Immunophysiology of Keratinocyte Cytokines

Brigham And Women'S Hospital, Boston MA

Investigators

Linked publications & trials

Abstract

This competing renewal application seeks to extend a paradigm that places[unreadable] the epidermal keratinocyte in a central role Th the recruitment and[unreadable] maintenance of T cell infiltration into skin. During the first funding[unreadable] cycle. the principal investigator identified a series of novel cytokines[unreadable] produced by keratinocytes and attempted to integrate them into coherent[unreadable] models of cutaneous inflammation. Such models have been fundamentally[unreadable] intestable in vivo, however, until very recently. In this application, an[unreadable] approach will be used involving transgenic mice constructed so as to[unreadable] express different cytokines and adhesion molecules in epidermis. In this[unreadable] fashion, hypotheses that epidermal cytokines and adhesion molecules are[unreadable] involved in certain types of inflammation can be tested experimentally with[unreadable] scientific rigor.[unreadable] The present proposal will focus on interactions between T cells and[unreadable] keratinocytes, and has evolved to incorporate not only cytokines produced[unreadable] by keratinocytes that influence T cells, but also keratinocyte adhesion[unreadable] molecules that bind to T cell surface molecules and can costimulate T[unreadable] cells. Using a keratin 14 (basal keratinocyte) promoter, we have made[unreadable] transgenic mice that constitutively express ICAM-1, B7, and lL-7 in[unreadable] epidermis; the first two molecules are important in T cell costimulation,[unreadable] and the third is a potent T cell growth factor. Each of these molecules has[unreadable] been reported to be expressed under certain conditions by keratinocytes in[unreadable] vitro and in vivo.[unreadable] Three aims are proposed. In the first, the role of B7 and ICAM- 1[unreadable] expression on keratinocytes in the capacity of keratinocytes to activate T[unreadable] cells in vivo and in vitro will be studied. In the second, the ability of[unreadable] constitutive epidermal production of IL- 7, coupled with secondary stimuli,[unreadable] to recruit and sustain a T cell infiltrate will be studied. In the third,[unreadable] the capacity of these transgenes expressed by experimentally induced[unreadable] keratinocytederived neoplasms to elicit a T cell mediated anti-tumor[unreadable] response will be evaluated. These questions, which can only be answered in[unreadable] our transgenic system, will provide important insights into the[unreadable] relationship between keratinocytes, T cells, and skin disease.[unreadable]