The long-term goals of this project are to understand immune regulation of asthma, a serious public health problem that has doubled in prevalence in industrialized countries over the last two decades. We have examined different cell types that are involved in the pathogenesis of and in the protection against asthma, and we now propose to study the role of subsets of NK T cells in these processes. Our focus on NK T cells in asthma is based on striking and novel preliminary data demonstrating that mice deficient in NK T cells do not develop allergen-induced airway hyperresponsiveness (AHR), a cardinal feature of asthma. Thus, neither CD1d knockout nor Ja281 knockout mice sensitized and challenged with ovalbumin, develop AHR. Since NK T cells produce large quantities of cytokines on activation, NK T cells are thought to have a profound influence on the development of immune responses, and therefore we hypothesize that NK T cells in the lungs play a major role in regulating the development of asthma. We will examine the mechanisms by which NK T cells enhance the development of AHR by further examination of Ja281 knockout mice. We will use a model in which BALB/c Jaa281 knockout mice are reconstituted with NK T cells from histocompatible wild type mice or from mice deficient in IL-4, IL-13, IL-10 or costimulatory molecules, isolated with CD1d tetramers and NK T cell specific monoclonal antibodies. These studies will determine the specific cytokines and molecules that NK T cells require for inducing the development of AHR and asthma. In addition, we will determine if subsets of NK T cells, activated to enhance cytolytic activity and IFN-gamma but not IL-4 production, will protect against, rather than enhance, the development of AHR. Finally, we will determine whether NK T cells play a significant role in regulating the development of human asthma by examining the number, distribution and cytokine profiles of NK T cells in the blood and lungs of asthmatic patients and matched control subjects. These studies will ascertain the precise role of NK T cells in the development of asthma, and greatly enhance our understanding of pathogenic and protective mechanisms in asthma.
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