Development Of Oral Tolerance Research Articles

Human milk–specific mucosal lymphocytes of the gastrointestinal tract display a TH2 cytokine profile

Background: A number of gastrointestinal disorders, including allergic eosinophilic gastroenteritis and food protein-induced enteropathy, have been associated with milk hypersensitivity. The immunologic reactions appear to involve T cells that are activated by specific food proteins. Objective: The present study was performed to examine the cytokine profiles of milk-specific lymphocytes from the duodenal lamina propria from children with milk-induced gastrointestinal diseases. Methods: Duodenal biopsy specimens obtained from 10 patients with allergic eosinophilic gastroenteritis, food protein-induced enteropathy, or both and 12 control subjects were mechanically minced and cultured with either mitogens (ie, polyclonal T-cell expansion) or milk proteins (ie, milkspecific T-cell expansion). By using flow cytometry, expanded T cells were phenotyped with anti-CD4, anti-CD8, anti-IL-4, anti-IL-5, and anti-IFN-γ mAbs. The milk specificity of the lines was evaluated by means of the lymphocyte proliferation assay. In addition, the release of TH1, TH2, and TH3 cytokines was determined after restimulation. Results: In patients and control subjects polyclonal expansion of mucosal lymphocytes resulted in predominantly TH1 cells. Milk-specific mucosal T-cell lines could be established in 60% of the patients but in none of the control subjects. In contrast to the polyclonal expansion of T cells, the milk-specific expansion of mucosal T cells showed a clear TH2 cytokine profile. On restimulation with milk protein, these cells showed a high proliferative response. They released TH2 cytokines, predominately IL-13, but failed to release TH3 cytokines important in the development of oral tolerance. Conclusion: The release of TH2 cytokines after stimulation of milk-specific mucosal T cells may play a pathogenic role in the inflammatory changes seen in milk-induced gastrointestinal disorders. (J Allergy Clin Immunol 2002;109:707-13.)

CD40L in autoimmunity and mucosally induced tolerance.

The administration of soluble antigens to the oral or nasal mucosa can lead to systemic unresponsiveness to a subsequent challenge with the same antigens (1). Such mucosally induced tolerance probably protects the body from hypersensitivity reactions to food proteins, pollen, and commensal bacterial antigens present in the normal mucosa and thus helps maintain an appropriate immunological balance between the host and its normal flora. Numerous molecular and cellular inhibitory mechanisms are involved in this unique and important immunological phenomenon. Several lines of evidence show that mucosally induced tolerance does not occur passively, by means of anergy, clonal deletion, or the simple absence of autoreactive immune cells, but also involves ignorance, receptor downregulation, or active cellular suppression (ref. 2; Figure ​Figure11a). Figure 1 Models for the effects on mucosally induced tolerance of perturbing the CD40L-CD40 interaction. (a) In the untreated wild-type mouse, CD40 on dendritic cells (DCs) and other APCs interacts with CD40L expressed on T cells of several subsets, including ... The fact that mucosally induced tolerance can suppress antigen-specific T cell proliferation, delayed-type hypersensitivity responses, and antibody production suggests attractive ap-proaches for the prevention and control of autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, encephalomyelitis, and type 1 diabetes (3). However, although mucosal administration of different autoantigens has been tested in human trials, this strategy has not yet yielded a successful therapy (4, 5). Some previous studies have suggested that this failure of human trials was due to concomitant induction of harmful cytotoxic T lymphocytes (CTLs) by mucosally administered antigen (6, 7). In an attempt to overcome this obstacle, as reported in this issue of the JCI, Hanninen et al. (8) have induced a temporary blockade of the interaction between the costimulatory protein CD40 and its ligand CD40L. This interaction has been suggested to foster mucosally induced tolerance by several mechanisms, as shown in Figure ​Figure1a.1a. In their present report, the authors show that blocking antibodies to CD40L can prevent the development of antigen-specific CTL responses without affecting the development of oral tolerance. Hanninen and colleagues (8) tested this approach in rat insulin promotor-OVA (RIP-OVA) mice, a diabetic transgenic strain in which the expression of the model antigen chicken ovalbumin (OVA) in the pancreatic β-islet cells provokes an autoimmune response to these cells. The consequent destruction of these islet cells thus provides a model for the events seen in type I diabetes. Oral administration of a high dose of OVA can promote mucosally induced tolerance, but this treatment also elicits CTL specific for OVA. However, Hanninen et al. observed that transient blockade of CD40L in this system prevented CTL responses without affecting mucosally induced tolerance toward OVA, either in wild-type or in RIP-OVA transgenic mice (Figure ​(Figure1b).1b). Furthermore, the severity of diabetes, as measured, for example, by blood glucose, was significantly improved after transient blockade of CD40L, suggesting that modulation of CD40L-CD40 interaction could be used clinically to uncouple the desired systemic, autoantigen-specific unresponsiveness from the oral induction of CTLs.

Low-Protein Diet Induces Oral Tolerance to Ovalbumin in Mice.

The suitable development of oral tolerance against ingested dietary foods is of critical importance to escaping food allergy. Using mice as an animal model for oral tolerance against ovalbumin (OVA) as a dietary antigen, we investigated the effects of dietary protein on their immunological tolerance. Female BALB/c mice fed either a 20% or 5% protein diet were orally administered 5 mg of OVA for four consecutive days, then immunized intraperitoneally with 100 microg of OVA. The immunized group of mice were fed and treated in the same manner, except that they received orally distilled water for four consecutive days before receiving intraperitoneal immunization with the antigen. Immunization alone with OVA elevated the total IgE and induced the production of OVA-specific antibodies IgE, IgG, IgG1, and IgG2a in the sera of both the 20% and 5% protein diet groups. The oral administration of OVA to mice before intraperitoneal immunization significantly reduced the total IgE and OVA-specific antibodies in mice fed 5% protein diet, but it had hardly any effect on those in mice fed a 20% protein diet. When spleen cells from these groups of mice were cultured with OVA as a mitogen, they responded substantially to OVA in the immunized groups fed 20% and 5% protein diets and in the presensitized group fed 20% protein, but those from the presensitized group fed a 5% protein diet did not respond. Furthermore, when IL-4 was assayed in the spleen cell cultures of the 20% and 5% groups, mice in the presensitized group fed a 5% protein diet produced a significantly less amount of IL-4 than those fed a 20% protein diet. Moreover, irrelevant to the protein amount in the diet, the production of IFN-gamma from spleen cell cultures dramatically decreased in the group without presensitization and profoundly increased in the presensitized group of mice fed a 5% protein diet. These findings suggest that a low-protein diet leads to an induction of oral tolerance against dietary antigens; this appears to involve a clear down-regulation of Th2 cytokine, IL-4.

Mucosal barrier and immune mediators

The intestinal mucosa functions is an immunologic organ that plays a major role in the development of oral tolerance and host-defense mechanisms. Antigens must cross the intestinal epithelium in a controlled manner to interact with dendritic antigen-presenting cells, because bacteria or their products are a primary risk factor for the development of intestinal inflammation. Therefore, the regulation of the intestinal epithelial cell barrier is central to the development of intestinal immunity and inflammation, but the involved mechanisms are largely unknown. Intestinal barrier function relies on the formation of tight junctions at the apical contact areas of intestinal epithelial cells. Tight junctions have a highly dynamic structure whose permeability, assembly, or disassembly can be regulated by a variety of cellular and metabolic mediators, including cytokines, which have major functions in the immune system. Immune modulators control tight junction dependent intestinal barrier function during development, wound healing, and pathologic processes such as cancer, infection, and chronic inflammation.

Mechanisms in adverse reactions to foods: a review

Human diet consists of an enormous variety of both plants and animal proteins, many of which are potentially immunogenic. Industrial processing of foods and digestion in the gastrointestinal tract causes changes and breakdown of proteins into peptides, which are also potential immunogens. Foods commonly known to cause allergic reactions are fish, milk, eggs, fruits, vegetables, nuts, legumes and meat. Once sensitised to a particular antigen, subsequent exposure may result in a marked and immediate reaction characterised by vomiting, diarrhoea, abdominal cramps, itching and swelling of the mouth and skin, dizziness and occasionally systemic anaphylaxis. Allergic reactions involve complex processes and interactions between the allergen and immunological components in the digestive tract such as antigen absorption, processing and presentation, T cell and B cell activation, development of oral tolerance or allergic sensitivity, antigen‐specific IgE antibody synthesis. Allergen binding to allergen‐specific mast cell membrane‐bound IgE antibodies triggers mast cell degranulation. This results in the release of histamine and other chemotactic mediators responsible for clinical symptoms.

Cooperation of liver cells in health and disease.

Cooperation of liver cells in health and disease.

Improved general health status in an unselected infant population following an allergen reduced dietary intervention programme The ZUFF-STUDY-PROGRAMME

The best nutritional option for newborn infants is mother's milk. However, some newborn babies may not be exclusively breastfed during the first months of life, potentially leading to reduced overall health status and the early onset of allergic diseases in some infants. Considerable research has been devoted to the development and assessment of infant nutrition programmes, particularly to the prevention of allergies in high-risk infants. However, equal numbers of infants with and without an elevated familial risk of allergies will eventually develop allergic diseases. Therefore, optimizing nutritional programmes for the early infant population as a whole is an important--but as yet insufficiently studied--area of investigation. Moreover, although safe and effective nutrition must primarily support healthy development of the infant, few studies have evaluated the overall health benefits of nutritional interventions, but have focussed on specific allergic manifestations. In animal models, an allergen-reduced moderate whey hydrolysate formula (pHF, Nestlé Beba HA) induces the development of oral tolerance towards cow's milk proteins, without inducing sensitization. In infants with a high risk for allergies, pHF formulae reduce the early onset of allergic disease during the first 5 years of life by approximately 50% compared with a dietary regimen of unaltered proteins. At present, very little is known about the overall health benefits of such a dietary intervention on the unselected infant population as a whole. The aim of our prospective, controlled study was to investigate the overall health benefits of an allergen-reduced nutritional programme in a newborn infant population unselected for atopic risk factors. The population in our study was as comparable as possible to the general population of healthy newborn infants. Our study included exclusive breastfeeding, use of a moderate whey hydrolysate formula (pHF, Nestlé Beba HA) if infant formula was needed, and delayed introduction of low-allergenic weaning foods. The study included assessments of compliance with the dietary programme, and evaluated nutritional habits, growth, and overall health status for 24 months. The health evaluation included allergic manifestations but did--by porpose--not define or evaluate them specifically. Part I of this paper gives results for nutritional habits during the first 6 months of life, Part II gives results for growth and general health status for the same time period, Part III will present feeding habits during the second half of the first year of life, and Part IV will present results to 24 months of age. The complete study report is published as a supplement to this journal. Nutritional assignment was to demographically comparable intervention (Z) or control (FF) cohorts according to the infant's place of birth. In the intervention cohort (Z, n = 564), the recommended dietary regimen was breastfeeding and/or the pHF formula, with no weaning food before 4 months of age. In the control cohort (FF, n = 566), there was no intervention. Longitudinal diet groups, defined for 4 months, excluding dropouts and noncompliants, were exclusive breastfeeding (eBF, Z, n = 201, FF, n = 162), partial breastfeeding (pBF, Z, n = 222, FF, n = 311), or non-breastfeeding (nBF, Z, n = 43, FF, n = 62). Imbalances between groups and cohorts in confounding factors that could influence health-related symptoms were integrated as covariates into the main analyses using logistic regression. Nutritional surveillance was carried out using continuous prospective monitoring. The overall rate of breastfeeding, irrespective of partial or exclusive breastfeeding or the additional use of weaning foods, was similar in both cohorts at 4 and 6 months. However, from ages 3 to 6 months, significantly more Z than FF infants were exclusively breastfed (p < 0.05), and weaning foods were introduced at a significantly later age in Z t

Immune responses of chickens to dietary protein antigens: I. Induction of systemic and intestinal immune responses following oral administration of soluble proteins in the absence of adjuvant

Oral administration of protein antigens in solution leads to the development of oral tolerance in most mammals but rarely so in the chicken. As dietary proteins are not expected to be immunogenic, the present study was undertaken to evaluate immunological consequences following oral exposure to protein antigens in chicks, and to determine whether or not this form of antigen is ignored. Chicks and turkey poults were fed solutions containing bovine serum albumin (BSA), porcine serum albumin, β-lactoglobulin or bovine hemoglobin over a period of 6 days (25 mg/chick/day). At different time points after feeding serum and bile were examined for presence of specific antibodies by ELISA. Surprisingly, the fed antigens induced robust antibody responses in the absence of added adjuvant. This immune response was further characterised to show that (1) a daily feeding regimen was more immunogenic than single dose feedings, (2) by using a daily feeding regimen, as little as 2 mg/chick/day was fully immunogenic, (3) effective immunization was attained in chicks older than 10 day of age, (4) the main antibody class in the serum was IgG, and (5) high IgA levels were detected in the bile after booster feedings. These observations are difficult to reconcile with current concepts on peripheral tolerance to innocuous antigens, and indicate that the bird regulates tolerance and response in a manner different from that described in mammals.

Defective tumor necrosis factor-alpha production in infants with cow's milk allergy.

As an aid to clarifying the role of immune mechanisms in the development of cow's milk allergy (CMA) in suckling infants, we studied the capacity of peripheral blood mononuclear cells (PBMC) to produce tumor necrosis factor-alpha(TNF-alpha) in vitro. The study population consisted of 43 infants, aged 0.12-11.2 months; of these, 31 had challenge-proven cow's milk allergy manifested with either skin or gastrointestinal symptoms or both. In addition, 12 healthy infants were studied as controls. The spontaneous, unstimulated and mitogen-induced production of TNF-alpha and interferon-gamma (IFN-gamma) by isolated peripheral blood leukocytes was evaluated. TNF-alpha and IFN-gamma production of PBMC was significantly lower in infants with cow's milk allergy than in healthy children. Our results indicate that, in infants with CMA, the function of TNF-alpha-producing cells is defective. This might disturb the development of oral tolerance and thereby lead to cow's milk allergy. These results may help to clarify the etiopathology of CMA.

Study of the possible mechanisms involved in the mucosal immune system activation by lactic acid bacteria.

The induction of a mucosal immune response is not easy due to the development of oral tolerance, but under some conditions, bacteria can activate this immune system. Antigens administered orally can interact with M cells of Peyer's patches or bind to the epithelial cells. We have demonstrated that certain lactic acid bacteria are able to induce specific secretory immunity, and others will enhance the gut inflammatory immune response. The aim of this work was to establish the reason for these different behaviors and to define possible mechanisms involved in the interaction of lactic acid bacteria at the intestinal level. We studied IgA+ and IgM+ B cells comparatively in bronchus and intestine and CD4+ T cells and IgA anti-lactic acid bacteria antibodies in the intestinal fluid, induced by oral administration of Lactobacillus casei, Lb. delbrueckii ssp. bulgaricus, Lb. acidophilus, Lb. plantarum, Lb. rhamnosus, Lactococcus lactis, and Streptococcus salivarius ssp. thermophilus. The increase in the IgA+ B cells in the bronchus means that these lactic acid bacteria were able to induce the IgA cycle by interaction with M cells from Peyer's patches or intestinal epithelial cells. The IgM+ cells increased when the stimulus did not induce the switch from IgM+ to IgA+. The increase in the CD4+ cells suggests interaction of Peyer's patches and enhancement of the B- and T-cell migration. The anti-lactic acid bacteria antibody is related to the processing and presentation of the microorganisms to the immune cells. We demonstrated that Lb. casei and Lb. plantarum were able to interact with Peyer's patch cells and showed an increase in IgA-, CD4+ cells, and antibodies specific for the stimulating strain. Lactobacillus acidophilus induced gut mucosal activation by interaction with the epithelial cells without increase in the immune cells associated with the bronchus. Although Lb. rhamnosus and Strep. salivarius ssp. thermophilus interact with epithelial cells, they also induced an immune response against their epitopes. Lactococcus lactis and Lb. delbrueckii ssp. bulgaricus induced an increase of IgA+ cells entering the IgA cycle but not CD4+ cells; thus, these bacteria would have been bound to epithelial cells that activated B lymphocytes without processing and presenting of their epitopes. We did not determine specific antibodies against Lc. lactis or Lb. bulgaricus.

IL-4 and IL-10 Are Both Required for the Induction of Oral Tolerance

Protection from the development of experimental autoimmune uveitis (EAU) can be induced by feeding mice interphotoreceptor retinoid binding protein before uveitogenic challenge with the same protein. Two different regimens are equally effective in inducing protective tolerance, although they seem to do so through different mechanisms: one involving regulatory cytokines (IL-4, IL-10, and TGF-beta), and the other with minimal involvement of cytokines. Here we studied the importance of IL-4 and IL-10 for the development of oral tolerance using mice genetically engineered to lack either one or both of these cytokines. In these animals we were able to protect against EAU only through the regimen inducing cytokine-independent tolerance. When these animals were fed a regimen that in the wild-type animal is thought to predominantly induce regulatory cells and is associated with cytokine secretion, they were not protected from EAU. Interestingly, both regimens were associated with reduced IL-2 production and proliferation in response to interphotoreceptor retinoid binding protein. These findings indicate that both IL-4 and IL-10 are required for induction of protective oral tolerance dependent on regulatory cytokines, and that one cytokine cannot substitute for the other in this process. These data also underscore the fact that oral tolerance, manifested as suppression of proliferation and IL-2 production, is not synonymous with protection from disease.

Murine model of oral tolerance. Induction of Fas-mediated apoptosis by blockade of interleukin-12.

We explored the immunological mechanisms underlying the development of oral tolerance with the use of ovalbumin (OVA) T-cell receptor (TCR)-transgenic mice. Feeding high doses of OVA induced tolerance in the peripheral lymphoid tissues, and the degree of peripheral tolerance was enhanced when antigen feeding was combined with systemic administration of antibodies to interleukin-12 (anti-IL-12). Using the TUNEL technique by which apoptotic cells can be specifically identified, we found evidence that peripheral clonal deletion occurs in OVA-TCR transgenic mice in vivo after oral antigen delivery and treatment with anti-IL-12, but only to a minor degree after antigen feeding alone. The mechanism that accounts for the dramatic loss of peripheral cells is Fas-mediated, since > 90% of antigen-specific Fas+ T cells were lost. In addition, antagonizing Fas but not TNF reversed the phenomenon when cells were stimulated in vitro. These findings suggest that IL-12 negatively regulates apoptosis, a major mechanism of peripheral tolerance. A combination of oral antigen feeding and administration of anti-IL-12 may thus be useful in the treatment of autoimmune diseases and may be a potent means to modulate peripheral tolerance.

Review article: Local and systemic regulation of mucosal immunity.

An increased interest in mucosal immunity has stemmed from the identification of novel T-cell populations and developments in oral vaccines and oral tolerance. The development of physiological inflammation is antigen driven. Upon recognition of antigen, the lamina propria (LP) is populated with lymphocytes and activated peripheral cells acquire the capacity to home to the gut. Antigen entry to the gut is via follicle-associated epithelium or M cells. The antigen now interacts with macrophages or CD4+ cells, and go on to the Peyer's patch where B cells undergo a transforming growth factor beta (TGF-beta)-mediated isotope switch to immunoglobulin (Ig) A. TGF-beta may also play a role in the development of oral tolerance. The intestinal epithelium is seen as the site for the activation of CD8+ suppressor cells. Controlled inflammation is therefore explained by the interaction of LP lymphocytes and intra-epithelial cells (IEC). IECs are capable of extending processes that express regulatory surface molecules coupled with antigen processed from luminal uptake. CD8+ T-cell activation is favoured over CD4+ T-cell activation due to the size of the antigenic binding peptide. The result is suppressed inflammation. Other antigen-presenting cells (APCs) and dendritic cells may also contribute to local immunosuppression.

High dose oral tolerance in ovalbumin TCR-transgenic mice: systemic neutralization of IL-12 augments TGF-beta secretion and T cell apoptosis.

The immune response to oral Ag administration, including the development of oral tolerance, was explored with the use of OVA TCR-transgenic mice. Feeding high doses of OVA enhanced IFN-gamma production in the Peyer's patches, but induced tolerance in the peripheral lymphoid tissues marked by suppressed proliferative and cytokine responses. Systemic administration of Abs to IL-12 (anti-IL-12) simultaneous with Ag feeding modestly enhanced the degree of tolerance in the peripheral lymphoid tissues, as shown by increased suppression of proliferative responses after in vitro restimulation, and secondary responses in the popliteal lymph nodes following in vivo challenge and in vitro restimulation. Systemic anti-IL-12 treatment was associated with augmented TGF-beta production and T cell apoptosis in both Peyer's patches and peripheral lymphoid tissues. Cell mixing studies and proliferation assays in the presence of anti-TGF-beta provided evidence that the increased suppression of responses induced by anti-IL-12 was due primarily to the secretion of TGF-beta. These findings suggest that IL-12 negatively regulates two of the main mechanisms of oral tolerance, TGF-beta production and clonal deletion via apoptosis. in addition, they suggest that the combination of oral Ag feeding and systemic anti-IL-12 administration may be of benefit in the treatment of autoimmune diseases.

Differences in epitopes recognized by T cells during oral tolerance and priming.

Feeding protein antigens to mice normally leads to the development of oral tolerance but under some circumstances, feeding can lead to immunity, for example, following pretreatment of mice with cyclophosphamide (CY). In both cases, however, it is possible to detect sensitized T cells in the spleen and mesenteric lymph nodes (MLN) by in vitro lymphokine release for granulocyte-macrophage-CSF (GM-CSF) and IFN-gamma. This study examines the recognition of the immunodominant T cell epitope on ovalbumin (OVA) following intragastric priming and tolerance. T cells from CY/OVA treated mice and cells from mice injected subcutaneously with OVA in CFA responded well to both OVA and the H2d restricted peptide epitope pOVA323-339 releasing GM-CSF. On the other hand MLN or spleen T cells from tolerized mice which responded to the protein in vitro did not recognize the immunodominant determinant. The cells responding from tolerized mice were restricted by the class II MHC so these results show there can be differential recognition of T cell epitopes between oral priming and tolerance.

Analysis of responsive cells in tolerance by the oral administration of ovalbumin.

The induction of immune tolerance is the most common consequence of protein feeding, i.e., "oral tolerance". In this study we investigated the genetic basis of oral tolerance using various kinds of recombinant and congenic mice, and the cells involved in the development of this phenomenon in mice. The footpad swelling response to ovalbumin (OVA) was inhibited in mice that were orally fed OVA 7 days before sensitization. No effect of strain of mouse was seen in this inhibition. This inhibition could be transferred by Peyer's patch cells. The CD4-8+ T cells were responsible for the inhibition of footpad swelling. The number of CD4+ cells from OVA-fed tolerant mice decreased significantly, but CD8+ cells did not. The number of CD4-8+ T cells was increased in Peyer's patches of OVA-fed tolerant mice, and were involved in the development of oral tolerance.

Management - Disease interactions in pigs 3: Nutrition - disease interactions

Both level of feeding and dietary composition have been demonstrated to influence bacterial colonisation and diarrhoea in the weaned pig (Smith &amp; Hall 1968, Bertschinger et al 1978, Lecce et al 1983). Kenworthy and Allen 1966 proposed that “the stimulus to bacterial growth derives from the hosts response mechanisms to intestinal irritation” and that the enterotoxigenic E Coli “Acts as an exacerbating agent rather than a primary pathogen” (Kenworthy et al 1967).Several workers have suggested that the primary intestinal response is villus atrophy, an elevation in crypt cell mitosis (by up to x10) and crypt cell hyperplasia, associated with malabsorption, mal-digestion and increased intra-epithelial lymphocytes. Such a response is characteristic of a T cell mediated type IV hypersensitivity (Ferguson 1980). Miller et al (1984) have therefore suggested that one of the factors which may contribute to the aetiology of postweaning diarrhoea is a transient hypersensitivity to dietary antigens prior to the development of oral tolerance.

Mucosal immune response to poliovirus vaccines in childhood.

Comparative evaluation of the systemic and secretory antibody response to live attenuated (oral) poliovirus vaccine ( OPV ) or inactivated poliovirus vaccine (IPV) has suggested that both vaccines are highly effective in inducing seroconversion and in preventing paralytic poliomyelitis. However, parenteral immunization with IPV does not appear to be highly effective in inducing secretory antibody response in the nasopharynx or alimentary tract during primary immunization. Reimmunization with IPV in subjects previously primed with parenterally administered IPV appears to result in a mild booster effect on the development of secretory antibody response. More significantly, rechallenge by the oral route with OPV in IPV-primed subjects resulted in a marked enhancement of secretory antibody response. In general, no suppression of systemic or secretory response to poliovirus was observed with either form ( OPV vs. IPV) or with route of immunization. These observations are discussed in relation to the immune response observed with other mucosally or parenterally administered antigens. Their implications in the development of oral tolerance are briefly reviewed.

Serum and salivary antibody responses and the development of oral tolerance after oral and intragastric antigen administration.

Repeated administration of human serum albumin to female Wistar rats via stomach tube or dropwise into the oral cavity resulted in simultaneous induction of serum and salivary antibody together with a state of specific systemic hyporesponsiveness. The induction of the hyporesponsive state was found to be related to the level and class of serum antibody elicited by ingested antigen. Rats dosed intragastrically produced low levels of serum antibody, predominantly of the IgM class; some of the rats dosed orally responded similarly, and both groups were hyporesponsive on subsequent parenteral immunisation with human serum albumin. However, other rats dosed orally produced IgG serum antibody and were not hyporesponsive, except when assayed for cross-reacting antibodies to bovine serum albumin. The kinetics of the immune response after parenteral challenge was similar in experimental and control rats over the 5-week test period.