Miao Ling, Klapproth Henning, Stepkes Michael R, Wegner Joanna, von Stebut Esther
Department of Dermatology, Faculty of Medicine, University of Cologne, Cologne, Germany.
Department of Dermatology, Johannes Gutenberg University, Mainz, Germany.
Exp Dermatol. 2025 Jul;34(7):e70131. doi: 10.1111/exd.70131.
Treatment against leishmaniasis is associated with severe side effects, high costs, and parasitic resistance. Preclinical models such as humanised mice would aid therapeutic improvement or the development of a vaccine. We developed a model in which human skin transplants on immunodeficient mice are infected with Leishmania major. Parasite inoculation of the skin transplant led to a robust infection with increasing numbers of parasites in the skin and visceral organs. In addition, intraperitoneally co-administered allogeneic peripheral blood mononuclear cells (PBMCs) were strongly recruited to skin lesions, with ≥ 65% of the cells being positive for anti-human CD45; we identified ~20% CD4 and ~50% CD8 human T cells. The number of skin-resident macrophages or dendritic cells was unaltered compared to healthy skin prior to transplantation, and PBMC administration did not alter their numbers. Together, we show that parasitic infection provides a strong inflammatory signal that leads to recruitment of T cells into skin transplants. The presence of antigen-presenting cells in the transplants-as an important prerequisite for proper APC-T-cell interaction-recreates a fully human skin microenvironment that allows for stroma/immune cell interactions upon infection. This model may be of high interest to researchers interested in translating skin research questions into the human system in vivo.
利什曼病的治疗存在严重副作用、成本高昂以及寄生虫耐药性等问题。诸如人源化小鼠之类的临床前模型将有助于治疗方法的改进或疫苗的研发。我们构建了一个模型，在免疫缺陷小鼠上移植人皮肤，并使其感染硕大利什曼原虫。对皮肤移植部位接种寄生虫会引发强烈感染，皮肤和内脏器官中的寄生虫数量不断增加。此外，腹腔内共同注射的异体外周血单核细胞（PBMC）会大量募集到皮肤损伤部位，其中≥65%的细胞抗人CD45呈阳性；我们鉴定出约20%的CD4和约50%的CD8人T细胞。与移植前的健康皮肤相比，皮肤驻留巨噬细胞或树突状细胞的数量没有变化，注射PBMC也未改变其数量。我们共同表明，寄生虫感染会提供强烈的炎症信号，导致T细胞募集到皮肤移植部位。移植部位存在抗原呈递细胞——这是APC与T细胞正确相互作用的重要前提——可重建一个完整的人皮肤微环境，使感染时基质/免疫细胞能够相互作用。对于有兴趣将皮肤研究问题转化为体内人体系统研究的科研人员而言，该模型可能具有很高的价值。
