Alopecia areata (AA) is an autoimmune disease characterized by hair loss, which occurs when T cells of the immune system mistakenly attack hair follicles. To restore control over hyperactive immune cells, investigators from Brigham and Women's Hospital, a founding member of the Mass General Brigham healthcare system, and MIT developed a cutting-edge approach to deliver T cell regulators directly to sites of hair loss and halt autoimmune activity. Findings, published in Advanced Materials, demonstrated marked and lasting increases in hair regrowth in models of the disease.
Our immune system evolved to safeguard against the overactivation that occurs when it mistakenly attacks our own tissues, as seen in autoimmune conditions. In conditions like AA, the specialized cells known as Regulatory T cells (Tregs) fall short in protecting hair follicles. Current immunosuppressants used in AA target both T cells and Tregs, failing to address the core issue and increasing the risk of disease recurrence once treatment stops. Moreover, systemic immune therapy suppresses the entire immune system, leaving patients vulnerable to infections and malignancies.
The approach tested in this study marks a departure from current therapeutic strategies, which typically utilize immunosuppressants to suppress the immune system. Rather than globally suppressing the immune system, the researchers aimed to locally restore well-controlled immune activity directly at sites of hair loss by increasing levels of Tregs, whose numbers are reduced in AA. This targeted approach was achieved with a microneedle patch, which delivers drugs across the tough outer layer of skin more effectively than topical creams and avoids stimulation of pain receptors, which are located deeper within the skin.
"Our strategy tackles two major challenges in treating autoimmune skin diseases," said co-corresponding author Natalie Artzi, PhD, of the Brigham's Engineering in Medicine Division in the Department of Medicine. "Our patches enable local delivery of biologics, which, instead of suppressing the immune system, promote regulatory T cells in the skin. This restores immune balance and resolves the T cell attack on hair follicles, offering a potential long-term solution without compromising the immune system's ability to defend against infections and malignancies."
"When it comes to autoimmune-mediated skin diseases, where we have direct access to the skin, we must surpass the use of systemic immunosuppressants that shut down the entire immune system," said co-corresponding author Jamil Azzi, MD, PhD, an immunologist in the Brigham's Renal Division in the Department of Medicine. "While topical therapy often fails to penetrate the skin's outer layer, our patches improve the local delivery of biologics to the deeper layers of diseased skin and reprogram the immune system to generate tolerance at the site of antigen encounter."
The researchers, including co-first authors Nour Younis, MD, and Núria Puigmal, PhD, both of Brigham's Department of Medicine, observed with RNA sequencing that in AA tissues, there were changes in the STAT-5/Interleukin-2 (IL-2) signaling pathway. IL-2, which promotes Treg proliferation, and CCL22, which the researchers had previously shown attracts and expands the presence of Tregs in a specific area, were therefore loaded into the microneedle patch. The patches were applied to murine models of AA 10 times over a course of three weeks, with more than eight weeks of observation. Hair regrowth was observed as early as three weeks after the initiation of treatment. The researchers also tested microneedle patches loaded with baricitinib, a drug approved for severe AA, but found that Treg recruitment was inferior to that associated with the IL-2/CCL22 patch.
The microneedle patch was also found to have good shelf-life stability, improving prospects of its clinical translation. While the therapy is not ready for clinical use, the researchers are pursuing further development and testing. Additionally, they are exploring the possibility of applying their approach to other immune-mediated skin diseases, such as vitiligo and psoriasis.
"Microneedles offer a promising avenue for targeted and localized delivery of therapeutics to the skin," said Artzi. "Their ability to precisely administer drugs directly to the affected area of the skin enables more effective modulation of the immune response while minimizing systemic side effects. This targeted approach holds great potential for improving treatment outcomes and reducing the burden of autoimmune and immune-mediated diseases on patients' lives."
Authorship: In addition to Azzi, Artzi, Younis and Puigmal, co-authors from BWH include Andrew Badaoui, Dongliang Zhang, Claudia Morales, Anis Saad, Diane Cruz, Nadim Al Rahy, Andrea Daccache, Triana Huerta, Christa Deban, Ahmad Halawi, John Choi, Pere Dosta, and Christine Lian. Additional authors include Abdallah El Kurdi.
Disclosures: None
Funding: The Department of Medicine at Brigham and Women's Hospital supported this work through the Ignite Fund Award and the Shark Tank Fund Award.
Paper cited: Younis, N et al. "Microneedle-mediated Delivery of Immunomodulators Restores Immune Privilege in Hair Follicles and Reverses Immune-Mediated Alopecia" Advanced Materials DOI: 10.1002/adma.202312088
