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PubMed1988

Abnormalities of the intestinal immune system in AIDS.

Significant abnormalities in the distribution of lymphocyte subsets have been noted in the intestinal mucosa of ARC and AIDS patients. Abnormalities are most striking among the CD4 helper-inducer T-cell subset and likely reflects the direct effects of HIV infection of those cells. A deficiency in CD4-positive T cells in the intestinal mucosa potentially could result in significant abnormalities in mucosal immune function, including defects both in cell-mediated immunity and in the secretory IgA system. Such alterations in mucosal immunity and mucosal defense may render AIDS and ARC subjects susceptible to enteric infections and systemic infections in which the intestinal tract is the portal of entry.

Acquired Immunodeficiency Syndrome↗
PubMed2002

Open system gene expression profiling and identification of novel genes for targeted vaccine delivery.

Ongoing development of vaccines is limited by the techniques used to identify routes to immunization. Using open system gene expression profiling, researchers can now directly identify receptors used by M-cells in the transport of antigens to the mucosal immune system. These receptors will be ideal for targeted delivery of new synthetic vaccines. In addition, gene expression profiling will provide important new information on the biology of the M-cell and mucosal immune mechanisms.

Gene Expression Profiling↗
PubMed2000

Recent advances in mucosal vaccine development.

Proper stimulation of the mucosal immune system is critical for the effective protection of mucosal surfaces against colonization and invasion of infectious agents. This requires administration of vaccine antigens directly to various mucosal sites. Due to the low absorption efficiency of mucosally delivered vaccines, however, almost all of the currently marketed vaccines are administered parentally. In addition, sub-optimal immune responses are frequently induced by mucosal immunization and the use of mucosal adjuvants is commonly required. As a result, development of successful mucosal vaccines depends largely on the improvement of mucosal antigen delivery and on the discovery of new and effective mucosal adjuvants. In this review, recent advances in both areas are briefly discussed.

Animals↗
PubMed2003

Intranasal immunization with formalin-inactivated virus vaccine induces a broad spectrum of heterosubtypic immunity against influenza A virus infection in mice.

It has been known that influenza A virus infection induces a cross-protective immunity against infection by viruses with different subtypes of viral envelope proteins, hemagglutinin (HA) and neuraminidase (NA). This heterosubtypic immunity is generally mediated by cytotoxic T lymphocytes (CTL) reactive to specific epitopes in the viral internal proteins, such as nucleoprotein and matrix protein. By contrast, immunization with inactivated virus antigens has been thought to be unable to generate heterosubtypic immunity, since inactivated antigens do not usually induce CTL responses. However, we show that intranasal immunization with formalin-inactivated intact virus, but not ether-split vaccines, induced a broad spectrum of heterosubtypic protective immunity in mice. The protection may be mediated by the mucosal immune response, most likely secretory IgA antibodies to the viral proteins. This approach may overcome limitations in the efficacy of inactivated influenza vaccines and confer potent immunity to humans against viruses with new pandemic potential.

Administration, Intranasal↗
PubMedDate not supplied

Interleukin-7 dose-dependently restores parenteral nutrition-induced gut-associated lymphoid tissue cell loss but does not improve intestinal immunoglobulin a levels.

BACKGROUND: Without enteral nutrition, the mass and function of gut-associated lymphoid tissue (GALT), a center of systemic mucosal immunity, are reduced. Therefore, new therapeutic methods, designed to preserve mucosal immunity during parenteral nutrition (PN), are needed. Our recent study revealed that exogenous interleukin-7 (IL-7; 1 microg/kg twice a day) restores the GALT cell mass lost during intravenous (IV) PN but does not improve secretory immunoglobulin A (IgA) levels. Herein, we studied the IL-7 dose response to determine the optimal IL-7 dose for recovery of GALT mass and function during IV PN. We hypothesized that a high dose of IL-7 would increase intestinal IgA levels, as well as GALT cell numbers. METHODS: Male mice (n = 42) were randomized to chow, IL-7-0, IL-7-0.1, IL-7-0.33, IL-7-1 and IL-7-3.3 groups and underwent jugular vein catheter insertion. The IL-7 groups were fed a standard PN solution and received IV injections of normal saline (IL-7-0), 0.1, 0.33, 1, or 3.3 microg/kg of IL-7 twice a day. The chow group was fed chow ad libitum. After 5 days of treatment, the entire small intestine was harvested and lymphocytes were isolated from Peyer's patches (PPs), intraepithelial (IE) spaces, and the lamina propria (LP). The lymphocytes were counted and phenotypes determined by flow cytometry (alphabetaTCR, gammadeltaTCR, CD4, CD8, B cell). IgA levels of small intestinal washings were also examined using ELISA (enzyme-linked immunoabsorbent assay). RESULTS: IL-7 dose-dependently increased total lymphocyte numbers in PPs and the LP. The number of lymphocytes harvested from IE spaces reached a plateau at 1 microg/kg of IL-7. There were no significant differences in any phenotype percentages at any GALT sites among the groups. IgA levels of intestinal washings were significantly higher in the chow group than in any of the IL-7 groups, with similar levels in all IL-7 groups. CONCLUSIONS: Exogenous IL-7 dose-dependently reverses PN-induced GALT cell loss, with no major changes in small intestinal IgA levels. IL-7 treatment during PN appears to have beneficial effects on gut immunity, but other therapeutic methods are needed to restore secretory IgA levels.

Animals↗
PubMed2002

A study of systems for delivering antigens and plasmid DNA for intranasal immunization against tick-borne encephalitis virus.

Our previous studies indicated the possibility for some neurotropic viruses to spread into the brain of immune animals through the olfactory pathway. Thus, nasal mucosa in the olfactory region is likely to be a promising target for mucosal immunization to protect the CNS from neurotropic viral infections. THE MAIN IDEA OF THE RESEARCH: Intranasal immunization inducing mucosal and systemic immune responses blocks the propagation of neurotropic virus into the brain via the olfactory pathway and neutralizes the multiplication of virus in visceral organs, allowing more effective protection against neurotropic infections transmitted by bloodsucking arthropods to be achieved. Thus, study of the efficiency of delivery systems for intranasal immunization against tick-borne encephalitis (TBE) virus is an urgent task in the development of anti-TBE mucosal vaccine. To study intranasal immunization against TBE virus, we have chosen four delivery systems (DSs), namely, (i) biodegradable microparticles, (ii) cationic liposomes, and live attenuated (iii) bacterial and (iv) viral vectors. The gene of TBE virus protein E was inserted into the pcDNA3 plasmid (designated as pcDNA3/E-TBE). Three types of delivery system for plasmid DNA were developed and studied in vitro. The first system, artificial virus-like microparticles (VLP), consists of polyglycan-spermidine complexes that cover pcDNA3/E-TBE DNA. The second system is cationic liposomes with DNA of the plasmid pcDNA3/E-TBE. The third system is an attenuated Salmonella strain containing pcDNA3/E-TBE. The fourth system is a recombinant vaccinia strain with inserted genes of TBE virus proteins C, prM, E, NS1, NS2a, NS2b, and NS3. The DSs were tested in COS-7 and CV-1 cell lines and macrophages by ELISA of cell lysate. The results obtained showed the expression of the E gene in transfected cells, thereby demonstrating that these DSs are suitable for mucosal immunization. High levels of immune response shifted to the Th1 type were detected in BALB/c mice following intranasal immunization with recombinant vaccinia-TBE strain and VLP-pcDNA3/E-TBE. The mice immunized intranasally with recombinant vaccinia-TBE strains were completely protected against intraperitoneal challenge with TBE virus strain Sofjin, whereas intranasal immunization with killed TBE vaccine failed to induce a significant level of protection.

Administration, Intranasal↗
PubMed2006

The effect of vitamin A supplementation on the intestinal immune response in Mexican children is modified by pathogen infections and diarrhea.

Vitamin A supplementation has consistently reduced infant mortality and the severity of pathogen-induced diarrhea. The mechanism by which vitamin A modulates the mucosal immune response to produce these effects remains poorly defined. To address this issue, stools collected during the summer months from 127 Mexican children 5-15 mo old enrolled in a larger, randomized, double-blind, placebo-controlled, vitamin A supplementation trial were screened for interleukin (IL)-4, IL-6, interferon-gamma (IFN-gamma), and gastrointestinal pathogens. Fecal cytokine values were categorized into 3 levels (undetectable, or =median). Multinomial regression models were used to determine the probability that vitamin A-supplemented children had higher categorical values of a cytokine than children in the placebo group. Differences in categorical values were also analyzed after stratification by gastrointestinal pathogen infections and diarrheal symptoms. Overall, fecal cytokine categorical levels did not differ between children randomized to the 2 arms. Vitamin A-supplemented children infected with enteropathogenic E. coli (EPEC) had reduced IL-4 and IFN-gamma levels [odds ratio (OR) = 0.3, 95% CI 0.13-0.67 and OR = 0.34, 95% CI 0.14-0.83, respectively] compared with children in the placebo group. Vitamin A-supplemented children had increased IL-4 levels when infected with A. lumbricoides (OR = 12.06, 95% CI 0.95-153.85). In contrast, IL-4 levels increased (OR = 2.14, 95% CI 0.94-4.87) and IFN-gamma levels decreased (OR = 0.51, 95% CI 0.26-0.99) among vitamin A-supplemented children with diarrhea compared with children in the placebo group. These findings suggest that the regulation of the mucosal immune response by vitamin A may depend on the type of enteric pathogen infecting the child and the presence of clinical symptoms.

Animals↗
PubMed1987

Fetal intestinal transplants in syngeneic rats: a developmental model of intestinal immunity.

We conducted a longitudinal study of the development of lymphoid tissue in fetal small intestine transplanted to a subcutaneous site in adult syngeneic Fischer strain rats. Fetal jejunoileal segments obtained between 18 and 21 days of gestation were transplanted to a dorsal subcutaneous site on syngeneic adult rats. Three weeks later, intestinal segments greater than 2.5 cm in length were found in 70% of recipients. Each week for 6 wk post-transplantation, a full-thickness biopsy was obtained for histologic and immunohistologic examination. At the time of transplantation, fetal rat intestine did not display Peyer's patches, intraepithelial lymphocytes, lymphoid follicles, or IgA-containing plasma cells. These lymphoid structures reached adult levels by 4 wk after transplantation, and the sequence of development of the lymphoid structures in the transplants appeared to match the postnatal development of normal small intestine. After immunizing the in situ intestine or the transplanted fetal intestine with cholera toxin, the number of cells producing specific antibodies to the immunogen increased significantly in intestinal transplants and in situ intestine. In contrast, few if any cells synthesizing antibodies to cholera toxin developed in the transplants after i.p. immunization. This study suggests that fetal intestinal transplants behave as part of the mucosal immune system. This model may provide useful approaches to studying the development of mucosal immunity.

Animals↗
PubMed1991

Secretory immune responses in the mouse vagina after parenteral or intravaginal immunization with an immunostimulating complex (ISCOM).

Immunostimulating complexes (ISCOMs) are subunit vaccines that are particularly effective in producing immunity against systemic viral infections, but their effectiveness against mucosal infections has received little attention. To study their ability to produce mucosal immune responses in the female reproductive tract, a model ISCOM was prepared containing sheep erythrocyte membrane proteins, and anti-erythrocyte IgA and IgG titres in mouse vaginal washings were measured after immunization at parenteral or local mucosal sites. The ISCOM was prepared by a modified procedure that resulted in incorporation of 10-15% of initial membrane protein compared with 1-5% previously reported. Electrophoretic analysis demonstrated that four out of five erythrocyte membrane proteins were incorporated into the ISCOM, and electron microscopic observations indicated that the ISCOM had a cage-like structure with a diameter of 40 nm, similar to previous ISCOMs. Immunization in the pelvic presacral space (p.s.-p.s.) stimulated significantly higher anti-erythrocyte IgA titres in vaginal fluid than were produced by intraperitoneal (i.p.-i.p.), subcutaneous (s.c.-s.c.), intravaginal (i.vag.-i.vag.), or i.p.-i.vag. immunizations with the same vaccine. Specific IgG titres were less dependent on the route of immunization, with p.s.-p.s., i.p.-i.p. and s.c.-s.c. administration all giving similar high titres while i.p.-i.vag. treatment induced lower titres. These observations using a model ISCOM indicate that mucosal immune responses against membrane proteins were elicited in the female reproductive tract, and that non-mucosal immunization in the pelvis was a more effective route of administration than local application of the ISCOM to the vaginal mucosa.

Adjuvants, Immunologic↗
PubMed2002

T-bet and mucosal Th1 responses in the gastrointestinal tract.

T cells play an essential role in regulating mucosal immune responses in the gastrointestinal tract. Recent observations on T helper cell differentiation and activation by regulatory transcription factors-especially T-bet-in chronic inflammatory diseases have provided new perspectives for understanding mucosal immunity. Here we summarise recent advances in the field of transcription factors and discuss the implications of these findings for future therapeutic approaches in inflammatory bowel diseases. In particular, we have focused on the role of T-bet in controlling mucosal Th1 responses in the gastrointestinal tract.

Animals↗
PubMed2001

Lactic acid bacteria and their effect on the immune system.

Lactic acid bacteria (LAB) are present in the intestine of most animals. The beneficial role played by these microorganisms in the humans and other animals, including the effect on the immune system, has been extensively reported. They are present in many foods and are frequently used as probiotics to improve some biological functions in the host. The activation of the systemic and secretory immune response by LAB requires many complex interactions among the different constituents of the intestinal ecosystem (microflora, epithelial cells and immune cells). Through different mechanisms they send signals to activate immune cells. Thus the knowledge of the normal intestinal microflora, the contribution of LAB and their role in the numerous functions in the digestive tract as well as the functioning of the mucosal immune system form the basis for the study and selection of a probiotic strain with immunostimulatory properties. In the selection of LAB by their immunostimulatory capacity it helps to know not only the effect which they have on the mucosal immune system, but the specific use to which these oral vaccine vectors are being put. Although there are reports of the protection of animals and humans against diseases such as microbial infections and cancer, more work remains to be done on the factors affecting the design of oral vaccine vectors and the use of LAB for therapeutic purposes. The basic knowledge of LAB immunostimulation and the criteria for selection of LAB by their immunostimulatory capacity, will be extensively discussed and appraised in this review.

Animals↗
PubMed2019

Cold chain and virus-free oral polio booster vaccine made in lettuce chloroplasts confers protection against all three poliovirus serotypes.

To prevent vaccine-associated paralytic poliomyelitis, WHO recommended withdrawal of Oral Polio Vaccine (Serotype-2) and a single dose of Inactivated Poliovirus Vaccine (IPV). IPV however is expensive, requires cold chain, injections and offers limited intestinal mucosal immunity, essential to prevent polio reinfection in countries with open sewer system. To date, there is no virus-free and cold chain-free polio vaccine capable of inducing robust mucosal immunity. We report here a novel low-cost, cold chain/poliovirus-free, booster vaccine using poliovirus capsid protein (VP1, conserved in all serotypes) fused with cholera non-toxic B subunit (CTB) expressed in lettuce chloroplasts. PCR using unique primer sets confirmed site-specific integration of CTB-VP1 transgene cassettes. Absence of the native chloroplast genome in Southern blots confirmed homoplasmy. Codon optimization of the VP1 coding sequence enhanced its expression 9-15-fold in chloroplasts. GM1-ganglioside receptor-binding ELISA confirmed pentamer assembly of CTB-VP1 fusion protein, fulfilling a key requirement for oral antigen delivery through gut epithelium. Transmission Electron Microscope images and hydrodynamic radius analysis confirmed VP1-VLPs of 22.3&#xa0;nm size. Mice primed with IPV and boosted three times with lyophilized plant cells expressing CTB-VP1co, formulated with plant-derived oral adjuvants, enhanced VP1-specific IgG1, VP1-IgA titres and neutralization (80%-100% seropositivity of Sabin-1, 2, 3). In contrast, IPV single dose resulted in <50% VP1-IgG1 and negligible VP1-IgA titres, poor neutralization and seropositivity (<20%, <40% Sabin 1,2). Mice orally boosted with CTB-VP1co, without IPV priming, failed to produce any protective neutralizing antibody. Because global population is receiving IPV single dose, booster vaccine free of poliovirus or cold chain offers a timely low-cost solution to eradicate polio.

Animals↗
PubMed1996

Mutants of the Escherichia coli heat-labile enterotoxin with reduced ADP-ribosylation activity or no activity retain the immunogenic properties of the native holotoxin.

The Escherichia coli heat-labile enterotoxin (LT) is a potent inducer of mucosal immune responses. In a previous study (L. DeHaan, W. R. Verweij, M. Holtrop, E. Agsteribbe, and J. Wilschut, Vaccine 14:620-626, 1996), we have shown that efficient induction of an LTB-specific mucosal immune response by LT requires the presence of the LTA chain, suggesting a possible role of the enzymatic activity of LTA in the induction of these responses. In the present study, we generated LT mutants with altered ADP-ribosylation activities and evaluated their immunogenicity upon intranasal administration to mice. The results demonstrate that the mucosal immunogenicity of LT is not dependent on its ADP-ribosylation activity.

Adenosine Diphosphate↗
PubMed2002

Serum antibody response and nasal lymphoid tissue (NALT) structure in the absence of IL-4 or IFN-gamma.

Immunization via the nasal route is effective for inducing not only mucosal immunity but also antibody (Ab) response in serum. Nasal lymphoid tissue (NALT) is important for induction of systemic immunity. It remains controversial which T effector cell response is important for serum Ab response after nasal immunization. We investigated serum Ab responses and NALT structures in interleukin (IL)-4 gene targeted (IL-4(-/-)) and interferon (IFN)-gamma gene targeted (IFN-gamma(-/-)) mice. Mice were immunized via nostrils with ovalbumin (OVA) and cholera toxin as adjuvant and serum Ab titers were measured 1 week after final antigen challenge. OVA-specific IgG titers in sera of IL-4(-/-) mice indicated a Th(1) type response, whereas titers in IFN-gamma(-/-) mice and wild-type mice indicated a Th(2) type response. Enhanced serum Ab responses were observed in IL-4(-/-) mice but not IFN-gamma(-/-) mice. OVA-specific Ab-forming cells were detected in the cervical draining lymph nodes but were rare or absent in and around the NALT of all strains of mice. Numbers of OVA-specific Ab-forming cells in cervical lymph nodes were significantly higher in IL-4(-/-) mice than in wild-type and IFN-gamma(-/-) mice. Germinal centers of lymphoid follicles were present in NALT of IL-4(-/-) and other mice. Immunohistochemistry for B and T cell markers revealed that NALT of all mice had approximately the same cellular compositions. Although the absence of IL-4 had no effect on NALT structure, IL-4 may suppress induction of serum Ab responses by nasal immunization.

Animals↗
PubMed1995

Conjugation of cholera toxin or its B subunit to liposomes for targeted delivery of antigens.

Several immunoadjuvant systems have been proposed to enhance mucosal immune responses of orally administered purified antigens. Cholera toxin (CT) or its B subunit (CTB) have been found to promote immune responses to antigens when they are co-administered via mucosal routes. Oral administration of antigens incorporated into liposomes has also been shown to result in enhanced mucosal immune responses. Here, we describe the covalent coupling of CT and CTB to small unilamellar liposomes for targeting these vesicles to Peyer's patch M cells, following their oral administration. Conjugation was done by means of a thioether bond using succinimidyl(4-N-maleimidomethyl)cyclohexane-1-carboxylate to modify the dipalmitoylphosphatidyl-ethanolamine constituent of liposomes and N-succinimidyl-3-(2-pyridyldithio)propionate to thiolate CT or CTB. The biological activity of CT or CTB bound to liposomes was confirmed by a hemagglutination assay using GM1-enriched human erythrocytes. Furthermore, oral administration of CT-conjugated liposomes to rats resulted in the induction of serum IgG and salivary IgA anti-CT responses. CT-conjugated liposomes may prove to be a useful system for targeted delivery and immunoenhancement of weakly immunogenic antigens.

Adjuvants, Immunologic↗
PubMed1989

Secretory IgA and bacterial adherence to nasal mucosal cells.

The ability of Streptococcus pyogenes to adhere to nasal mucosal cells was investigated by an in vitro assay system in order to clarify the actual role of secretory IgA in mucosal immunity in the nose. The number of bacteria adhering to isolated mucosal cells was significantly larger in patients with chronic sinusitis than in normal control subjects. The ability of bacteria to adhere, however, was significantly lower in the group of subjects having specific secretory IgA antibody activity to the M protein than in those having no secretory IgA activity. Findings demonstrated that mucosal immunity preventing or blocking the adherence of bacteria is impaired in patients with chronic sinusitis.

Antigens, Bacterial↗
PubMed1996

The immunologic aspects of human immunodeficiency virus infection in the gastrointestinal tract.

The intestinal (in particular rectal) mucosa is an important portal of entry of human immunodeficiency virus (HIV) in homosexual men, who represent the vast majority of HIV-infected patients in Europe and North America. There are several possibilities for HIV to reach the CD4+ T cells, macrophages, and follicular dendritic cells in the intestinal mucosa. HIV may be transported through M cells directly to mucosal lymphoid follicles. Alternatively, HIV may infect enterocytes via Fc-receptor by antibody-bound HIV or via a CD4 independent receptor. By successive budding on the basal side of enterocytes, HIV may be released into the lamina propria. Furthermore, in patients not infected by the intestinal route, HIV may also rapidly enter the intestinal mucosa by other mechanisms: intestinal T-lymphocytes are mainly activated memory T cells reentering the mucosal surfaces after circulating through the peripheral blood. In the periphery they may have been preferentially infected by HIV. Accumulation of infected T cells could thus occur in the intestinal mucosa. The special phenotypical and functional characteristics of intestinal T lymphocytes may affect the replication and cytopathicity of HIV, resulting in an accelerated loss of CD4 positive T cells in the lamina propria. CD4 T cells play a critical role in antigen-dependent B cell differentiation, thus the pronounced CD4 T cell depletion in the intestinal mucosa may be responsible for the observed decrease of IgA plasma cells and a reduced secretion of IgA2. Depletion and functional impairment of activated mucosal lamina propria lymphocytes by HIV infection could explain the break-down of the mucosal immune barrier leading to secondary opportunistic or nonopportunistic infections and secondary malignancies. In addition, because of the interrelation between the mucosal immune system and the epithelium these changes might be responsible for the partial small intestinal mucosal atrophy and maturational defects in enterocytes observed in HIV-infected patients. To be effective, a future prophylactic vaccine against HIV has to be able to induce not only systemic but also a local mucosal cellular and humoral protective immune response.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Activation patterns of murine B cells after oral administration of an encapsulated soluble antigen.

Oral administration of soluble protein antigen, ovalbumin (OVA), encapsulated by an acid-resistant acrylic polymer, induced a strong immune response in BDF1 mice. Mice fed the encapsulated OVA showed activation of antigen-specific IgA, IgG and IgG1 isotype antibody-secreting cells which migrated to various lymphoid tissues via the common mucosal immune system traffic pathway. The highest number of antigen-specific antibody secreting cells was found in the Peyer's patches isolated from the upper segment of the small intestine, with their numbers declining along the length of the intestinal tract. Oral administration of this product suggests activation of lymphocytes exhibiting Th2 phenotype as shown by OVA-specific IgA and IgG1 isotype antibody responses. In conclusion, we demonstrated that oral administration of encapsulated soluble protein, in the absence of adjuvant, can activate the murine common mucosal immune system.

Administration, Oral↗