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Adaptive Immunity

Adaptive Immunity: Adaptive immunity describes immune responses that involve T and/or B cells, and target very specific proteins. Adaptive responses are slow to develop, but are highly potent, like a bloodhound catching the scent of a fugitive, and not giving up until he or she is found. A role for adaptive immunity in vitiligo is well-established. First, vitiligo associates with other autoimmune diseases in which adaptive immunity seems to play a role, like type 1 diabetes, autoimmune thyroiditis, alopecia areata, and pernicious anemia. Second, T cells, and in particular CD8+ “cytotoxic” T cells, infiltrate the epidermis and are found next to dying melanocytes in vitiligo. Third, melanocyte-specific CD8+ T cells are found at a higher frequency in the blood and skin of patients with vitiligo compared to healthy controls, and are capable of killing melanocytes directly. One group found that CD8+ T cells isolated from affected skin from vitiligo patients crawled into unaffected skin from that patient and killed melanocytes. Finally, genetic studies have found a number of genes that affect the risk of getting vitiligo, and a large number of these genes play major roles in adaptive immunity. These observations strongly implicate the adaptive immune system in vitiligo. 

Our own studies have focused on identifying cytokine pathways involved in promoting vitiligo, and how these pathways affect the migration of CD8+ T cells and their ability to target melanocytes for destruction. Using a mouse model of vitiligo that we developed, we found that the cytokine IFN-g is important for vitiligo to develop.

Cytokine IFN-g in Vitiligo Development Cytokine IFN-g in Vitiligo Development

In addition, we found that many of the other genes that are active in vitiligo skin are turned on by IFN-g. This suggests that IFN-g is an essential “master switch” that is turned on in the skin in vitiligo. Therefore, we hypothesized that turning off the IFN-g master switch would reverse the disease process and provide new treatments for vitiligo. However, consistent with the theme of IFN-g as a master switch, IFN-g in turn activates many additional switches that serve different purposes. One important purpose is control of infection, and mice and humans can die from certain infections if IFN-g is missing. We hypothesize that turning off the smaller switches downstream of IFN-g that are specifically responsible for vitiligo, while leaving on other switches important for infection control, is a better and safer strategy to develop new treatments.

We discovered that the IFN-g-induced chemokine CXCL10 is highly expressed in vitiligo patient skin and blood, and its receptor CXCR3 is found on melanocyte-specific CD8+ T cells, which cause vitiligo. Our mouse model revealed a similar pattern of expression, and in this model we found that we could both prevent and reverse vitiligo by treating the mice with an antibody that blocks CXCL10 signaling.  

Function of CXCL10 in Vitiligo Function of CXCL10 in Vitiligo

As a consequence of these discoveries, clinical trials are showing that JAK inhibitors, which block IFNg signaling and CXCL10 production, are effective treatments for vitiligo! You can read more about this here:

However, in most cases when treatments for vitiligo are stopped the disease relapses, meaning that the white spots reappear at the same location they were prior to treatment. Thus, we hypothesized that autoimmune memory forms within the skin when the spots appear, so that the spots “know” where to return when treatments are stopped.

We and three other laboratories searched for autoimmune cells that might be the source of this remaining disease memory in the skin. We looked in the skin of vitiligo patients as well as the skin of mice that get vitiligo, and discovered that “resident memory T cells”, or Trm, form within affected skin immediately when the white spots appear and remain at that location for a long period of time afterward. Similar cells form in the skin after a viral infection and are responsible for protecting the skin from reinfection in case the virus comes back again. We then hypothesized that if these cells could be removed from the skin, the disease would get better and this improvement would be long-lasting, since the autoimmune memory would be removed with them. 

Next, we looked for an “Achilles’ heel” of these cells that we could target therapeutically. We determined that the vitiligo-causing Trm cells required a cytokine protein called IL-15 for their survival and found that blocking the signaling of this cytokine in with an antibody treatment removed the Trm cells from the mouse skin and resulted in significant improvement. Importantly, even short-term treatment of the mice resulted in long-term, or durable, improvement, suggesting that this treatment strategy, unlike existing treatments, might provide lasting benefit for vitiligo patients. It also seemed to target only the autoreactive cells, not the normal ones, because the autoreactive cells were more dependent on IL-15 than the others. Studies in human vitiligo patients seemed to support this as well, suggesting that this therapy might be safer for the immune system than first thought.

While at this point the drug has only been proven to work in mice with vitiligo, we are excited to test it in humans because it would represent a significant advance over existing treatments. In fact, Dr. Harris founded a company to bring this new treatment into humans, it’s called Villaris Therapeutics. Stay tuned for updates about progress on this and other projects by subscribing to our newsletter!

We continue to explore this pathway to develop new and improved treatments for vitiligo.