, saliva, or urine can serve as a predictor of the release of specific IgA at intestinal surfaces after intragastric immunization, but the lack of correlations for high ovalbumin doses and for cholera toxin indicates a strong dependency on antigen type and dosage for these relationships.

Animals↗
PubMed2002

The host-microbe interface within the gut.

Colonization with bacteria is critical for the normal structural and functional development and optimal function of the mucosal immune system. Unrestrained mucosal immune activation in response to bacterial signals from the lumen is, however, a risk factor for inflammatory bowel disease. Therefore, mucosal immune responses to indigenous flora require precise control and an immunosensory capacity for distinguishing commensals from pathogens. The use of germ-free animal models with selective colonization strategies combined with modern molecular techniques promises to clarify the molecular signals responsible for host-flora interactions in health and disease. At least half of the resident flora cannot be cultured by conventional techniques but are identifiable by molecular methods. Collectively, the resident flora represent a virtual organ with a metabolic activity in excess of the liver and a microbiome in excess of the human genome. An improved understanding of this hidden organ holds secrets relevant to several infectious, inflammatory and neoplastic disease mechanisms.

Animals↗
PubMed2006

Rectal immunization with rotavirus virus-like particles induces systemic and mucosal humoral immune responses and protects mice against rotavirus infection.

To evaluate whether the rectal route of immunization may be used to provide appropriate protection against enteric pathogens such as rotaviruses (RV), we studied the antibody response and the protection induced by rectal immunization of mice with RV virus-like particles (VLP). For this purpose, 6-week-old BALBc mice were rectally immunized twice with RV 8-2/6/7-VLP derived from the bovine RV RF81 strain either alone or combined with various adjuvants including four toxins [cholera toxin (CT) and three attenuated Escherichia coli-derived heat-labile toxins (LTs), LT(R192G), LT(R72), and LT(K63)] and two Toll-like receptor-targeting adjuvants (CpG and resiquimod). Six weeks after the second immunization, mice were challenged with murine RV strain ECw. RV VLP administered alone were not immunogenic and did not protect mice against RV challenge. By contrast, RV VLP combined with any of the toxin adjuvants were immunogenic (mice developed significant titers of anti-RV immunoglobulin A [IgA] in both serum and feces and of anti-RV IgG in serum) and either efficiently induced complete protection of the mice (no detectable fecal virus shedding) or, for LT(K63), reduced the amount of fecal virus shedding after RV challenge. When combined with RV VLP, CpG and resiquimod failed to achieve protection, although CpG efficiently induced an antibody response to RV. These results support the consideration of the rectal route for the development of new immunization strategies against RV infection. Rectal delivery of a VLP-based vaccine might allow the use of adjuvants less toxic than, but as efficient as, CT.

Adjuvants, Immunologic↗
PubMed1987

Roles of mucosal mast cells in intestinal cell-mediated immunity.

Mucosal mast cells in rats with GvHR have been studied by cell counts, tissue levels of the specific protease RMCPII, and, as an index of MMC activation, serum RMCPII. In semi-allogeneic GvHR without host irradiation, GvHR produced modest increases in these three indices. In contrast, irradiation profoundly depleted MMC even though enteropathy was more severe than in non-irradiated hosts. We suggest that enteropathy is not dependent on the presence of MMC. In rats given cyclosporin A, lesions of GvHR were mild and numbers of MMC were low.

Animals↗
PubMed2003

Induction of optimal immune responses against human immunodeficiency virus at mucosal portals of entry.

Mucosal surfaces comprise the largest surface area of the human body and are the first line of defense against many pathogens. In fact, over 90% of common infectious disease pathogens in humans gain access to the host through mucosal membranes. A number of studies have demonstrated that mucosal immunizations induce local as well as systemic immunity. However, induction of mucosal responses by mucosal immunization is often hampered by a number of factors including degradation of vaccines at the site of delivery. Moreover, many pathogens, including the human immunodeficiency virus, HIV, primarily enter the host through a mucosal membrane after which they spread systemically. Thus, induction of optimal and protective immune responses are required at both mucosal and systemic sites. This review deals with current efforts on the induction of HIV-specific prophylactic humoral and/or cell mediated immunity in the female genital tract and rectal mucosa. The importance of the various routes of mucosal or systemic as well as combinations of mucosal and systemic immunizations through delivery of gene and protein based experimental vaccines will be reviewed. Furthermore, a summary of current and future therapeutic treatment targets will be presented.

AIDS Vaccines↗
PubMed1999

Optimal induction of upper respiratory tract immunity to reovirus 1/L by combined upper and lower respiratory tract inoculation.

There has been an increasing interest in developing vaccines which are both easy to administer and which elicit functionally protective immune responses at mucosal and/or systemic sites. Intranasally administered vaccines meet the criteria of ease of administration and are thought to stimulate respiratory-mucosal immunity via interaction with nasal associated lymphoid tissues (NALT). The aim of this study was to gain a better understanding of how best to stimulate respiratory-mucosal immunity using a murine model of respiratory reovirus infection. Either a predominantly upper respiratory tract infection or a combination upper and lower respiratory tract infection was established by administering the same virus dose in either a small or large inoculum volume. These studies demonstrate that stimulation of NALT alone by an upper respiratory tract infection does not induce an optimal primary antibody response even in the nasal cavity. Effective immunity of both the upper and lower respiratory tract was obtained when a combination upper and lower respiratory tract infection was established. These results have important clinical implications since they suggest that effective respiratory mucosal immunity will be best achieved by the combined stimulation of both the upper and lower respiratory tract and will likely require both intranasal as well as inhaled aerosol delivery of antigen to the lower respiratory tract in humans.

Administration, Intranasal↗
PubMed2000

Injection of plasmid DNA into the gastric mucosa induces mucosal and systemic immunity.

Nearly all mucosal surfaces participate in a common mucosal immune system, and application of an antigen to one mucosal surface elicits local as well as distant mucosal immune responses. However, whether the gastric mucosa is a part of this network has not been examined directly. We show here that the injection of plasmid DNA encoding beta-galactosidase into the gastric wall caused transfection of gastric mucosal epithelial cells, induced systemic and mucosal antibody responses at both local (digestive tract) and distant (genital and respiratory tracts) sites, and induced cytotoxic T lymphocyte responses in the spleen and the mesenteric and iliac lymph nodes.

Animals↗
PubMed1994

Antibody-secreting cells in acute urinary tract infection as indicators of local immune response.

Mucosal immune mechanisms are believed to be important in host defense against urinary tract infection. To study the human immune response in the urinary tract, peripheral blood antibody-secreting cells (ASC), believed to originate from the mucosal surfaces, were investigated with the enzyme-linked immunospot assay. Pathogen-specific ASC were found in 17 (89%) of 19 patients with pyelonephritis and in 12 (70%) of 17 with LUTI (lower urinary tract infection); for infections caused by Escherichia coli, the respective figures were 17 (100%) and 10 (71%). The responses in pyelonephritis were stronger (P < .001) and lasted longer than those in LUTI: 15 patients with pyelonephritis (74%) but only 1 with LUTI (6%) had > 100 ASC/10(6) cells. A similar difference was seen in the number of all immunoglobulin-secreting cells. The ASC assay offers a new means for assessing the human immune response in urinary tract infection and may be useful in localizing the infection. It might prove valuable in predicting harmful postinfection processes.

Acute Disease↗
PubMed2005

Immune responses induced by lower airway mucosal immunisation with a human papillomavirus type 16 virus-like particle vaccine.

Cervical cancer results from cervical infection by human papillomaviruses (HPV), especially HPV16. Previous studies have shown that intramuscular vaccination of women with an HPV16 virus-like particle (VLP) vaccine induced a strong IgG response and protected against genital HPV16 infection. However, an alternative route of administration that avoids parenteral injection while inducing mucosal immunity might facilitate vaccine implementation in some settings, and partially overcome the substantial variation in HPV16 antibodies at the cervix seen in ovulating women. In this study, women were vaccinated with escalating doses of HPV16L1 VLPs via nasal nebulisation, bronchial aerosolisation, or a combination of intramuscular and aerosol vaccination. The alternative routes of vaccination were well tolerated and many of the volunteers who received aerosol vaccinations exhibited serum antibody titers that were comparable to those induced by intramuscular vaccination. A mucosal immune response was induced by aerosol vaccination as demonstrated by the induction of anti-HPV16 VLP IgA secreting cells in PBMC and SIgA in secretions. Our data suggest that aerosol administration of HPV VLPs may represent a potential alternative to parenteral injection.

Administration, Intranasal↗
PubMed2002

Oral administration of recombinant adeno-associated virus elicits human immunodeficiency virus-specific immune responses.

Oral vaccines can induce both systemic and mucosal immunity. Mucosal immunity, especially regional cell-mediated immunity, plays an important role in protecting individuals from infectious diseases such as acquired immunodeficiency syndrome. In this study, a recombinant adeno-associated virus vector expressing human immunodeficiency virus type 1 env gene (AAV-HIV) was orally administered to BALB/c mice. Systemic and regional immunity was induced in the mice. Furthermore, the immunization significantly reduced viral load after an intrarectal challenge with a recombinant vaccinia virus expressing HIV env gene. Moreover, we also show that dendritic cells might contribute to the AAV-HIV vector-induced immune responses.

AIDS Vaccines↗
PubMed2000

Adenoviruses as vectors for delivering vaccines to mucosal surfaces.

Immunization of mucosal surfaces has become an attractive route of vaccine delivery because of its ability to induce mucosal immunity. Although various methods of inducing mucosal immunity are being developed, our laboratory has focused on developing adenoviruses as replication-competent and replication-incompetent vectors. The present report will summarize our progress in sequencing the entire bovine adenovirus-3 genome and identifying regions which can be deleted and subsequently used as insertion sites for foreign genes in developing recombinant viral vaccines. Using these recombinant viruses, we demonstrated the 'proof-of-principle' in developing mucosal immunity and, more importantly, inducing protection against bovine herpes virus in a natural host-cattle. Finally, we demonstrated that immunity and protection occurred even in animals that had pre-existing antibodies to the vector.

Adenoviridae↗
PubMed2001

The effect of monoclonal antibody and route of immunization on the humoral immune response against Porphyromonas gingivalis.

Immunomodulation mediated by exogenous antibodies has been proposed as a vaccine strategy to improve immune protection against pathogenic microorganisms and suggested to contribute to protection following passive immunization. To test whether a monoclonal antibody directed against an adhesion epitope of the periodontal pathogen Porphyromonas gingivalis could influence the humoral immune response following mucosal immunization, BALB/c mice were immunized orally or intranasally with P. gingivalis alone or P. gingivalis coated with monoclonal antibody 61BG1.3. Differences in antigenic specificity of anti- P. gingivalis serum immunoglobulin G (IgG) were demonstrated between groups of mice that received monoclonal antibody-coated P. gingivalis versus those that received P. gingivalis alone by either route of immunization. Binding of monoclonal antibody 61BG1.3 to P. gingivalis prior to immunization did not influence the serum IgG subclass distribution. However, minor differences in subclass distribution were observed between the various routes of mucosal immunization. These results support the hypothesis that specific monoclonal antibody bound to a bacterial vaccine can alter the quality of the humoral immune response to that organism.

Administration, Intranasal↗
PubMed2005

Comparative evaluation of intranasal and subcutaneous route of immunization for development of mucosal vaccine against experimental tuberculosis.

Activation of mucosal immunity in the respiratory tract is crucial for protection against respiratory infections. Whether the intranasal route of vaccination imparts better protection against pulmonary tuberculosis than that of subcutaneous vaccination remains a debatable issue. In this study, we have investigated the effect of the routes of immunization on the induction of immunoprotection against experimental tuberculosis employing mycobacterial culture filtrate proteins complexed with dimethyldioctadecylammonium bromide. Vaccination via intranasal and subcutaneous routes triggered immune activation in the spleen and cervical lymph node, while the former route of vaccination lead to higher antigen-specific lymphocyte proliferation, interferon-gamma, interleukin-12 and interleukin-4 responses in cervical lymph node and induction of antigen-specific IgA responses at mucosal level of the respiratory tract. Mice vaccinated via the intranasal route were found to be better protected against experimental tuberculosis particularly in lung compared to subcutaneous-immunized mice. These results emphasize the importance of the intranasal route vaccination in tuberculosis.

Adjuvants, Immunologic↗
PubMed2004

The effect of aging on mucosal host defense.

Mucosal immune response is primed at birth and responses generated at this time support specific immunity in later life. Conversely development of mucosal immune response to new antigens is diminished in aging. Availability of key nutrients that are conditionally essential especially in the context of sub-acute infections may limit immune response. A critical hypothesis is that conditionally essential nutrient requirements are associated with aging and form the fundamental basis of observed immune senescence. Since mucosal immunity is modulated by the interaction of microflora with the gut immune system, it is likely that changes in the gut during aging affect this microenvironment. Probiotic lactic acid bacteria offer one approach to stimulating the gastrointestinal immune system thereby enhancing systemic as well as mucosal immune response in aging. The mechanisms of action appear to include specific stimulation of natural killer cells (NK) and the innate immune system.

Aged↗