The pathogenesis of asthma results from interactions between the innate (Project 1) and adaptive (Project 3) immune systems. A subset of immune cells, regulatory CD4+ T cells, play an important role in suppression of both innate and adaptive responses. Although there are indications that regulatory T cells participate in asthma, much remains to be learned before therapeutic interventions can be entertained. The goal of the first part of this Project is to better define the role of complement regulator (CD46) activated human T cells, which appear to represent a unique adaptive regulatory T cell subset.
In Aim 1, we will determine if complement activation plays an important role in asthma, as well as providing a physiologic in vivo stimulus for these adaptive regulatory T cells. We will ask if genetic deficiency in various complement components (beginning with C3) modulates the Sendai virus-induced acute infection and the chronic asthma phenotype in mice (as described in Project 1). We will also determine whether markers of altered complement activation occur in situ in human patients with asthma.
In Aim 2, we will look for the presence of T cells with the CD46 adaptive regulatory T cell phenotype in human patients with asthma. We will also determine if human CD46 adaptive regulatory T cells inhibit the function of pathogenic cells in asthma (Th2 cells and B cells). If so, this would argue for further studies into the use of these adaptive regulatory cells for the treatment of asthma. In the second part of this Project, we will complement the above studies on adaptive regulatory T cells and define the role of natural regulatory T cells in a mouse model of asthma. By moving to this model, we can utilize a newly described marker Foxp3-GFP for natural regulatory T cells to facilitate studies of natural regulatory T cell specificity. In summary, our goal is to further address the role of the complement system in asthma and whether adaptive or natural regulatory T cells participate in controlling the severity of asthma. Both avenues represent attractive therapeutic targets for the treatment of asthma. Asthma is a growing problem in the United States, but current therapies are expensive, chronic, and, unfortunately not curative. By exploring the body's innate immune system and natural regulatory mechanisms that inhibit excessive pathology, our hope is that curative therapies can eventually be generated not requiring global immunosuppression.
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