The USA, UK and Europe have recently approved the JAK inhibitor baricitinib/Olumiant® to treat severe cases of adult alopecia areata (AA). However, despite these good news, JAK inhibitors are still in an early stage of clinical investigation and until now many other countries do not allow their use outside of clinical trials. Currently their long-term safety needs to be further investigated, and it needs to be better understood why stopping therapy leads to relapse of alopecia in some cases.
Based on the authors’ pioneering work and long-standing experience in studying immune privilege (IP) collapse of the scalp hair follicle (HF), a key underlying mechanism in the pathogenesis of AA, they hypothesized that these shortcomings may partly be explained by the inability of JAK inhibitors to restore the IP status of HFs. This led the authors to search for novel, adjuvant strategies for AA management.
In this short communication, published in the Journal of the European Academy of Dermatology and Venereology, by our CEO Ralf Paus and his scientific team in Miami, the authors used isolated HF outer root sheath keratinocytes in vitro as a first, rapid and cost-effective screening approach to search for IP collapse preventing and/or restoring drugs (find out more about 2D/3D in vitro cell models)
The authors first tried to understand which pathways, distinct from JAK/STAT signaling, could be targeted in AA by focusing on the cellular interactions that might drive the HF IP collapse in AA. In this regard, the presence of Vd1+T cells, an immune cell type that secretes IFNγ, has recently been demonstrated in non-lesional and lesional AA scalp skin. Interestingly, Vd1+T cells express a surface receptor named NKG2D, which recognizes and binds MICA - a “danger signal”- expressed on stressed HFs. This NKG2D-MICA interaction leads to an immune attack against HFs, reminiscent of AA.
The authors hypothesized that interfering with the interaction between NKG2D and MICA could reduce the HF IP collapse that drives AA. MICA is cut by the enzymes ADAM10 and ADAM17, and once cut, it cannot bind to NKG2D anymore. Thus, the authors decided to seek drugs which would enhance ADAM10/17 expression and activity, leading to less overall NKG2D activation and subsequently reduced IP collapse. In this context statins are of interest, since they are safe, already widely used for the management of cardiovascular diseases, and have been shown to increase levels of ADAM10 and ADAM17.
In this study, the co-culture assay between human Vd1+ T cells and HF keratinocytes, which is established also in Monasterium Laboratory, was used to examine the effect of statins on HF keratinocyte function. Either HF IP collapse or stress were mimicked by exposing the HF keratinocytes to IFNγ or hydrogen peroxide, respectively. Interestingly, both treatments enhanced MICA expression on the HF keratinocytes, and their co-culture with human Vd1+ T cells induced immune cell activation and IFNy release. Next, the authors demonstrated that application of the statin, lovastatin to HF keratinocytes indeed up-regulated the expression of both ADAM10 and ADAM17 and, accordingly, reduced the expression of MICA.
This encouraging pilot study strongly suggests that revisiting statins as a potential adjuvant therapy in the management of AA is warranted and will be the subject for future work in the authors’ lab.
Read more about it here: Downregulation of pathogenic MICA-NKG2D interactions as a novel strategy in alopecia areata management: a new rationale for adjunct statin therapy? - PubMed (nih.gov)