The immune system reacts to the allergens that cause asthma, such as ragweed pollen, by producing antibodies against them. However, only about 25 percent of people produce the IgE that can lead to asthma, with the rest managing to suppress or avoid this allergic response through a process known as tolerance. Tolerance is based upon the fact that the immune system has evolved several mechanisms to maintain a state of non-responsiveness to innocuous antigens. In particular, clonal deletion, anergy, and active suppression, mediated by regulatory cells secreting transforming growth factor B and Interleukin 10 have been implicated in the down-regulation of immune responses. However, the immunological events and cellular mechanisms involved in inducing the T cell hyporesponsiveness to allergens in local and systemic allergic diseases are poorly defined. We have recently begun using a panel of double-cytokine knockout mice to help delineate the role of IL-10 in allergic diseases. This panel includes mice deficient in both IL-10 and IL-4, IL-10 and IFN-gamma, and IL-10 and IL-12 as well as their single cytokine knockout controls. We have used these animals in our models of allergic eye disease and allergic asthma, and have found a role for IL-10 in the suppression of both Th1 and Th2 responses. In particular, Il-10 appears to be essential for the regulation of eosinophils in the allergic response. We have also found a dichotomy between the role of IL-10 in controlling inflammation and increasing airway hyperresponsiveness to allergen challenge. We have also developed a mouse model that uses Ascaris suum infection to amplify allergic responses and the eventual induction of tolerance through the development of both Ascaris-specific and allergen-specific T regulatory cells. Finally, we have begun studies using Ascaris antigen alone instead of Ascaris infection to determine if the same T regulatory cells can be developed without infection
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