Our Approach
Treating atopic dermatitis/eczema depends on a better understanding of the roots of the disease. LJI Professor Michael Croft, Ph.D., is investigating how proteins related to tumor necrosis factor (TNF) and others called costimulatory molecules can contribute to atopic dermatitis. Costimulatory molecules act on individual T cells, and research indicates they play a role in causing T cells to attack tissues, and T cells can make TNF-related proteins that act on tissue cells to cause inflammation.
Dr. Croft discovered many activities of OX40, a costimulatory molecule that promotes division and cytokine production in T cells. This research has led to ongoing phase II clinical trials for atopic dermatitis with a neutralizing and depleting antibody to OX40 that blocks T cell activity.
LJI Professor Toshiaki Kawakami, M.D., PhD., has developed animal models of atopic dermatitis to study how immune cell signaling can make flare ups better or worse. His follow-up studies of human skin tissues, have confirmed that these mouse models mimic the allergic immune response seen in humans. One of Dr. Kawakami’s critical discoveries was that a protein that controls gene expression, called STAT5, drives up the number of immune cells called mast cells in the skin of some atopic dermatitis sufferers. His lab has also reported that a different signaling factor called phospholipase C-beta3 (PLC-β3) blocks STAT5. These discoveries suggest that atopic dermatitis severity could be modulated either by muffling STAT5 or boosting PLC-β3 activity. Dr. Kawakami went on to establish mouse models for eczema vaccinatum and eczema herpeticum, serious skin infections that are caused by vaccinia and herpes simplex viruses, respectively, in patients with eczema.
In collaborations with Dr. Kawakami, Dr. Croft’s lab also published research showing that LIGHT, another member of TNF family of proteins, directly controls the hyperproliferation of skin cells called keratinocytes as well as the expression of inflammatory proteins made by keratinocytes that contribute to the clinical features of atopic dermatitis. The researchers found that a therapeutic antibody that neutralizes LIGHT activity successfully suppresses disease symptoms, suggesting that therapies based on blocking LIGHT may additionally help patients suffering from atopic dermatitis.
Dr. Croft has also reported that another protein called TWEAK, which is again related to TNF, plays a role in the process to recruit immune cells into the skin. This work suggests TWEAK could be a further potential therapeutic target for the treatment of inflammatory skin diseases such as atopic dermatitis and even psoriasis.
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