The importance of activated T cells in the etiology of allergic pulmonary inflammation and airway hyperresponsiveness (AHR) has been well established. Our recent findings implicate an essential role for the nuclear transcription factor, NF-KB, specifically in T cells. In addition, our data suggest that NF-KB activation in T cells during an allergic inflammatory response regulates a Th1 component that is critical for the development of AHR in association with allergic inflammation. In this study we plan to 1. Determine whether NF-KB activation in T cells is critical for the development of allergic inflammation and AHR. 2. Determine whether NF-KB activation in T cells is critical in Th1 immunity and 3. Determine whether NF- KB activation in T cells mediates Th1 signals critical to the development of allergic inflammation and AHR.
The first aim will investigate the ability of T cells isolated from mice with normal, germ line deficient, germ line inhibited, or pharmacologically inhibited NF-KB function to adoptively transfer allergic inflammation and AHR (presumed Th2 predominant) to T and B cell deficient mice.
The second aim will assess the ability of mice with normal, germ line deficient, germ line inhibited, or pharmacologically inhibited NF-KB function to mount a delayed type hypersensitivity response (presumed Th1 predominant).
The third aim will analyze the kinetics of the allergic inflammatory response in mice with normal, germ line deficient, germ line inhibited, or pharmacologically inhibited NF-KB function. Specifically we will investigate the association between NF-KB activation, Th1 immunity, AHR, and inflammation (at the tissue, cellular, and molecular level), at critical time points during the allergic inflammatory response. The focus of this application is to examine the role for NF-KB in T cells in a presumed Th2 predominant inflammatory response (allergic inflammation) and in a presumed Th1 predominant response (DTH). Focusing on mediators implicated by comparison of the results of Aims 1 and 2, Aim 3 will determine the association of NF-KB activation in T cells with Th1 immunity, AHR, and allergic inflammation throughout an allergic inflammatory response. Current therapies for Asthma involve treating symptoms of a well-differentiated inflammatory response. A better understanding of the allergic inflammatory response and its regulation may lead to novel interventions for treatment or prevention of Asthma.
| Mikhak, Zamaneh; Fleming, Carolyn M; Medoff, Benjamin D et al. (2006) STAT1 in peripheral tissue differentially regulates homing of antigen-specific Th1 and Th2 cells. J Immunol 176:4959-67 |
