Hair can fall out for many different reasons, but for the millions of people worldwide grappling with alopecia areata, the cause is an overactive immune system (1). Current therapies for this autoimmune condition include topical or injected corticosteroids and a systemic immunosuppressive drug, but these are often ineffective or have undesirable side effects, leaving many patients eager for safer and more reliable treatment options.
Now, a team of researchers led by Harvard Medical School immunologist Jamil Azzi developed a microneedle patch system that can deliver a treatment directly onto affected skin in animal models to regulate the immune response (2). This research presents a potential new treatment option for alopecia areata and other conditions that may require targeted immunomodulation.
“Whenever you want to give an immunosuppressant to [the skin],” Azzi said, “you really need to give systemic therapies because the stratum corneum will inhibit any penetration of your topical biologics or small molecules. So, with that in mind, I have always been thinking, how can we deliver therapy to the deep tissue where the immune system is activated?”
As hairs grow, a specific region of the hair follicle exists in an immune-privileged state. Regulatory T cells (Tregs) help maintain that state by acting as a natural "brake" on the immune system, preventing overactive immune responses that can lead to tissue damage. In alopecia areata, hair follicle immune privilege is lost. Tregs are often absent or impaired in areas of the skin with alopecia, and autoreactive T cells mistakenly target hair follicles, triggering localized hair loss in patches.
Azzi and his team wondered if they could treat alopecia areata by bringing the Tregs back into homeostasis at the hair follicle. To do this, they fabricated a hydrogel-based patch that uses tiny needles to painlessly pierce the stratum corneum, the outermost layer of the skin, where they could deliver therapeutic drugs precisely to the site of hair loss.
They decided to deliver two different molecules: interleukin-2 (IL-2) and C-C motif chemokine ligand 22 (CCL22). IL-2 promotes Treg growth and function, and CCL22 acts as a chemoattractant, specifically recruiting Tregs to the site of hair loss. With this targeted approach, Azzi and his team aimed to bolster the Treg population and suppress the activity of T cells attacking hair follicles.
The researchers tested the effectiveness of the microneedle patch in a mouse model of alopecia areata. They applied the patch every other day for three weeks. Mice treated with the patch exhibited significant hair regrowth at the application sites compared to control groups. Further analysis revealed an increase in Tregs at these locations, quantified through flow cytometry, alongside a decrease in inflammatory markers. Notably, the treatment did not affect Treg levels in other organs, such as the spleen and lymph nodes, suggesting its localized effect.
“What surprised us most was the durability of the therapy,” said Azzi. “We stopped therapy at three weeks, and long term, we still see protection.”
The researchers then grafted healthy human skin onto mice with a humanized immune system to gauge the patch’s effectiveness in a system closer to a human immune environment. The treatment with the microneedle patch induced Treg proliferation.
What surprised us most was the durability of the therapy. … We stopped therapy at three weeks, and long term, we still see protection.
- Jamil Azzi, Harvard Medical School
The microneedle patch has an additional component that allows for monitoring treatment progress. After drug delivery, the hyaluronic acid in the patch swells, absorbing a small amount of interstitial fluid (ISF) from the surrounding skin tissue. This ISF contains immune cells and biomarkers that researchers can analyze to assess Treg levels and inflammation markers using flow cytometry and gene expression analysis. This feature could aid future clinical trials and personalized treatment plans for patients with alopecia areata.
“The mechanism of action is very compelling, that it actually interferes directly with the immune system that otherwise has the capability of destroying your hair follicles,” said Mark Poznansky, an immunologist at Massachusetts General Hospital who was not involved in the study. “Now, this needs to be accelerated into first-in-human safety and efficacy studies as soon as possible to see whether this likely very safe, self-deploying type of treatment actually does what it needs to do.”
Azzi’s team is enthusiastic about the potential of this technology and is actively working on refining the microneedle patch design further. They are in the process of launching a startup to bring this work to the clinic in a Phase 1 safety trial. Additionally, the researchers envision adapting this approach to treat other autoimmune skin diseases where similar immune system imbalances contribute to the pathology.
“We are very passionate about it, and we believe that the potential will be enormous for patients,” Azzi said.
References
- Mostaghimi, A. et al. Trends in Prevalence and Incidence of Alopecia Areata, Alopecia Totalis, and Alopecia Universalis Among Adults and Children in a US Employer-Sponsored Insured Population.JAMA Dermatol 159, 411–418 (2023).
- Younis, N. et al. Microneedle-Mediated Delivery of Immunomodulators Restores Immune Privilege in Hair Follicles and Reverses Immune-Mediated Alopecia.Adv Mater 4, (2024)
