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

斑秃是一种皮肤破坏生长期毛囊的自身免疫性疾病。我们在小鼠AA模型中成功地将两种毛发和指甲特异性角蛋白K31和K71定义为自身抗原，当树突状细胞呈现时可诱导AA，但K31和K71肽以耐受性形式阻止AA的发生和进展，尽管不足以逆转持续的AA。此外，我们还阐述了慢性接触性湿疹的治疗效果依赖于髓系来源的抑制细胞(MDSC)的诱导和激活，MDSC主要通过促进促凋亡分子的表达而发挥作用，从而干扰激活的T细胞凋亡抵抗。基于这些发现，我们建议通过结合抗原特异性耐受诱导和MDSC诱导激活的AA效应细胞的凋亡来优化AA治疗，其中我们将探索使用MDSC外切体而不是细胞的可能性。Exosome是一种内源性的小囊泡，可以携带和转移具有功能的蛋白质、mRNA和miRNA到靶细胞中，并将提供一种可储存的治疗方法，以避免持续接触性过敏原的诱导。树突状细胞外切体取代供体细胞的有效性已被广泛研究，而树突状细胞外切体足以诱导T细胞活化。相反，MDSC外切体并没有受到太多关注。初步研究表明它们的抑制活性，我们将控制这些发现，确定MDSC外体的靶点，并阐述MDSC外体活性的分子机制。MDSC外切体的有效免疫抑制使其也可用于治疗其他器官相关的自身免疫性疾病以及慢性感染和同种异体移植排斥反应，在这些领域诱导MDSC是临床上有利的。对于再生障碍性贫血，通过MDSC外切体诱导和消除激活的自身反应性T细胞，与AA自身抗原特异性耐受相结合的疗法应该可以获得长期的疗效。

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.