IL 7 signal transduction in cutaneneous disease

Brigham And Women'S Hospital, Boston MA

Investigators

Linked publications & trials

Abstract

Several important skin disorders involve cutaneous inflammation and T cell infiltration. Some of these are short-live; however others are serious chronic ailments. Increased understanding of the molecular signals controlling inflammation may lead to new rational drugs and treatments to manage these disorders. Interleukin 7 (IL-7) is one of several molecules that carry signals to cells in the immune system. These signals are critical for the coordination of cells that eliminate bacteria, viruses, parasites and tumors from the body. IL-7 has a fundamental role in the development of lymphocytes and is also particularly important for T cells within tissue such as skin. A number of observations indicate that IL-7 is an important molecule for normal skin immunity as well as some skin diseases. The release of IL-7 by keratinocytes supports the viability of T cells in the skin. This mechanism is likely to be important for inflammation in normal skin immunity as well as in several diseases including graft-versus-host disease (GVHD), cutaneous lymphoma. If IL-7 is a key molecule in inflammatory skin disease then it will may be a useful pharmacological target. First, I propose to conduct in vivo tests of two promising new drugs that are targeted at the IL-7 signaling proteins and may be useful for treating inflammatory skin diseases. One is similar to the recently approved 'magic bullet" toxin Ontak.. It specifically kills T cells that respond to IL-7. The other is a kinase inhibitor that blocks IL-7 signal transduction. These drugs will be tested in transgenic mice that develop disease as a result of inappropriate IL-7 signals. Then the drugs will be evaluated to learn whether they block normal immune responses in the skin and the pathology of GVHD. Second, I will develop a program to identify novel inhibitors of the action of IL-7. This will involve high through-put screening of chemical libraries for compounds that block the growth of an IL-7- dependent cell line. Compounds identified will be examined for specificity by assaying for toxicity against other cell lines and molecular signaling events. Ultimately, these compounds will also be tested to determine their effectiveness in vivo.