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 an active regulatory process known as tolerance. In order to uncover the mechanism(s) involved in the induction of tolerance we have developed models whereby the immune response to allergens is hyperactivated. These systems involve the use of helminth infection and the use of animals such as inhibitory receptor or cytokine deficient animals. By using these systems, we have discovered that regulatory cells secreting Interleukin 10 are important in the down-regulation of the allergic response 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 used a panel of double-cytokine knockout mice to help delineate the role of IL-10 in allergic diseases. This panel includes mice deficient in 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. These studies have recently been expanded to use Ascaris antigen alone in lieu of Ascaris infection to determine if the same T regulatory cells can be developed without detrimental physiologic aspects associated with infection. Finally studies examining a recently described cytokine thymic stromal lymphopoietin found this cytokine is a key intiator of allergic diseases through promotion of Th2 cell differentiation and recruitment. Blockade of TSLP either through recombinant antibodies or the use of TSLP KO mice lead to protection from the development of asthma
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