Patients with vitiligo, a condition of skin that alters their appearance, they can get relief thanks to an unlikely cocktail of a labor-inducing molecule, an immunosuppressant drug and controlled UVB irradiation.
This discovery led by the College of Veterinary Medicine uses drugs already approved by the FDA, speeding the path of a brand new treatment for the disease, vitiligo, to clinical trials.
The results of the study were published in Nature Communications.
Vitiligo: this is how the drug works
Vitiligo occurs when the immune system destroys the skin's melanocytes, the cells that create melanin to give the skin color and protection. As a result, patients' skin presents with depigmented white patches, which can cause social stigma and reduced quality of life.
Most existing drugs treat the autoimmune aspect of vitiligo by blocking the destruction of melanocytes. However, these drugs rarely lead to complete and long-lasting pigmentation of the skin.
“We wanted to find ways to repigment the skin in a more long-lasting and comprehensive way,” said Andrew White, associate professor in the Department of Biomedical Sciences and lead author of the study. To do this, White adopted an approach based on controlled UVB irradiation.
White's idea was inspired by a 2013 scientific paper that detailed how UVB triggers the movement of melanocytes from hair follicles to the skin. However, it was not known why exactly UVB caused the migration and how to control the process.
“There was basically no protocol for what we were trying to do,” White said.
Luye An, a doctoral student in White's lab, led the study. Using mouse models to study vitiligo, the team exposed the white skin of black-coated mice to UVB rays and caused melanocytes in the mice's follicles to migrate to their skin, just like in the 2013 study.
In this case however, the experiments revealed something disconcerting: the response was different between males and females. Initially unaware of sex differences, the researchers observed sometimes high and sometimes very low melanocyte migration, depending on the randomly selected mice.
“It was frustrating and confusing initially,” White said. “The sexual dimorphism was unexpected, but when we realized it it was really exciting.”
The team found that exposure to UVB triggers an inflammatory response in vitiligo skin, which is much higher in males than in females, who show lower inflammation and poor melanocyte migration.
Analysis of gene expression between males and females revealed that males' increased vitiligo skin inflammation in response to UVB rays was due to increased production of prostaglandins, a group of molecules produced in response to injury and tissue damage. Literature research has shown that prostaglandins could stimulate melanocytes in various ways.
To confirm the effect of prostaglandin, the researchers exposed the white skin of mice to UVB rays before injecting a prostaglandin solution. They observed that, with prostaglandin, the migration of melanocytes from hair to skin was higher than with UVB alone, and became equally high in females as in males.
“This gave us the ability to control the amount of melanocytes present in the skin,” White said. “We were thinking, what molecule can we rub on our skin to make this happen?”
Using UVB exposure with prostaglandin to treat vitiligo is particularly promising because a form of prostaglandin already exists on the market as a topical gel, used to speed up labor in humans.
White has filed a provisional patent for his therapeutic strategy against vitiligo, combining existing immunosuppressive drugs recommended to treat vitiligo with controlled UVB irradiation and prostaglandin supplementation – a three-pronged approach that has shown the highest migration of melanocytes in his mouse models.
As a next step, White wants to test possible topical applications that could penetrate deeper into the skin and fine-tune the drug's specificity by understanding “who the melanocytes are talking to” in the skin, he said.
Unique cell-cell communication networks that can perpetuate inflammation and prevent repigmentation in vitiligo patients.
The study, titled “Multimodal Vitiligo Skin Analysis Identifies Tissue Characteristics of Stable Disease,” was published today in JCI Insight.
“In this study, we combine advanced imaging with transcriptomics and bioinformatics to uncover the cell-to-cell communication networks between keratinocytes, immune cells, and melanocytes that drive inflammation and prevent repigmentation caused by vitiligo,” said Anand K Ganesan, MD, Ph.D., professor of dermatology and vice president for dermatology research at the UCI School of Medicine.
“This discovery will allow us to determine why white patches continue to persist in stable vitiligo, which could lead to new therapies to treat this disease.”
Vitiligo is an autoimmune skin disease characterized by the progressive destruction of melanocytes, which are mature skin cells that produce melanin, by immune cells called autoreactive CD8+ T cells resulting in disfiguring patches of depigmented white skin.
This disease has been shown to cause significant psychological distress among patients. Destruction of melanocytes in active vitiligo is mediated by CD8+ T cells, but until now why white patches in stable disease persist was poorly understood.
“Until now, the interaction between immune cells, melanocytes and keratinocytes in situ in human skin has been difficult to study due to the lack of appropriate tools,” said Jessica Shiu, M.D., Ph.D., assistant professor of dermatology and one of the researchers. of the first authors of the study.
“By combining noninvasive imaging with multiphoton microscopy (MPM) and single-cell RNA sequencing (scRNA-seq), we identified distinct subpopulations of keratinocytes in the lesional skin of patients with stable vitiligo along with changes in cellular compositions in the skin with stable vitiligo driving persistence of the disease.
In patients who responded to punch graft treatment, these changes were reversed, highlighting their role in disease persistence.
MPM is a unique tool that has broad applications in human skin. MPM is a noninvasive imaging technique capable of providing images with submicron resolution and label-free molecular contrast that can be used to characterize keratinocyte metabolism in human skin. Keratinocytes are epidermal cells that produce keratin.
Most studies on vitiligo have focused on active disease, while stable vitiligo remains a bit of a mystery. Studies are currently underway to investigate when metabolically altered keratinocytes first appear and how they may affect the repigmentation process in patients undergoing treatment.
The results of this study raise the possibility of targeting keratinocyte metabolism in the treatment of vitiligo. Further studies are needed to improve understanding of how keratinocyte states influence the tissue microenvironment and contribute to disease pathogenesis.
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