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Investigating contributions of both melanocytes and immune cells to vitiligo

John HarrisThe goal of my laboratory is to better understand what causes vitiligo in order to develop new treatments.

Vitiligo is an autoimmune disease that results in the appearance of white spots on the skin. It affects 0.5-2% of the population (about 1/100 people) regardless of race and gender, and can be psychologically devastating for patients due to its disfiguring appearance. The white spots are due to the destruction of melanocytes by T cells. As a physician-scientist, I treat patients with vitiligo and also manage a laboratory that is focused on studying the disease.

In the lab, we focus on two aspects of vitiligo:

VIT HandsFirst, we study how abnormal, “stressed” melanocytes alert the immune system to their presence. We believe that, once stressed, melanocytes produce signals that recruit T cells to the skin, which then find the melanocytes and kill them.

Second, we study how the T cells detect these signals, enter the skin, find the melanocytes, and kill them.

We use four major systems to answer these questions:

First, we use a mouse model of vitiligo that we developed, where the mice get spots of vitiligo on their ears, tails, feet and noses. Examining these mice from many angles, their disease looks very much like human vitiligo. The benefit of this system is the powerful tools available to study diseases in mice.
Second, we are developing humanized mouse models of vitiligo, where we transfer human T cells, or both T cells and skin, from vitiligo patients to immunosuppressed mice that permit the growth of human tissues. The benefit of this system is the ability to study human T cells and skin, and it has the potential to test new treatments on human tissues before attempting clinical trials.
Third, since I manage a specialty clinic in vitiligo, I regularly collect skin and blood from willing donors to study these processes directly. The benefit of this approach is that we can study the key cells that participate in vitiligo directly from patients, without variables that may change them, including their transfer into mice.
Fourth, we are conducting a clinical trial to test an investigational new drug as a treatment for vitiligo.

Using these systems, we have identified one of the critical pathways used by T cells to crawl into the skin and find melanocytes. The first signal in the pathway is IFN-g, a protein made by immune cells, which acts as a powerful master switch to turn on immune responses. IFN-g then turns on CXCL10, which is required for the ability of T cells to find melanocytes and kill them. Imagine an ant that has found a new piece of food on the ground. The ant then lays a chemical trail that others follow to the food. CXCL10 acts like that chemical trail, promoting both proper localization of T cells to “find” the melanocytes, and also increases their determination to kill them. There are existing drugs that have been developed by pharmaceutical companies that block the ability of CXCL10 to function in humans, and so they may be effective treatments in vitiligo. (See PDF of this article: Click Here)

We have also begun to identify the signals produced by stressed melanocytes that activate immune cells. We believe that studying the communication between stressed melanocytes and immune cells will tell us how vitiligo gets started in the first place, and how to better prevent its onset and spread. Also part of this project is better understanding how chemicals in the environment cause stress in melanocytes. Certain chemicals are well known to cause vitiligo and make it worse, and it is likely that there are many more that we come into contact with every day (in chemical dyes, cleaning products, etc). While we can guess at which chemicals do this based on their chemical structure, we are using our systems to definitively identify the chemicals, so that patients can avoid them and companies can change the ingredients of their products.
 

 


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