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PubMed1995

[Mucosal immunity with implications for use in developing a new generation of vaccines].

The mucosal immune system is a very important component of the body's defence against pathogenic organisms, especially those responsible for enteric infections. On the basis of the concept of a common mucosal immune system, there is currently much interest in the possibility of developing oral vaccines against respiratory and urogenital tracts infections. There is also a great need to develop strategies for enhancing delivery of antigens to the mucosal immune system as well as to identify mucosa-active immunostimulating adjuvants.

Animals↗

PubMedDate not supplied

Vaccines for mucosal immunity to combat emerging infectious diseases.

The mucosal immune system consists of molecules, cells, and organized lymphoid structures intended to provide immunity to pathogens that impinge upon mucosal surfaces. Mucosal infection by intracellular pathogens results in the induction of cell- mediated immunity, as manifested by CD4-positive (CD4 + ) T helper-type 1 cells, as well as CD8 + cytotoxic T-lymphocytes. These responses are normally accompanied by the synthesis of secretory immunoglobulin A (S-IgA) antibodies, which provide an important first line of defense against invasion of deeper tissues by these pathogens. New-generation live, attenuated viral vaccines, such as the cold-adapted, recombinant nasal influenza and oral rotavirus vaccines, optimize this form of mucosal immune protection. Despite these advances, new and reemerging infectious diseases are tipping the balance in favor of the parasite; continued mucosal vaccine development will be needed to effectively combat these new threats.

B-Lymphocytes↗

PubMed2002

Effects of intestinal survival surgery on systemic and mucosal immune responses in SIV-infected rhesus macaques.

Evaluation of cellular immunity in the intestinal lamina propria of rhesus macaques has been used previously to assess protective immunity against mucosal simian immunodeficiency virus (SIV) challenges. As this technique requires survival surgery to obtain jejunal tissue, effects of surgical stress on the immune system were investigated. SIV-specific immune responses, including IgG and IgA binding antibodies in sera and mucosal secretions, IgG and IgA secreting cells in peripheral blood, IgG neutralizing antibodies, T-cell proliferative responses, and interferon-gamma secretion by peripheral blood mononuclear cells, were evaluated pre- and post-surgery in macaques immunized with adenovirus-SIV recombinant vaccines and SIV envelope protein and in SIV-infected macaques. No differences in these immune parameters were observed in SIV-naïve, immunized macaques or healthy SIV-infected macaques with regard to surgery. A dramatic increase in total IgA antibody level following surgery in the rectal secretions of one SIV-infected macaque that was rapidly progressing to AIDS and failed to recover from surgery was attributed to an abscess that developed at the intestinal site. To date, nearly 30 other macaques have undergone the intestinal survival surgery, some on more than one occasion, without experiencing any clinical difficulty. Overall, our results suggest that in healthy macaques, intestinal resection survival surgery can be conducted safely. Further, the method can be used to reliably sample the intestinal mucosa without major or persistent impact on humoral or cellular immune responses.

Animals↗

PubMed1998

Lipidation as a novel approach to mucosal immunization.

We describe the design and development of a novel peptide-based approach for mucosal immunization. The design contains an amplified peptide chain as multiple antigen peptide (MAP) with a cluster of lipids. Such a design would confer on lipidated MAP the ability to self-assemble in water, mimicking enveloped viral particles. The importance of lipidation for mucosal immunization was confirmed by oral immunization with lipidated MAP in phosphate-buffered saline (PBS), which induced mucosal and systemic immune responses at local and distant sites, including sera and vaginal IgG as well as secretory IgA in saliva, vaginal secretions and fecal matter. T-cell proliferative responses were found in spleen, Peyer's patches and genital lymph nodes. In addition, significant splenic cytotoxic T-cell responses were also observed. No significant immune responses were observed with non-lipidated MAPs by oral delivery in PBS. Furthermore, these responses were selectively enhanced by different regimens, systemic priming and microparticle delivery. These results demonstrate the effectiveness of lipidated MAP for mucosal immunization to evoke both systemic and mucosal immune responses without the use of carrier or extraneous adjuvant.

Administration, Oral↗

PubMed2002

PELA microspheres loaded H. pylori lysates and their mucosal immune response.

AIM: To prepare poly (D,L-lactide)-polyethylene glycol copolymer (PELA) microspheres loaded H.pylori lysates or Cystografin and observe their targeting in gastrointestinal mucous membrane or analyze the mucosal immune responses by oral administration. METHODS: PELA microspheres loaded H.pylori lysates or Cystografin were prepared by double emulsion evaporation method. Their distribution in gastrointestinal mucous membrane was observed by CT. Balb/c mice orally immunized in mucosal immune responses, whose antibody production in salivary and gut washing and antibody secreting cells in Peyer's patches (PP) were estimated by ELISA and ELISPOT, respectively. The microspheres physical properties, such as particle size, protein level and morphology were investigated. RESULTS: All prepared microspheres were found to have a smooth surface morphology from 3.20-4.05 microm in diameter and high encapsulation efficiency from 74.9-82.2 %. No significant correlation in their physical properties was shown, depending on their molecular weight at the similar composition ratio. Immunization with all types of PELA-Hp microspheres elevated the saliva sIgA level at week 3 by approximately 3-4 times that with soluble antigen, which was greatly enhanced after boosting. At one week after last immunization with all types of PELA-Hp microspheres (week 8), the specific sIgA-ASCs, IgG-ASCs and sIgA in salivary rose obviously. In intestinal Peyer's patches, the specific sIgA-ASCs were 5.92-6.98X10(4)/ml cell and IgG-ASCs were 3.47-4.02X10(4)/ml cell, about 5-9 times higher than those with soluble antigen (P<0.01). ASCs in intestine were more than those in stomach and the majority of the ASCs were sIgA-ASCs. The sIgA in gut washing fluid was 1.62-1.85 OD, about 3-6 times tthat of those with soluble antigen. There were significant differences of the ASCs and sIgA in gut washing fluid as compared with those of PBS and MS-0 (P<0.05). There appeared to be good correlation between sIgA level in gut washing fluid and sIgA-ASCs in intestinal Peyer's patches. CONCLUSION: PELA microspheres may be used as vehicle to delivery antigen and adjuvant in designing oral vaccination.

Administration, Oral↗

PubMedDate not supplied

BCG-induced mucosal immune responses.

The induction of mucosal immune responses is particularly important for protection against diseases for which entry and pathogenesis are clearly related to the mucosal system, such as salmonellosis, AIDS or tuberculosis. We investigated the immune responses in guinea-pigs vaccinated by BCG via the respiratory compared to the intradermal route. The results demonstrate that the aerogenic BCG induced a better activation of broncho-alveolar macrophages and a substantially improved protective effect against a virulent challenge with Mycobacterium tuberculosis. We also used a DNA recombinant BCG expressing LacZ gene to investigate the influence of various routes of administration on the immunogenicity of the beta-galactosidase, a foreign antigen expressed by the LacZ-BCG recombinant. Thus, lymph-node proliferative responses, delayed type hypersensitivity and antibody responses specific for beta-galactosidase can be produced in guinea-pigs immunized orally, respiratorily and intradermally. The respiratory and especially the oral route of administration produced higher mucosal and systemic immune responses compared with the intradermal route of immunization. Moreover, the oral immunization of mice with recombinant BCG induced IgA responses which can be detected both in sera and in intestinal secretions. In conclusion, BCG recombinants may be of potential use as an adjuvant vaccine.

Animals↗

PubMed1999

Interleukin 12 and innate molecules for enhanced mucosal immunity.

Recent strategies for understanding the mechanisms underlying mucosal immune responses and subsequent development of mucosal vaccines for induction of targeted immunity now include cytokines and molecules of innate immunity. These studies have shown that cytokines influencing the development of T helper (Th) cells differentially affect the outcome of mucosal vs. systemic immune responses to mucosal vaccines. Serum antigen-specific antibody (Ab) responses were enhanced when either IL-6 or IL-12 was mucosally administered with a protein antigen, while only IL-12 induced antigen-specific mucosal IgA Ab responses. Mucosal IL-6 and IL-12 also affected the type of Th cell responses induced by CD4+ T cells from mice that received IL-12 secreted larger amounts of IFN-gamma and IL-6 when compared with mice nasally treated with IL-6. Discrepancies in the ability to enhance mucosal or systemic immune responses were also observed when human neutrophil peptide (HNP) defensins or lymphotactin were nasally coadministered with protein antigens. Only lymphotactin promoted mucosal secretory IgA (S-IgA) Ab responses while both lymphotactin and defensins enhanced systemic immunity to mucosally co-administered protein antigens. Mixed antigen-specific Th1 -and Th2-type CD4+ T cell responses were induced in the systemic compartment by both lymphotactin and the mixture of HNP-1, HNP-2, and HNP-3 defensins. However, HNPs failed to significantly enhance cytokine secretion by mucosally derived, antigen-specific CD4+ T cells relative to those isolated from the systemic compartment. In summary, these studies clearly show that IL-12 and lymphotactin are able to trigger S-IgA Ab responses and provide new avenues for the design of safe and targeted mucosal vaccines.

Adjuvants, Immunologic↗

PubMed1992

Mucosal immunization with filamentous hemagglutinin protects against Bordetella pertussis respiratory infection.

Mucosal immunization of mice with purified Bordetella pertussis filamentous hemagglutinin (FHA), by either the respiratory or the gut route, was found to protect against B. pertussis infection of the trachea and lungs. Intranasal immunization of BALB/c and (C57BL/6 x C3H/HeN)F1 adult female mice with FHA prior to B. pertussis aerosol challenge resulted in a 2 to 3 log reduction in number of bacteria recovered from the lungs and the tracheas of immunized mice in comparison to unimmunized controls. Intraduodenal immunization of adult mice with FHA before infection also resulted in approximately a 2 log reduction in the recovery of bacteria from the lungs and the tracheas of immunized mice in comparison to unimmunized controls. Immunoglobulin A and immunoglobulin G anti-FHA were both detected in bronchoalveolar lavage fluids of mucosally immunized mice. Limiting dilution analysis revealed a 60-fold increase in the frequency of FHA-specific B cells isolated from the lungs of mice immunized intranasally with FHA in comparison to unimmunized control mice. These data suggest that both gut and respiratory mucosal immunization with a major adhesin of B. pertussis generates a specific immune response in the respiratory tract that may serve as one means of mitigating subsequent B. pertussis respiratory infection.

Adhesins, Bacterial↗

PubMed1991

Mucosal immunity induced by enhance-potency inactivated and oral polio vaccines.

Oral polio vaccine (OPV) is recommended for routine immunization in the United States in part because of its ability to induce intestinal and pharyngeal immunity to reinfection. Mucosal immunity produced by OPV and enhanced-potency inactivated polio vaccine (E-IPV) was compared by challenging vaccines with type 1 OPV. Fewer OPV (25%) than E-IPV (63%) vaccinees excreted OPV virus in stool after challenge. The mean stool virus titer was higher and the duration of shedding longer among E-IPV excreters. Only one E-IPV and three OPV vaccinees shed virus in the pharynx after challenge. Prechallenge serum neutralizing antibody levels were not statistically different among E-IPV vaccinees who did and did not shed virus; these levels were much higher than those of OPV vaccinees. Poliovirus-specific IgA levels in stool did not correlate with viral excretion. E-IPV was less effective than OPV in preventing and limiting intestinal infection, even though it induced higher postvaccination serum antibody levels.

Antibodies, Viral↗

PubMed1993

New perspectives in vaccine development: mucosal immunity to infections.

In this review, we focus on six key areas currently receiving attention in the mucosal immune system. These six areas are of considerable importance for development of vaccines. They are (a) the necessity to understand the unique features of the mucosal immune system; (b) the possibility that the common mucosal immune system may contain distinct compartments; (c) differences in antigen uptake and in types of antigen-presenting cells in mucosal inductive and effector sites; (d) more careful consideration of mucosal memory in vaccine development; (e) recent studies, which show that oral vaccines induce T-helper (Th)-cell subsets that regulate mucosal IgA responses; and (f) the mechanisms whereby mucosal S-IgA and T cells provide mucosal immune protection. An example of the above suffices to illustrate why the selected areas are of importance in vaccine development. Oral immunization preferentially induces type 2 Th (Th2) cell responses that directly correlate with antigen-specific IgA responses in mucosal effector sites. It is likely that activated, antigen-specific Th2 cells that are induced in Peyer's patches are continuously supplied to mucosal effector sites for regulation of IgA responses. These Th2 cells are producing cytokines such as interleukin (IL)-5 and IL-6 and these cytokines may direct antigen-specific surface IgA-positive B cells to become IgA-producing plasma cells. Nevertheless, additional studies will be required to establish that IgA responses to T-cell-dependent antigens depend on Th2 cell-derived help. What are the implications of these studies for current oral vaccines, including novel antigen delivery systems? The most obvious would be that vaccines should be optimized for induction of Th2-cell responses in IgA inductive sites such as the gut-associated lymphoreticular tissues. It is now clear that induction of Th2-type responses in both mucosal inductive and mucosal effector sites are essential for oral vaccines to induce S-IgA responses. However, antigens delivered by live vectors such as Salmonella typhimurium in the murine system and S. typhi in humans must consider T-cell responses induced against a live vector in addition to the inserted recombinant antigen. In this regard, it has been shown that these microorganisms induce cell-mediated immunity responses that largely result from Th1-type cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2003

Mucosal immunization with a replication-deficient adenovirus vector expressing murine cytomegalovirus glycoprotein B induces mucosal and systemic immunity.

The murine cytomegalovirus (MCMV) glycoprotein B (gB) gene was expressed in an adenovirus replication-deficient vector. This virus, designated Ad-gB, was used to immunize BALB/c and B6 mice by the intranasal (i.n.) route to induce an immune response. Following primary immunization, antibody was detected in serum of 100% of vaccinees, as well as the bronchoalveolar lavage, fecal suspensions and vaginal washings. The viral titer of lung and salivary gland of vaccinees 10 days after intranasal challenge with MCMV at 10(5) or 10(3)plaque forming units (PFU) were significantly reduced compared to controls. Re-exposure of vaccinees to Ad-gB 30 days after primary immunization induced a remarkable boost of serum and mucosal antibody responses and further reduction of MCMV titers in the lung and salivary glands. The ability to induce both a systemic and mucosal immune response to a specific gene product may be important in reducing horizontal transmission of CMV infections across mucosal surfaces and in altering host immunity to CMV.

Animals↗

PubMed2002

Trends in mucosal immunity in Antarctica during six Australian winter expeditions.

The mucosal immune status of Australian Antarctic personnel was monitored during six wintering expeditions at two Australian Antarctic Research Stations, Casey in 1992, 1993, 1994, and Mawson in 1992, 1995, 1996. Salivary immunoglobulin and albumin levels were examined for differences between stations and expeditions, and for monthly changes over the expedition year. Salivary IgA and IgM concentrations were on average higher for the 1993 Casey expeditioners, and all salivary protein levels were lower for 1996 Mawson expeditioners compared to levels of the other expeditions. The change in salivary IgA and IgM concentrations over the 1-year period revealed a consistent pattern between expeditions. Salivary IgA levels were lower in March, April and May compared to other months of the year (P = 0.0002). Salivary IgM levels were lowest in the first 4 months of the year, with peak levels in June and July (P < 0.0001). There were no changes in salivary IgG and albumin concentrations over the expedition year. Though the cause of the changes in salivary IgA and IgM levels over the year is unknown, the changes could reflect alterations in mucosal immunity in response to stressors associated with isolation.

Adult↗

PubMed1999

Regulation of the mucosal immune response.

Infectious diseases continue to exact an extensive toll on populations living closest to the equatorial regions of the globe. A substantial proportion of these infections gain access to the host via the mucosal tissues. Thus, the development of new vaccines that enhance mucosal immunity is considered to be of paramount importance in order to prevent or limit the impact of these infections. Mucosal immune responses must discriminate between commensal flora within the lumen and potential pathogens. These responses are highly adapted to induce protection without excessive amounts of inflammation. The balances that regulate mucosal immune and inflammatory responses have to be understood if effective mucosal immunity is to be induced through local immunization. This review will summarize some of the unique properties of mucosal immune responses and focus on recent advances that have significantly influenced our understanding of the regulation of immune and inflammatory responses following infection.

Animals↗

PubMed1995

Induction of mucosal immunity in cotton rats to haemagglutinin-esterase glycoprotein of bovine coronavirus by recombinant adenovirus.

An effective vaccine against enteric bovine coronavirus (BCV) must be able to induce mucosal immunity. We recently described the construction of recombinant human adenovirus type 5 (hAd5) carrying the BCV haemagglutinin-esterase (HE) gene in the early transcription region 3 of the adenovirus genome. In this study, we examined the induction of systemic and mucosal immune responses to the hAd5 vector carrying the BCV HE gene (AdBcHE) following intranasal or enteric immunization of cotton rats. Regardless of the route of administration, mucosal immunization with AdBcHE induced significant levels of anti-HE IgG antibodies in serum. In addition, following intranasal immunization with AdBcHE, significant levels of anti-HE IgA antibodies were found in lung washes of immunized cotton rats. Furthermore, the specific anti-HE antibodies in sera and mucosal secretions efficiently neutralized BCV infectivity in vitro. T-cell proliferation and cell-mediated cytotoxic responses against the BCV HE were elicited in the spleen of intranasally immunized animals. The results demonstrate that mucosal immunization with AdBcHE is capable of inducing both systemic and mucosal immunity to the BCV HE. These immune responses may be important in protecting animals from BCV infection.

Adenoviridae↗

PubMed1992

Ageing compromises gastrointestinal mucosal immune response in the rhesus monkey.

Most research on the effects of ageing on gut mucosal immunity has been performed using rodents. However, there are inherent difficulties in the extrapolation of rodent data to humans. This study was initiated to define age-related changes in the gastrointestinal (GI) mucosal immune response in non-human primates. Antibody responses were measured in young and old rhesus monkeys (Macaca mulatta) immunized intraduodenally with cholera toxin (Ctx)/cholera toxoid (Ctd). Antigen-specific immunoglobulin A (IgA) antibody levels were markedly lower while anti-Ctx IgG and IgM titres were higher in the intestinal lavage samples of old as compared to young animals. Total IgA concentrations in gut lavage were independent of age or immune status. Measurable titres of anti-Ctx IgA in the saliva of both age groups support the common mucosal immune hypothesis. Flow cytometric analysis was used to identify age-related shifts in the expression of cell surface antigens on peripheral blood lymphocytes. The relative number of both IgA+ and Ctx+ cells was dramatically reduced in the blood of old monkeys. Collectively, these data suggest that the GI mucosal immune response to Ctx is compromised in old rhesus macaques. The deficit in immune responsiveness, namely reduced anti-Ctx IgA antibody secretion into the intestinal lumen, may be a consequence of alterations in the process of maturation and homing of specific antibody-secreting B lymphocytes.

Aging↗

PubMed2006

[Crossing between mucosal immunity and epithelial regeneration/differentiation in the human intestine].

We have demonstrated that IL-7 is produced by intestinal epithelial cells (IECs) and regulates the proliferation of IL-7R+ mucosal T cells. IEC-derived IL-7 is indispensable for both organization of mucosal lymphoid tissues and regulation of mucosal immune responses. Dysreguration of mucosal IL-7-dependent pathway leads to chronic intestinal inflammation. On the basis of the fact that IL-7R is expressed in both mucosal T cells and IECs, we found the crossing between mucosal immunity and epithelial regeneration/differentiation in human intestine. Human IECs are partly of bone marrow (BM) origin and BM-derived IECs promote the regeneration of the damaged intestinal epithelium. During regeneration following severe damage, BM-derived IECs trigger the change of IEC differentiation. BM-derived IECs mainly repopulate the absorptive IECs in normal condition, but IEC differentiation is changed toward the secretory lineage IECs during regeneration. Transcription regulation of IEC-derived IL-7 shows close relation to IEC cell specific lineage and is disturbed in chronic intestinal inflammation. Moreover, expression and function of transcription factors downstream of Notch signaling pathway that mediates IEC differentiation is changed in chronic intestinal inflammation. All these results indicated that the disorder of both IEC differentiation and mucosal immunity cause human inflammatory bowel disease.

Cell Differentiation↗

PubMed1984

The mucosal immune system in health and disease, with an emphasis on parasitic infection.

This article briefly describes the network of immunity involving selected humoral and cellular elements shared between mucosal surfaces that are both exposed to and remote from antigen challenge. The mechanisms promoting the production, concentration, and secretion of specific antibody isotypes, as well as the migration and localization of various lymphoid cell populations, have been discussed with regard to host mucosal protection against pathogenic agents and other potentially harmful macromolecules.Although certain aspects of the mucosal immune system may be viewed as separate from the systemic immune system, they are not exclusively so. We have drawn attention to their interactions with systemic immune reactants and other, nonimmunological, cellular and humoral constituents of mucosal surfaces and tissues such as the liver. At another level of interaction we have considered the teleological translation of host defence and immunoregulation from one generation to the next through the medium of colostrum and breast milk.The manipulation of the mucosal immune system in order to enhance host resistance, modulate autoimmune and allergic systemic reactivity, or even modify fertility holds great promise. Achievement of these goals depends on gaining further insight into the mechanisms that contribute to mucosal immunity and their interactions with the systemic immune system. Much of our current knowledge is based upon experimental animal models or human populations living in relative prosperity. However, the results of oral vaccination, for example, are known to differ considerably in populations that suffer from parasitic infestations, lack adequate nutrition, and are very old or very young. We have chosen to focus attention on these groups because they constitute a large proportion of the world's population and because mucosal infections are a common cause of illness and death among them.Lastly, the recent discovery that immune deficiencies due to insufficient dietary zinc may extend to subsequent generations of optimally nourished offspring calls for a re-evaluation of immunization protocols in malnourished populations, and of our current understanding of disease inheritance and susceptibility.

Antibodies, Anti-Idiotypic↗

PubMed1994

Mucosal immunity to infection with implications for vaccine development.

The induction of effective mucosal immunity that also provides systemic immunity is a considerable challenge. Over the past two years, efforts to develop novel mucosal vaccine delivery systems to induce mucosal immunity against bacterial and viral diseases, including HIV, have dramatically increased. Here we cite novel vaccines and delivery systems being used to establish effective mucosal immunity.

Animals↗