Long-term repeated daily use of intragastric gavage hinders induction of oral tolerance to ovalbumin in mice.

Oral tolerance is dependent on the complex architecture of the mucosal system of the gastrointestinal tract, its associated lymphoid tissue, and specialized immune cells. Changes in this architecture or the failure of any of its components may hinder the generation of oral tolerance. The larynx and esophagus are the gateway to the gastrointestinal tract, serving as the site of oral antigen introduction to the immune system and may have an important role in establishing tolerance. Intragastric gavage is a common method for precise oral dosing of rodents, particularly in studies examining oral tolerance. However, complications such as esophageal trauma can occur and induce complicating factors that affect experimental outcomes. In this study, we examined the esophageal epithelium for alterations resulting from long-term repeated daily use of intragrastric gavage and its effect on the induction of tolerance. Tolerance to ovalbumin could not be achieved after using intragastric gavage for 14 d or more consecutively to introduce ovalbumin. However, tolerance was achieved when intragastric gavage was used for shorter durations. After 14 d of gavage, disruption of the esophageal mucosal epithelium indicative of an inflammatory pathology, cellular influx into the esophageal tissue, and proinflammatory cytokines in the tissue were absent, and the CD3(+) cell population in the esophageal epithelium decreased. These findings provide initial evidence for the important roles of esophageal integrity and cellular populations in the induction of oral tolerance and suggest possible immunologic sequelae in experiments involving the use of extended, repeated gavage.

Short term statin treatment improves survival and differentially regulates macrophage-mediated responses to Staphylococcus aureus.

Staphylococcus aureus is the most prevalent etiologic agent of sepsis. Statins, primarily prescribed for their cholesterol-lowering capabilities, may be beneficial for treating sepsis due to their anti-inflammatory properties. This study examined the effect of low dose, short term simvastatin pretreatment in conjunction with antibiotic treatment on host survival and demonstrated that pretreatment with simvastatin increased survival of C57BL/6 mice in response to S. aureus infection. In vitro studies revealed that short term simvastatin pretreatment did not reduce S. aureus-stimulated expression of surface proteins necessary for macrophage presentation of antigen to T cells, such as MHC Class II and costimulatory molecules CD80 and CD86, but did reduce both basal and S. aureus-stimulated levels of C5aR. Additionally, this work demonstrated the ability of simvastatin to dampen macrophage responses initiated not only by bacteria directly but by membrane vesicles shed in response to infection, revealing a new mechanism of immune modulation by statins. These data demonstrate the ability of short term simvastatin pretreatment to modulate immune responses and identify new insights into the underlying mechanisms of the anti-inflammatory properties of simvastatin that may decrease the pathophysiological effects leading to sepsis.

Erythromycin treatment hinders the induction of oral tolerance to fed ovalbumin.

The mucosal immune system is constantly exposed to antigen, whether it be food antigen, commensal bacteria, or harmful antigen. It is essential that the mucosal immune system can distinguish between harmful and non-harmful antigens, and initiate an active immune response to clear the harmful antigens, while initiating a suppressive immune response (tolerance) to non-harmful antigens. Oral tolerance is an immunologic hyporesponsiveness to an orally administered antigen and is important in preventing unnecessary gastrointestinal tract inflammation, which can result in a number of autoimmune and hypersensitivity diseases. Probiotics (beneficial intestinal bacteria), T regulatory cells, and dendritic cells (DCs) are all essential for generating tolerance. Antibiotics are commonly prescribed to fight infections and often necessary for maintaining health, but they can disrupt the normal intestinal probiotic populations. There is increasing epidemiologic evidence that suggests that antibiotic usage correlates with the development of atopic or irritable bowel disorders, which often result due to a breakdown in immune tolerance. This study investigated the effect of the antibiotic erythromycin on oral tolerance induction to ovalbumin. The results demonstrated that antibiotic treatment prior to exposure to fed antigen prevents tolerance to that antigen, which may be associated with a reduction in intestinal Lactobacillus populations. Furthermore, antibiotic treatment resulted in a significant decrease in the tolerogenic CD11c(+)/CD11b(+)/CD8α(-) mesenteric lymph node DCs independent of tolerizing treatment. These results provide evidence that antibiotic treatment, potentially through its effects on tolerogenic DCs and intestinal microflora, may contribute to autoimmune and atopic disorders via a breakdown in tolerance and support prior epidemiologic studies correlating increased antibiotic usage with the development of these disorders.