Targeting T-Cell–Based Therapies to Treat Alopecia Areata

Alopecia surrounded by medication | Image Credit: greenapple78 - stock.adobe.com

A research review described the role of T cells and T-cell signaling pathways in pathogeneses of AA, focusing on the medications in development that hold promise for future treatments.

The only approved systemic medication for severe AA is Janus kinase (JAK) ½ inhibitor baricitinib (2022) and the selective JAK3/tyrosine kinase expressed in hepatocellular carcinoma (TEC) inhibitor ritlecitinib (2023). Researchers reviewed publications through March 2023 on the unknown etiopathogenesis of T cells in AA using evidence suggesting immune system dysfunction and T cell attacks on hair follicles (HFs).

The review explores immune privileged sites, where mechanisms shield HFs from immune cells, potentially preventing autoimmune attacks. Several methods assumed responsibility for immune privilege, including physical barriers to lymphocyte infiltration, downregulation of major histocompatibility complex I, localized expression of immunosuppressants, and more. The loss of immune privilege in HFs leads to immune attacks by T cells, mediated by antigen-presenting cells.

Alopecia areata involves increased levels of interferon (IFN)-γ and interleukin (IL)-15, which contribute to inflammation through a JAK/signal transducers and activators of transcription (STAT) pathway. Other cytokines like IL-4, IL-9, and IL-21 also play a role in immune system regulation.

Patients with AA have higher prevalence of IL-4, IL-5, IL-6, chemokine ligand 17, and immunoglobulin E with elevated levels of eosinophilia in their serum and blood. Dupilumab is an IL-4/13 blocker acting as an atopic dermatitis and AA treatment. Elevated reports of AA lesions included levels of Th17-related cytokines like IL-17 and IL-22.

Key proteins in this process are lymphocyte-specific protein tyrosine kinase, zeta chain-associated protein kinase, and the linker for activation of T cells. General concepts of T cell receptor signal strength, including affinity, avidity, and functional avidity, contribute to the pathophysiology of AA and could be potential targets for therapeutic development.

The 2 oral medications targeting T cells to treat AA are baricitinib (JAK1/2 inhibitor) and ritlecitinib (selective JAK3/TEC kinase inhibitor), both approved in the US and Europe.

Several new JAK inhibitors are being studied for the treatment of AA. These drugs work by blocking the JAK-STAT pathway, which is involved in the immune system's response. Baricitinib and ruxolitinib are already approved for other conditions and are being investigated for AA. Jaktinib, ivarmacitinib (SHR0302), and KL130008 are other JAK inhibitors in development.

Ritlecitinib, a dual inhibitor drug targeting specific enzymes involved in the immune system, reduces the production of inflammatory chemicals, and promotes the growth of beneficial immune cells. This drug appears to work in ways beyond what was originally understood, affecting various parts of the immune system, and potentially promoting hair regrowth.

Cytokine inhibitor, EQ101 (formerly BNZ-1), is a selective inhibitor of IL-2, IL-9, and IL-15 targeting common g-chain signaling receptor subunits shared by cytokines. A proinflammatory or immunosuppressive cytokine associated with allergic diseases commonly co-occurring with AA is known as IL-9.

Drugs that target S1P receptors have been successful in treating autoimmune diseases like multiple sclerosis. Etrasimod, a drug that modulates S1P receptors, is being investigated as a treatment for AA. It is thought to work by preventing immune cells from migrating to HFs.

In the early stages of AA, a protein called immunoglobulin-like transcript 7 is a type of immune cell known as plasmacytoid dendritic cell that might influence the immune response by reducing the production of a molecule called IFN-α. This could be linked to how the immune system recognizes and responds to threats.

New treatments for AA target different immune pathways. These treatments aim to overcome limitations of current therapies, such as drug resistance. Three promising approaches include targeting harmful immune cells, promoting immune tolerance, and modifying the gut microbiome.

As the disease progresses, the specific T-cells involved change, so new drugs need to target pathways beyond JAK/STAT. Studying patient responses to different treatments could help identify phenotypes or endotypes of AA and develop more targeted therapies improving efficacy, safety, and patient tolerability of AA treatments.

Reference

Passeron T, King B, Seneschal J, et al. Inhibition of T-cell activity in alopecia areata: recent developments and new directions. Front Immunol. 2023;14:1243556. doi:10.3389/fimmu.2023.1243556