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The Effects of Aging in Oral Tolerance


(30 lines): This is a revised application. Oral tolerance is an important immunological phenomenon that refers to the suppression of immune responses to an antigen that has been previously administered by the oral route. It is believed to have evolved as a mechanism to avoid hypersensitivity reactions to food antigens. The mechanisms involved in oral tolerance induction have been described as active suppression by regulatory T cells, anergy and deletion. Some factors, such as age, are able to affect and modulate oral tolerance induction. Neonates are less susceptible and aging impairs the susceptibility to oral tolerance induction. Our groups have described that aging impairs oral tolerance induction but continuous feeding of the antigen is able to overcome this impairment. Moreover, aging affects oral tolerance induction but not its maintenance in mice. Other groups have shown that aging affects Peyer's patches function but the relationship between this and oral tolerance induction is still elusive. In this project our aim is to address the role of aging in oral tolerance induction using BALB/c mice at 4 different ages (6-8 weeks, 28-32 weeks, 53 weeks and 100 weeks). Oral tolerance will be induced either by single feeding or by continuous feeding and an experimental model of food allergy will also be used to test tolerance induction. We will address the following questions:1) How the immunological changes brought about by aging interfere with oral tolerance;2) How oral tolerance induced in young animals is maintained throughout their lives;3) Why continuous feeding is able to induce oral tolerance in aged animals. Our working hypothesis is that oral tolerance is impaired in aged animals due to a defect in de novo generation of regulatory T cells (Tregs) in the gut. We will test this hypothesis by flow cytometry analysis of Tregs (Th3, Tr1, CD4+CD25+ Foxp3+ and LAP+ T cells) and by the measurement of regulatory cytokines in the gut of young and aged mice. The ability of antigen presenting cells from aged versus young mice to induce Tregs in vitro will also be tested. This application has been revised in order to clarify the aims and to focus our analysis on the role of aging in the generation of Tregs. With the increasing number of elderly worldwide, studies on the impact of aging in natural immunological processes such as tolerance to dietary protein will help care for this population. (3 sentences): The decline in oral tolerance induction to food proteins during aging raises concern about possible allergic reactions in the older individuals upon oral exposure to novel dietary proteins. With the increasing number of elderly worldwide, studies on the impact of aging in these immune processes will help care for this population.


Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.