Approaching Alopecia Areata therapy by combined anergy induction and myeloid-derived suppressor cell exosomes

• Applicant: Professorin Dr. Margot Zöller
• Subject Area: Dermatology ; Immunology
• Term: from 2007 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 44090193

Alopecia areata (AA) is an autoimmune disease of the skin destroying anagen stage hair fol¬licles. We succeeded in a mouse AA model to define two hair- and nail-specific keratins, K31 and K71, as autoantigens that induce AA when presented by dendritic cells, but in a tolerogenic form K31 and K71 peptides prevented AA onset and progression, though not sufficing to revert a persisting AA. In addition, we elaborated that the therapeutic efficacy of chronic contact eczema relies on induction and activation of myeloid-derived suppressor cells (MDSC) that mostly act by promoting pro-apoptotic molecule expression and thereby interfere with activated T cell apoptosis resistance. Based on these findings we suggest optimizing AA therapy by combining antigen-specific tolerance induction, which should hamper AA-specific T cell activation, with MDSC-induced apoptosis of activated AA effector cells, where we will explore the possibility to use MDSC exosomes rather than cells. Exosomes are small vesicles of endocytic origin that carry and transfer function-competent proteins, mRNA and miRNA into target cells and would provide a storable therapeutics circumventing persisting contact allergen induction. The efficacy of exosomes in replacing their donor cells is well explored for dendritic cell exosomes, which suffice to induce T cell activation. Instead, MDSC exosomes did not receive much attention. Preliminary studies indicating their suppressive activity, we will control these findings, identify the targets of MDSC exosomes and elaborate the molecular mechanisms of MDSC exosome activities. Efficient immunosuppression by MDSC exosomes offers their use as therapeutics also in other organ-related autoimmune diseases as well as chronic infections and allograft rejection, where induction of MDSC is clinically favorable. For AA a combined therapy with AA autoantigen-specific tolerance induction and elimination of activated autoreactive T cells by MDSC exosomes should allow for a long lasting curative treatment.

• DFG Programme: Research Grants