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PubMed2006

Immune activation of peripheral blood and mucosal CD3+ lymphocyte cytokine profiles in children with autism and gastrointestinal symptoms.

Gastrointestinal pathology, characterized by lymphoid nodular hyperplasia and entero-colitis, has been demonstrated in a cohort of children with autistic spectrum disorder (ASD). Systemic and intestinal mucosal immune dysregulation was assessed in ASD children with gastrointestinal (GI) symptoms (n = 18), and typically developing controls (n = 27), including non-inflamed controls (NIC) and inflamed GI control children with Crohn's disease (CD), by analysis of intracellular cytokines in CD3+ lymphocytes. In both peripheral blood and mucosa, CD3+ TNFalpha+ and CD3+ IFNgamma+ were increased in ASD children compared with NIC (p < 0.004) and reached levels similar to CD. In contrast, peripheral and mucosal CD3+ IL-10+ were markedly lower in ASD children with GI symptoms compared with both NIC and CD controls (p < 0.02). In addition, mucosal CD3+ IL-4+ cells were increased (p < 0.007) in ASD compared with NIC. There is a unique pattern of peripheral blood and mucosal CD3+ lymphocytes intracellular cytokines, which is consistent with significant immune dysregulation, in this ASD cohort.

Autistic Disorder↗
PubMed2002

A new intra-NALT route elicits mucosal and systemic immunity against Moraxella catarrhalis in a mouse challenge model.

Mucosally administered antigens are often poorly immunogenic due to the difficulty of transporting antigens through the mucosal epithelium. We investigated a new route of intranasal-associated lymphoid tissue (intra-NALT) administration of antigens to circumvent the antigen transportation barrier. A comparative study was carried out on mice administered with killed whole cells of Moraxella catarrhalis strain 25238 plus cholera toxin (CT) by intra-NALT injection and nasal inoculation. Both routes induced significant elevations of several isotype antibodies against strain 25238 in saliva, lung lavage, and serum as measured by an enzyme-linked immunosorbent assay (ELISA). Most of these antibodies were paralleled by the numbers of their corresponding antibody forming cells in mucosal or systemic lymphoid tissues. However, intra-NALT injection elicited higher levels of immunoglobulin (Ig) A and IgG in saliva, IgA and IgG in lung lavage, and IgG and IgM in sera than nasal inoculation (P<or=0.05). In addition, both routes generated significant reductions of bacteria in lungs following an aerosol challenge with strain 25238 in a mouse model of pulmonary clearance. Once again, intra-NALT route showed better bacterial clearance in mouse lungs than nasal inoculation (P<0.01). These results demonstrate that intra-NALT administration of antigens is a convenient and effective route for mucosal immunization that elicits improved mucosal and systemic immunity. This new route can be used as a model to study mucosal antigens or vaccine candidates for antigen activation and interaction with the NALT that is one of major inductive sites for common mucosal immune system.

Administration, Intranasal↗
PubMed2005

Early antiretroviral therapy for simian immunodeficiency virus infection leads to mucosal CD4+ T-cell restoration and enhanced gene expression regulating mucosal repair and regeneration.

Simian immunodeficiency virus (SIV) and human immunodeficiency virus (HIV) infections lead to rapid depletion of CD4(+) T cells from gut-associated lymphoid tissue (GALT). Although the administration of antiretroviral therapy (ART) has been shown to increase CD4(+) T-cell levels in the peripheral blood in both SIV and HIV infections, its efficacy in restoring intestinal mucosal CD4(+) T cells has not been well investigated. To gain insights into the molecular mechanisms of virally induced disruptions in the mucosal immune system, we have evaluated longitudinal changes in viral burden, T-cell subsets, and mucosal gene expression profiles in SIV-infected rhesus macaques in the absence or presence of ART. Our results demonstrate a dramatic suppression of mucosal viral loads and rapid reconstitution of CD4(+) T cells in GALT in animals receiving ART that were not observed in untreated SIV-infected animals. DNA microarray-based gene expression profiling indicated that CD4(+) T-cell restoration in GALT was associated with up regulation of growth factors and genes involved in repair and regeneration of the mucosal epithelium. In contrast, untreated SIV-infected animals increased expression of lymphocyte activation and inflammatory response-associated genes and did not up regulate mucosal growth and repair associated transcription. In conclusion, these data indicate that initiating ART in primary SIV infection may lead to the restoration of the mucosal immune system through reduction of inflammation and promotion of epithelial repair in the intestinal mucosa.

Adenine↗
PubMed2002

Current aspects of mucosal immunology and its influence by nutrition.

BACKGROUND: A significant body of clinical literature demonstrates that enteral feeding significantly reduces the incidence of pneumonia compared to patients fed parenterally. An immunologic link between the gastrointestinal tract and respiratory tract is postulated via the common mucosal immune hypothesis. This hypothesis states that cells are sensitized within the Peyer's patches of the small intestine and are subsequently distributed to submucosal locations in both intestinal and extra intestinal sites. This system is exquisitely sensitive to route and type of nutrition. DATA SOURCE: This review examines the laboratory data regarding cell numbers, cell phenotypes, cytokine profile, and immunologic function in both intestinal and extra intestinal sites in animals that have been administered either parenteral feeding or various types of enteral feeding. It also establishes links between a specific nutrient, glutamine, the enteric nervous system, by way of neuropeptides, and mucosal immunity. CONCLUSION: Progress in understanding relationships between nutrient availability, enteric nervous system stimulation, and nutrient delivery on mucosal immunity offers opportunities to explore immune systems previously not appreciated by clinicians and basic scientists. These opportunities offer new challenges to the physician scientist, basic scientist, and clinician to understand, manipulate, and apply these concepts to the critically ill patient population by favorably influencing immunologic barriers and the inflammatory response.

Animals↗
PubMed1991

The inhibition effect of cholecystokinin in human colonic lamina propria lymphocyte proliferation, and reversal by the cholecystokinin receptor antagonist L-364718.

Cholecystokinin (CCK) is a potent neuropeptide hormone with activity on various gastrointestinal organs during the digestive process. It was recently suggested that CCK may also act on the immune system. In this study we investigated the effect of CCK on the human mucosal immune system as represented by colonic lamina propria lymphocytes (LPL). Our results demonstrated that CCK at concentrations of 10(-13) M to 10(-7) M inhibits thymidine incorporation into Con A-stimulated LPL DNA by up to 40%. Moreover, this inhibitory effect was reversed by the specific CCK receptor antagonist, L-364718, at concentrations of 10(-8) M to 10(-5) M. In addition, CCK did not affect DNA synthesis of LPL stimulated with phorbol ester (PDB) and calcium ionophore (ionomycin). It is postulated that the CCK effect may involve intracellular metabolic steps proximal to protein kinase C activation and calcium flux. Our results suggest that CCK may play a role in modulating the human mucosal immune system during digestion and thus, should be added to the list of the neuropeptides that affect the mucosal immune system.

Adult↗
PubMed2006

Novel foods to treat food allergy and gastrointestinal infection.

The gastrointestinal tract communicates directly with the external environment. Necessary nutrients must be absorbed and commensal bacteria tolerated, and foreign proteins, antigens, and pathogens must be simultaneously excluded or destroyed. Immaturity or disruption of the mucosal immune defenses increases vulnerability to food allergy, intolerance, and infectious disease. Diseases resulting from ingested foreign proteins and organisms are increasing and cause morbidity and mortality worldwide. There is no specific treatment for food allergy other than avoidance. Vaccination for infectious disease is limited by the cost and logistics of distribution and administration, particularly in developing countries. Novel strategies are being explored to modulate the gut mucosal immune system by altering protein expression in food. Crops are being developed to remove deleterious allergens to prevent immunogenic exposure while preserving nutritional quality. Local food plants that express protein fragments of pathogens might provide an effective means to stimulate gut mucosal immunity while increasing vaccine accessibility.

Food Hypersensitivity↗
PubMed1992

Local immunity in the male reproductive tract.

In previous studies we have demonstrated that the male urinary tract forms part of the common mucosal immune system, and that the gut contributes to local defences at this site. The question arises as to the extent to which the reproductive tract also forms part of the common mucosal immune system. Rats were immunized by a variety of routes designed to stimulate a local response in the intestine and/or the reproductive tract. Rats immunized only by the intratesticular (i.t.) route yielded no antibody-containing (ACC) response in any of the tissues examined. Intestinal immunization using intraperitoneal priming followed by intraduodenal challenge (i.p./i.d.) yielded a substantial IgA-specific ACC response in the jejunum, but no ACC were detectable in any of the reproductive tract tissues. However, when intestinal and testicular immunizations were combined, large numbers of IgA-specific antibodies were detected in all tissues examined. Chronic drainage of the thoracic lymphatic duct throughout the post-challenge period abrogated the ACC response in all tissues of the reproductive tract, indicating that the ACC appearing at these sites after immunization were of gut origin. The IgA-specific anti-OVA antibody detectable in serum, saliva and testis homogenate reflected the ACC counts in histological sections. The studies reported here confirm that the male reproductive tract does form part of a common mucosal immune system and that gut-associated lymphoid tissues may contribute cellular precursors for ACC, particularly those of IgA specificity, appearing in the tract after local challenge.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Rational design of Salmonella-based vaccination strategies.

A permanently growing body of information is becoming available about the quality of protective immune responses induced by mucosal immunization. Attenuated live bacterial vaccines can be administered orally and induce long-lasting protective immunity in humans without causing major side effects. An attenuated Salmonella enterica serovar Typhi strain is registered as live oral vaccine against typhoid fever and has been in use for more than two decades. Recombinant attenuated Salmonella strains are also an attractive means of delivering heterologous antigens to the immune system, thereby, stimulating strong mucosal and systemic immune responses and consequently provide an efficient platform technology to design novel vaccination strategies. This includes the choice of heterologous protective antigens and their expression under the control of appropriate promoters within the carrier strain. The availability of well-characterized attenuated mutants of Salmonella concomitantly supports fine tuning of immune response triggered against heterologous antigens. Exploring different mucosal sites as a potential route of immunization has to be taken into account as an additional important way to modulate immune responses according to clinical requirements. This article focuses on the rational design of strategies to modulate appropriate immunological effector functions on the basis of selection of (i) attenuating mutations of the Salmonella strains, (ii) specific expression systems for the heterologous antigens, and (iii) route of mucosal administration.

Animals↗
PubMed1994

Neuropeptide Y (NPY) enhances proliferation of human colonic lamina propria lymphocytes.

Neuropeptide Y (NPY) is one member of a family of peptides with a wide range of physiological effects on the CNS, cardiovascular, and respiratory systems. NPY is widely distributed throughout the peripheral and central nervous systems. It has also been found within the colon, liver and gallbladder in close anatomic proximity to the mucosal immune system. In this study, we investigated the effect of NPY on human gut mucosal immune function. We examined colonic lamina propria lymphocyte (LPL) proliferation by measuring DNA synthesis, ornithine decarboxylase (ODC) activity, and polyamine biosynthesis. NPY enhanced ODC activity and polyamine biosynthesis in Con A-stimulated LPL, and enhanced thymidine incorporation into Con A-stimulated LPL but not into monocyte-depleted LPL. Moreover, exogenous IL1-beta partially restored NPY's stimulatory effect on monocyte-depleted LPL DNA synthesis. Our results demonstrate that NPY enhances human colonic LPL proliferation and that this effect is partially IL1-beta dependent. Our data also suggest that NPY's effect may be mediated via polyamine biosynthesis. We postulate that the NPY may have an important impact on human mucosal immune function.

Cell Division↗
PubMed2002

Prospects for a human Toxoplasma vaccine.

Human toxoplasmosis is usually benign, but may occasionally lead to severe or lethal damages when combined with immunosuppressive states or when transmitted to the fetus during pregnancy. Only a vaccine could prevent these harmful effects. The oral route is the natural portal of entry of T. gondii. A protective immune response at the mucosal level is required to kill the parasite as soon as it penetrates the intestinal barrier thus preventing toxoplasma from invading the host and settling into tissues. The probable major roles played by both CD8 T cells and antibodies, specially IgA, suggest that the best strategy would be to stimulate both the cellular and humoral arms of the mucosal immune system. Mucosal dendritic cells have been shown to induce good protection against oral toxoplasma challenge. Our hypothesis is that an acceptable and effective human vaccine would have to carry the optimized synthetic vaccine (subunit, DNA or replicon) plus an appropriate adjuvant and to target the mucosal dendritic cells by means of an inert delivery system such as polymer microparticles, which can be endocytosed by M cells of the gut or nasal-associated lymphoid tissues.

Animals↗
PubMed2000

Kinetics of the mucosal antibody secreting cell response and evidence of specific lymphocyte migration to the lung after oral immunisation with attenuated S. enterica var. typhimurium.

The kinetic of mucosal secretory responses elicited by the vaccine vector Salmonella enterica var. typhimurium (S. typhimurium) was examined by enzyme linked immunospot (ELISPOT) and compared with serum responses. Mice immunised orally with BRD509, the aroA, aroD mutant of virulent S. typhimurium SL1344 expressing the C Fragment of tetanus toxin (TT), simultaneously developed an IgA antibody secreting cells (ASC) response in the gastrointestinal lamina propria, the spleen and the lung, against both S. typhimurium lipopolysaccharide (LPS) and TT. The magnitude of the ASC response was greatest in the gut, was boosted by a secondary immunisation at day 25, and the kinetic of the response did not correlate with the appearance of serum antibodies. This study suggests that S. typhimurium can engage the common mucosal immune system to effect mucosal secretory responses at distal sites, however, the magnitude of the responses is both greatest in the gut and antigen-specific. The ASC origin of the serum antibodies specific for S. typhimurium and antigens expressed by the bacterium is yet to be elucidated.

Animals↗
PubMed2002

Specific mucosal IgA immunity in turkey poults infected with turkey coronavirus.

The objective of this study was to elucidate the kinetics and magnitudes of specific IgA antibody responses in intestines of turkey poults infected with turkey coronavirus (TCV). Turkey poults were orally inoculated with TCV at 10 days of age. Intestinal segment cultures were administered for duodenum, jejunum, and ileum and the IgA antibody responses were analyzed at 1, 2, 3, 4, 6, or 9 weeks post-infection (PI) in two different experiments. The kinetics of virus-specific IgA antibody responses in duodenum, jejunum, and ileum were similar: gradually increased from 1 week PI, reached the peak at 3 or 4 weeks PI, and declined afterward. The virus-specific IgA antibody responses in duodenum, jejunum, and ileum showed negative correlation with duration of TCV antigen in the corresponding locations of intestine with Spearman's correlation coefficient of -0.85 (p=0.034), -0.74 (p=0.096), and -0.75 (p=0.084), respectively. Moreover, the virus-specific IgA antibody responses in serum were positively correlated with that of duodenum (coefficient=0.829, p=0.042), jejunum (coefficient=0.829, p=0.042), and ileum (coefficient=0.771, p=0.072) segment cultures, suggesting that the induction of specific IgA response in serum was predictive of an IgA response in intestine. The results indicate that intestinal mucosal IgA antibodies to TCV are elicited in turkeys following infection with TCV. The local mucosal antibodies may provide protective immunity for infected turkeys to recover from TCV infection.

Animals↗
PubMed1994

Early stages of 1,2-dimethylhydrazine-induced colon carcinogenesis suppress immune-regulated ion transport of mouse distal colon.

Genetic events, such as gene deletion, mutation, and amplification, are involved in the development and progression of colonic neoplasia. The importance of interactions between immune cells and neoplastic cells in influencing the pathogenesis of colon cancer is suggested by the clinical efficacy of levamisole, an immunostimulant, in the treatment of colon cancer and by the association of local lymphocytic infiltration with improved prognosis. Thus, the immune cell-neoplastic cell interaction can be viewed as being analogous to various host-parasite relationships that involve the immune system attempting to contain the intruding parasite on the one hand and the parasite attempting to escape detection and rejection on the other. This study is an attempt to gain a better understanding of such interactions by examining possible effects of a developing tumor on the immune system. Colon cancer was experimentally induced in mice to examine potential effects of carcinogenesis in the colon on local mucosal immune function in situ, using the expression of type I hypersensitivity as an index of immune function. Antigen-induced changes in net ion transport, a quantifiable correlate of type I hypersensitivity, were measured in the colon of mice following the administration of the procarcinogen 1,2-dimethylhydrazine (DMH). Segments of colon and small intestine from mice immunized by infection with Trichinella spiralis secrete ions, manifested as a rise in transmural short-circuit current, when challenged with T. spiralis antigen in Ussing chambers. Antigen-induced rise in transmural short-circuit current is mast cell dependent and occurs only in immunized mice. To determine the effects of early stages of colon carcinogenesis on this mucosal immune response, mice were immunized with T. spiralis prior to and after 6 weekly injections of DMH. Responsiveness to antigenic challenge was suppressed in the distal colon 4-6 weeks after the final injection of DMH. Although responsiveness to antigen was suppressed, the colonic epithelium remained sensitive to direct stimulation by exogenous secretagogues. Decreased antigen responsiveness observed in the distal colon was not due to generalized immune suppression by DMH, because the proximal colon and the jejunum retained their responsiveness to antigen, and immune rejection of a secondary T. spiralis infection from the small intestine was not altered. Visible tumors eventually developed 30 weeks after the final injection of DMH only in the distal portions of the colon. These results suggest that early stages of DMH-induced carcinogenesis are associated with the suppression of mucosal immune function, as measured by immune-regulated ion secretion, in the distal colon but not in the proximal colon or jejunum.(ABSTRACT TRUNCATED AT 400 WORDS)

1,2-Dimethylhydrazine↗
PubMed2002

Immunization for protection of the reproductive tract: a review.

PROBLEM: Local application of non-replicating antigens to the female reproductive tract is ineffective in stimulating the common mucosal immune system, and induces only weak genital antibody responses. Studies of immune responses to genital infections such as gonorrhea also support the concept that, lacking mucosal immune inductive sites, the reproductive tract is ill-equipped to mount effective immune responses. METHOD OF STUDY: Intranasal (i.n.) and intravaginal (i.vag.) routes of immunization of mice with a protein antigen coupled to cholera toxin (CT) B subunit, or genetically engineered as chimeric proteins with the A2/B sunbunits of CT or type II heat-labile enterotoxin, were compared for their ability to induce specific antibody responses in vaginal fluids, saliva, and serum. RESULTS: Mice immunized i.n. developed substantially stronger vaginal immunoglobulin A (IgA) and immunoglobulin G (IgG) and serum IgG and IgA antibodies, than those immunized i.vag. which also failed to develop salivary antibodies. Vaginal antibody responses induced i.n. persisted for at least 1 year, and were recallable by booster immunization after a prolonged period. CONCLUSIONS: Such alternative strategies for inducing potent genital antibody responses offer the prospect of prophylactic immunization against genital infections. Further studies are required to evaluate their applicability to humans, and to comprehend the cellular and molecular mechanisms involved in delivering effective immune responses to the reproductive tracts.

Administration, Intranasal↗
PubMed2001

Vaccines and mucosal immunisation.

The earliest attempts to protect humans against infectious diseases and toxins were by administering foreign substances to mucosal membranes, predominantly by the oral route. In the late 1880s, significant attention was given to the concept of 'local' immunisation, and the discipline of mucosal immunology was born in the early 1900s. However, despite the early enthusiasm, progress has been slow, with few mucosal vaccines being efficacious. The complexities of mucosal immune regulation and the lack of appropriate antigen delivery systems which can access mucosal inductive sites, have remained substantial obstacles. Recent studies demonstrating compartmentalisation of the common mucosal immune system create further challenges for the development of organ-specific vaccines. In the 21st century, our knowledge of mucosal immunoregulatory mechanisms, coupled with new technology for antigen delivery and immunomodulation will provide the necessary know-how to see the development and widespread use of mucosal vaccines for both preventative and therapeutic use.

Administration, Oral↗
PubMed2005

Development of a lavage procedure to collect lung secretions from chickens for evaluating respiratory humoral immunity.

Mucosal immunology research has been hampered by the difficulty and labour-intensiveness of collecting samples. This is especially true for sites such as the lung, and the present paper describes a simple method for obtaining samples from this organ in chickens. Following sacrifice, the bird was placed on its back and the trachea was cut and exteriorized. Narrow-diameter tubing, to which a 30 ml syringe was attached, was threaded down the trachea to the bronchi and air was evacuated from the lung. Warm buffer was administered and the lung sample then aspirated, processed and frozen. In the current experiment this sampling system was tested on hens that were challenged with Salmonella Enteritidis. Elevated anti-Salmonella Enteritidis antibody levels in lung from infected hens were observed in significantly more infected hens than non-infected control hens in two trials. The simplicity and utility of this sampling system will make it a useful tool for those laboratories wishing to expand their humoral mucosal immunology capabilities, even for study of non-respiratory pathogens.

Animals↗
PubMed2005

Non-classical MHC class I molecules on intestinal epithelial cells: mediators of mucosal crosstalk.

The mucosal immune environment consists of a complex combination of lymphoid cells, non-lymphoid cells, and lumenal bacteria. Signals from lumenal bacteria are constantly transmitted to the underlying tissues across the intestinal epithelial barrier. Intestinal epithelial cells (IECs) can sense these signals, integrate them, and interpret them for lamina propria lymphoid populations. One mechanism by which these signals are communicated is by the expression of non-classical major histocompatibility complex (MHC) class I molecules by IECs. Epithelial cells can express a surprising variety of non-classical MHC class I molecules. In some cases, IECs can act as non-professional antigen-presenting cells utilizing the expression of such non-classical MHC class I molecules to directly present bacterial antigens. In other cases, the expression of non-classical MHC class I molecules may act as a co-stimulatory molecule or adhesion molecule that can modify the mucosal immune response. Finally, the expression of these molecules on IECs can lead to a broad array of responses ranging from tolerance to inflammation. Overall, the IEC, via the expression of non-classical MHC class I molecules, is a central mediator of the constant crosstalk between the intestinal lumen and the mucosal immune system.

Animals↗