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PubMed2006

Topical/mucosal delivery of sub-unit vaccines that stimulate the ocular mucosal immune system.

Mucosal vaccination is proving to be one of the greatest challenges in modern vaccine development. Although ocular mucosal immunity is highly beneficial for achieving protective immunity, the induction of ocular mucosal immunity against ocular infectious pathogens, particularly herpes simplex virus type 1 (HSV-1), which is the leading cause of infectious corneal blindness, remains difficult. Recent developments in cellular and molecular immunology of the ocular mucosal immune system (OMIS) may help in the design of more effective and optimal immunization strategies against ocular pathogens. In this review, we highlight ocular mucosal immunoprophylactic and immunotherapeutic vaccine strategies that have been evaluated to control the many pathogens that attack the surface of the eye. Next, we describe the current understandings of the OMIS and elucidate the structure and the function of the humoral and cellular immune system that protects the surface of the eye. Results from our recent experiments using topical ocular delivery of peptides-CpG and lipopeptide-based vaccines against HSV-1 infection are presented. The future challenges and issues related to the ocular mucosal delivery of molecularly defined sub-unit vaccines are discussed.

Administration, Topical↗
PubMed2001

Multiple intestinal 'loops' provide an in vivo model to analyse multiple mucosal immune responses.

Mucosal immunity plays an important role in preventing disease but the induction of protective mucosal immune responses remains a significant challenge. We describe a novel in vivo model to analyze the induction of multiple mucosal immune responses in the small intestine. A sterile segment of intestine ('intestinal-segment'; 2-3 m long) was surgically prepared in the jejunum of 4-6-month-old lambs. This 'intestinal-segment' was then subdivided into consecutive segments, designated as 'loops' (15-20 cm long), that included a Peyer's patch (PP), or 'interspaces' (15-70 cm long), that lacked a visible PP. All 'loops' were sterile when collected 1-4 weeks post-surgery and there was no macroscopic or histological evidence of altered lymph or blood flow. Flow cytometric analysis of cells isolated from PP, mucosal epithelium (IEL) and the lamina propria (LPL) revealed no significant alterations in the cell populations present in 'loop' tissues. The functional integrity of M-cell antigen uptake in sterile intestinal 'loops' was evaluated by comparing the immune response induced by varying doses of soluble versus particulate porcine serum albumin (PSA formulated in alginate microspheres). A dose-dependent, PSA-specific antibody-secreting cell response was restricted to PP present in 'loops' injected with particulate PSA. These observations suggested that PP present in sterile 'loops' were functional and this conclusion was confirmed by detecting cholera toxin-specific antibody-secreting cells and secreted antibody in PP and intestinal contents, respectively, of immunized 'loops.' Thus, each 'loop' provided an independent site to analyze antigen-uptake and the induction of mucosal immune responses by a variety of antigen or vaccine formulations.

Animal Population Groups↗
PubMed2005

Induction and recall of immune memory by mucosal immunization with a non-toxic recombinant enterotoxin-based chimeric protein.

Previous reports have suggested that peroral delivery of antigens chemically coupled to non-toxic recombinant enterotoxin B subunits, such as the cholera toxin B subunit (CTB), induces tolerance to the antigen that may be abrogated by the toxic enzyme activity of intact enterotoxins, such as cholera toxin (CT). The aim of this study was to examine the immunogenicity of a genetically coupled protein composed of the saliva-binding region (SBR) of the Streptococcus mutans surface antigen AgI/II and the non-toxic A2 and B subunits of CT (SBR-CTA2/B) compared with that of recombinant SBR admixed with CT (SBR + CT) and SBR chemically coupled to recombinant CTB (SBR-CTB) following peroral delivery by intragastric (i.g.) immunization. The results showed that i.g. immunization with SBR-CTA2/B, like SBR + CT, induced antigen-specific serum immunoglobulin G (IgG) and salivary IgA antibodies, and sensitized splenic T cells. Comparison studies with SBR-CTB produced serum IgG but not salivary IgA titres and failed to sensitize splenic cells. Immunization with SBR-CTA2/B via the intranasal route also primed for the recall of antigen-specific memory antibody responses 6 months later. These findings show that SBR-CTA2/B is an immunogenic, not tolerogenic, chimeric protein that can induce and recall antigen-specific memory responses upon mucosal immunization.

Adjuvants, Immunologic↗
PubMed1999

Novel strategies using DNA for the induction of mucosal immunity.

The mucosal surfaces are the primary sites for transmission of most infectious diseases. However, most conventional vaccines are administered parenterally [e.g., by intramuscular (IM) or intradermal (ID) injection] and induce systemic but rarely mucosal immunity. Novel vaccination strategies capable of inducing both systemic and mucosal immune responses could greatly reduce infection and morbidity worldwide. One of the most exciting advances in vaccine technology in recent years has been the development of DNA vaccines, through which the antigen is synthesized in vivo after direct introduction of its encoding sequences. The vast majority of DNA vaccines have been delivered parenterally; however, in recent years a number of studies have reported successful mucosal immunization with DNA vaccines. The induction of strong immune responses following the introduction of DNA appears to be partly due to the potent adjuvant effect of unmethylated immunostimulatory CpG motifs present in the DNA backbone. Synthetic oligodeoxynucleotides (ODN) containing such immunostimulatory CpG motifs are potent adjuvants systemically and mucosally in mice, and have synergistic action with other adjuvants, such as alum and cholera toxin (CT). This article highlights the recent advances in vaccination strategies using DNA delivered to mucosal surfaces either as an antigen-encoding plasmid or as an adjuvant.

Adjuvants, Immunologic↗
PubMed2001

Symposium on 'dietary influences on mucosal immunity'. How dietary antigens access the mucosal immune system.

The intestinal epithelium is a selective barrier where incompletely-digested food antigens are transmitted to the immune system. Food antigens are often the starting point of intestinal diseases such as food allergy or coeliac disease. The intestinal epithelial cells (IEC) take up and process food antigens mainly by fluid-phase transcytosis involving two functional pathways, one minor direct pathway without degradation and another major lysosomal degradative pathway. Among the peptidic metabolites generated during transepithelial transport of luminal antigens, some have a molecular mass compatible with a binding to restriction (major histocompatibility complex; MHC) molecules; the latter can be up regulated on enterocytes, especially in inflammatory conditions. Indeed, interferon-gamma not only increases the paracellular absorption of antigens, but also their transcytosis across epithelial cells. It has been reported that enterocytes may even directly present peptidic epitopes to underlying T-cells. As a new potential way of transmitting peptidic information to the local or systemic immune system, the secretion by IEC of antigen-presenting vesicles called exosomes and bearing MHC-peptide complexes has recently been proposed. Many other factors such as nutritional or environmental factors can also influence the properties of the epithelial barrier and the outcome of the immune response to lumen antigens.

Animals↗
PubMed2005

[Discovering of mucosal immunity].

The mucosal surface area of gastrointestinal, respiratory and urogenital tracts of an adult individuals is about 400 m2 and is the main route of infection and potential harmful agents penetration. It emphasize the essential role of the mucosal immune system (MALT). The beginnings of mucosal immunology, based on the people's observations and believes, descent from ancient times, when the attempt of immunization of human organism against distressed illness have been undertaken. Discovery of a MALT system elements and mechanisms of the mucosal immunity working occured in the 20th century. At that time, the base of beneficial properties of human and other animals' secretions have been recognized, starting from milk, through saliva, ending to feces. Nowadays, it is known, that in all secretions, beside innate defence, the main part of mucosal immunity perform antibodies synthetized locally, with the predominance of the class A (IgA). In this paper the greatest discoveries, leading to the understanding of mucosal immunization resulting in systemic resistance, have been approached.

Allergy and Immunology↗
PubMed2006

The effects of HIV infection on oral mucosal immunity.

Oral mucosal infections, especially candidiasis, are a feature of HIV disease, suggesting that compromised mucosal immunity within the oral cavity is a consequence of the viral infection. However, how this mucosal immunity is compromised and at what stage of HIV infection this occurs are unclear. Better understanding of the protection of the oral cavity against infection has allowed us to gain some insight into the local consequences of HIV infection. From a humoral perpective, IgA2 subclasses are reduced in HIV infection in saliva, and total secretory IgA levels are reduced in later disease. Similarly, mucosal antibody responses appear near normal in early HIV infection but reduced in AIDS. There is now convincing evidence that salivary IgA can be neutralizing to HIV 1 and HIV 2, as well as block epithelial transmigration. Oral cellular immunity is also affected by HIV infection. Transmission of HIV from one oral cell type to another appears to be confirmed by work showing that HIV can bind to or infect epithelial cells, Langerhans cells, and other mucosal cells. CXCR4 tropic (via GalCer and CXCR4) and dual tropic HIV strains have been shown to be able to infect normal human oral keratinocytes (NHOKs), and infectious HIV virions can also be conveyed from NHOKs to activated peripheral blood lymphocytes, suggesting a potential role of oral epithelial cells in the transmission of HIV infection. There is evidence of up-regulation of various receptors, including HIV receptors, on the surface of oral epithelium, and the epithelium may become more permeable. HIV may exploit this antigen uptake mechanism to cross epithelial barriers during co-infection with damage-inducing pathogens such as Candida. Immune responsiveness to many of the co-pathogens associated with HIV has been demonstrated to depend on a family of innate recognition molecules, known as Toll-like receptors (TLR), and recognition of a single pathogen can involve activation of multiple TLRs. Consequently, TLR-pathogen interactions could play an indirect but major role in regulating HIV-associated disease in the oral cavity. Thus, HIV infection appears to have both direct and indirect effects on oral mucosal immunity, affecting both cellular and humoral immunity as well as both specific and innate immunity.

AIDS Vaccines↗
PubMed1999

Brain-gut axis and mucosal immunity: a perspective on mucosal psychoneuroimmunology.

The role of the brain-gut axis has traditionally been investigated in relation to intestinal motility, secretion, and vascularity. More recently, the concept of brain-gut dialogue has extended to the relationship between the nervous system and mucosal immune function. There is compelling evidence for a reciprocal or bi-directional communication between the immune system and the neuroendocrine system. This is mediated, in part, by shared ligands (chemical messengers) and receptors that are common to the immune and nervous systems. Although the concept of psychoneuroimmunology and neuroimmune cross-talk has been studied primarily in the context of the systemic immune system, it is likely to have special significance in the gut. The mucosal immune system is anatomically, functionally, and operationally distinct from the systemic immune system and is subject to independent regulatory signals. Furthermore, the intestinal mucosal immune system operates in a local milieu that depends on a dense innervation for its integrity, with juxtaposition of neuroendocrine cells and mucosal immune cells. An overview of evidence for the biologic plausibility of a brain-gut-immune axis is presented and its potential relevance to mucosal inflammatory disorders is discussed.

Adult↗
PubMed2000

Gene gun-mediated DNA immunization primes development of mucosal immunity against bovine herpesvirus 1 in cattle.

Vaccination by a mucosal route is an excellent approach to the control of mucosally acquired infections. Several reports on rodents suggest that DNA vaccines can be used to achieve mucosal immunity when applied to mucosal tissues. However, with the exception of one study with pigs and another with horses, there is no information on mucosal DNA immunization of the natural host. In this study, the potential of inducing mucosal immunity in cattle by immunization with a DNA vaccine was demonstrated. Cattle were immunized with a plasmid encoding bovine herpesvirus 1 (BHV-1) glycoprotein B, which was delivered with a gene gun either intradermally or intravulvomucosally. Intravulvomucosal DNA immunization induced strong cellular immune responses and primed humoral immune responses. This was evident after BHV-1 challenge when high levels of both immunoglobulin G (IgG) and IgA were detected. Intradermal delivery resulted in lower levels of immunity than mucosal immunization. To determine whether the differences between the immune responses induced by intravulvomucosal and intradermal immunizations might be due to the efficacy of antigen presentation, the distributions of antigen and Langerhans cells in the skin and mucosa were compared. After intravulvomucosal delivery, antigen was expressed early and throughout the mucosa, but after intradermal administration, antigen expression occurred later and superficially in the skin. Furthermore, Langerhans cells were widely distributed in the mucosal epithelium but found primarily in the basal layers of the epidermis of the skin. Collectively, these observations may account for the stronger immune response induced by mucosal administration.

Animals↗
PubMed2004

Immune response after adjuvant mucosal immunization of mice with inactivated influenza virus.

Satisfactory mucosal immunity in the respiratory tract is very important for protection against influenza. It can be achieved only by mucosal immunization. Mucosal vaccination with inactivated influenza virus may not be sufficiently effective and suitable adjuvants are therefore sought. We tested intratracheal immunization of mice with inactivate B type influenza virus in a mixture with formolized G+ bacterium Bacillus firmus, whose adjuvant effects have previously been documented in another system. The treatment resulted in a marked increase of both systemic and mucosal antibody response in IgG and IgA classes. Stimulation of T lymphocytes after adjuvant immunization was very mild, no proliferation taking place after specific stimulation with antigen in vitro. However, slightly increased systemic (spleen) and local (lungs) production of cytokines without perceptible Th1/Th2 polarization was determined. B. firmus is an efficient adjuvant in respiratory tract immunization while with subcutaneous immunization it lowers the antibody response.

Adjuvants, Immunologic↗
PubMed2005

Heteropentameric cholera toxin B subunit chimeric molecules genetically fused to a vaccine antigen induce systemic and mucosal immune responses: a potential new strategy to target recombinant vaccine antigens to mucosal immune systems.

Noninvasive mucosal vaccines are attractive alternatives to parenteral vaccines. Although the conjugation of vaccine antigens with the B subunit of cholera toxin (CTB) is one of the most promising strategies for vaccine delivery to mucosal immune systems, the molecule cannot tolerate large-protein fusion, as it severely impairs pentamerization and loses affinity for GM1-ganglioside. Here we report a new strategy, in which steric hindrance between CTB-antigen fusion subunits is significantly reduced through the integration of unfused CTB "molecular buffers" into the pentamer unit, making them more efficiently self-assemble into biologically active pentamers. In addition, the chimeric protein took a compact configuration, becoming small enough to be secreted, and one-step affinity-purified proteins, when administered through a mucosal route, induced specific immune responses in mice. Since our results are not dependent on the use of a particular expression system or vaccine antigen, this strategy could be broadly applicable to bacterial enterotoxin-based vaccine design.

Animals↗
PubMed2000

Special feature for the Olympics: effects of exercise on the immune system: exercise effects on mucosal immunity.

The present review examines the effects of exercise on mucosal immunity in recreational and elite athletes and the role of mucosal immunity in respiratory illness. Habitual exercise at an intense level can cause suppression of mucosal immune parameters, while moderate exercise may have positive effects. Saliva is the most commonly used secretion for measurement of secretory antibodies in the assessment of mucosal immune status. Salivary IgA and IgM concentrations decline immediately after a bout of intense exercise, but usually recover within 24 h. Training at an intense level over many years can result in a chronic suppression of salivary immunoglobulin levels. The degree of immune suppression and the recovery rates after exercise are associated with the intensity of exercise and the duration or volume of the training. Low levels of salivary IgM and IgA, particularly the IgA1 subclass, are associated with an increased risk of respiratory illness in athletes. Monitoring mucosal immune parameters during critical periods of training provides an assessment of the upper respiratory tract illness risk status of an individual athlete. The mechanisms underlying the mucosal immune suppression are unknown.

Exercise↗
PubMed1993

The gastrointestinal mucosal immune system.

The mucosal immune system, consisting of lymphoid tissues associated with the lacrimal, salivary, gastrointestinal, respiratory and urogenital tracts and lactating breasts, quantitatively contains the majority of the lymphoid tissue of the body. There are a number of important features of the gastrointestinal mucosal immune system: the mucosal immune system contains specialized structures, such as the Peyer's patches, where immune responses are thought to be initiated; there is a pattern of relatively specific recirculation of lymphoid cells to the mucosa, known as mucosal homing; subsets of lymphoid cells, particularly IgA B cells and memory T cells, predominate at mucosal surfaces; and the predominant mucosal immunoglobulin, secretory IgA, is particularly well adapted to host defense at mucosal surfaces. These elements of the gastrointestinal mucosal immune system function together to generate an immune response which on the one hand protects the host from harmful pathogens, but on the other hand is tolerant of the ubiquitous dietary antigens and normal microbial flora.

B-Lymphocytes↗
PubMed2004

Mucosal immunization with purified flagellin from Salmonella induces systemic and mucosal immune responses in C3H/HeJ mice.

This study investigated the immune response elicited in C3H/HeJ mice after oral, parenteral and nasal immunization with purified flagellin from Salmonella enterica serovar Enteritidis alone or conjugated to starch microparticles as adjuvant or together with the uptake-enhancer recombinant cholera toxin B-subunit (rCTB). Systemic (IgM-IgG, IgA, IgG2a, IgG2b, IgG1) and local (s-IgA) humoral immune responses in the mice were analyzed using enzyme-linked immunosorbent assays (ELISA). Primed splenocytes were also stimulated in vitro with flagellin and the supernatants analyzed for cytokine production. Finally, immunized mice were challenged orally with live Salmonella. A high flagellin-specific IgM-IgG response was seen in all groups, especially in mice immunized nasally with flagellin plus rCTB or subcutaneously, but a strong systemic antibody response was also induced when free antigen was given orally. Intranasal or subcutaneous immunization of mice with flagellin plus rCTB or oral immunization with flagellin plus microparticles resulted in a significantly greater mucosal response (higher s-IgA titers in feces) than seen in the control group (P <0.05). The mucosal IgA responses were significantly correlated with the serum IgA titers. The subclass profile in serum revealed a mixed Th1/Th2-type response, with a predominance of Th1-type, as indicated by the subclass ratio (IgG1/IgG2a + IgG2b). The splenocytes stimulated in vitro produced interferon (IFN)-gamma, at levels, which increased with time. The group immunized with flagellin plus rCTB subcutaneously had a relatively higher IFN-gamma response than the other groups. Interleukin (IL)-2 was also produced, especially in mice immunized nasally or subcutaneously with flagellin conjugated to microparticles. However, neither IL-4 nor IL-5 was produced in any of the groups. After oral challenge with live serovar Enteritidis, the groups immunized orally or nasally with free flagellin had significantly lower degree of infection than the control group (P <0.05).

Adjuvants, Immunologic↗
PubMed2003

Role of systemic and mucosal immune responses in reciprocal protection against Bordetella pertussis and Bordetella parapertussis in a murine model of respiratory infection.

The roles of systemic humoral immunity, cell-mediated immunity, and mucosal immunity in reciprocal protective immunity against Bordetella pertussis and Bordetella parapertussis were examined by using a murine model of respiratory infection. Passive immunization with serum from mice infected with B. pertussis established protective immunity against B. pertussis but not against B. parapertussis. Protection against B. parapertussis was induced in mice that had been injected with serum from mice infected with B. parapertussis but not from mice infected with B. pertussis. Adoptive transfer of spleen cells from mice infected with B. pertussis or B. parapertussis also failed to confer reciprocal protection. To examine the role of mucosal immunity in reciprocal protection, mice were infected with preparations of either B. pertussis or B. parapertussis, each of which had been incubated with the bronchoalveolar wash of mice that were convalescing after infection with B. pertussis or B. parapertussis. Such incubation conferred reciprocal protection against B. pertussis and B. parapertussis on infected mice. The data suggest that mucosal immunity including secreted immunoglobulin A in the lungs might play an important role in reciprocal protective immunity in this murine model of respiratory infection.

Adoptive Transfer↗
PubMed1992

Mucosal defense mechanism in health and disease. Role of the mucosal immune system.

The mucosal immune system is characterized predominantly by the secretory antibody response and gut-associated lymphoid tissue, cellular part of the mucosal immune system. The secretory antibody system depends on local production and selective epithelial transport of secretory IgA and IgM. Furthermore, secretory antibodies and interactions between the intestinal epithelium and T cells are involved in the mucosal down-regulation of the systemic immune system. Neuropeptides play a crucial role in the regulation of mucosal immune responses. It is possible that impairment of the mucosal immune response contributes to the pathogenesis of various intestinal diseases, such as inflammatory bowel disease. Until recently, however, mucosal immunity received relatively little attention from both basic and clinical scientists. Further research on mucosal immunity seems to have promise in helping to provide new understanding of the immune mechanisms and pathogenesis of several gastrointestinal and systemic diseases.

Animals↗
PubMed2001

Effect of pre-existing immunity for systemic and mucosal immune responses to intranasal immunization with group B Streptococcus type III capsular polysaccharide-cholera toxin B subunit conjugate.

The effects of priming with a group B Streptococcus type III capsular polysaccharide (GBS CPS III)-recombinant cholera toxin B subunit (rCTB) conjugate, purified GBS CPS III or rCTB alone on the systemic and mucosal immune responses to CPS III after intranasal (i.n.) immunization were investigated in mice. Priming with purified GBS CPS III followed by boosting with GBS CPS III-rCTB conjugate or priming with the conjugate followed by boosting with free CPS induced comparable levels of specific IgG and IgA in both serum and in lungs and vagina. However, i.n. immunization comprising both priming and boosting with conjugate was superior to priming with CPS and boosting with conjugate or the reverse, especially with regard to inducing mucosal IgA anti-CPS responses. All the immunization schemes, except priming and boosting with free CPS, induced high and similar levels of IgG1 in serum. In contrast, mice primed with free CPS III and then boosted with CPS III-rCTB conjugate by the i.n. route failed to produce significant levels of IgG2a, IgG2b and IgG3 in serum, at difference from mice primed with the conjugate and boosted with either conjugate or free CPS. Pre-immunization with rCTB either i.n. or i.p. did not suppress specific serum IgG responses induced by GBS CPS III-rCTB conjugate intranasally, but did inhibit serum and especially mucosal IgA responses. Our findings suggest that priming with CPS affects the distribution of IgG subclasses to GBS CPS and that pre-existing anti-carrier rCTB immunity can have an inhibitory effect on mucosal immune responses elicited by the conjugate vaccine given by the i.n. route.

Administration, Intranasal↗
PubMed1989

Effect of cyclosporin A treatment on the enteropathy of graft-versus-host reaction in the rat: a quantitative study of intestinal morphology, epithelial cell kinetics and mucosal immune activity.

Mucosal graft-versus-host reaction (GvHR) of the small intestine exemplifies an immunologically mediated enteropathy that is associated with expansion of mucosal mast cells (MMC). Quantitative measures of intestinal morphology, epithelial cell kinetics and mucosal immune activity were used to assess the effect of the immunosuppressive agent, cyclosporin A (CyA), in ameliorating this enteropathy and on increased activity of MMC in the jejunum. GvHR was induced in two groups of PVGU x PVGC rats by irradiation (4.50 Gy) and intravenous injection of PVGC spleen cells (150 x 10(6)). One group remained untreated, while a second group of eight rats was treated with a 50 mg/kg dose of CyA subcutaneously given daily for the first 3 days and then every second day, and which had commenced the day before induction of GvHR. On day 14, all animals were killed. Treatment with CyA prevented intestinal crypt hyperplasia but did not affect villus length, and normalized the crypt cell production rate (CCPR) from 38 to 15 cells/crypt/h (P less than 0.0001). CyA reduced the number of MMC and jejunal content of the MMC associated protease, rat mucosal mast cell protease II (RMCPII). Mean serum RMCPII concentration was reduced from 302 (s.d. = 112) in GvHR animals to 10 (s.d. = 6) ng/mL in GvHR/CyA-treated rats (P less than 0.0001). We conclude that CyA ameliorates the enteropathy of GvHR and depresses the activation of MMC, as evident by the strongly depressed serum RMCPII concentration.

Animals↗