Sundarasetty Balasai, Volk Valery, Theobald Sebastian J, Rittinghausen Susanne, Schaudien Dirk, Neuhaus Vanessa, Figueiredo Constanca, Schneider Andreas, Gerasch Laura, Mucci Adele, Moritz Thomas, von Kaisenberg Constantin, Spineli Loukia M, Sewald Katherina, Braun Armin, Weigt Henning, Ganser Arnold, Stripecke Renata
Regenerative Biology to Reconstructive Therapies (REBIRTH), Laboratory of Regenerative Immune Therapies Applied, Hannover Medical School, Hannover, Germany; Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
Department of Pathology, Fraunhofer Institute for Toxicology and Experimental Medicine Hannover, Hannover, Germany.
Am J Pathol. 2017 Jun;187(6):1380-1398. doi: 10.1016/j.ajpath.2017.02.015. Epub 2017 Apr 20.
Humanized mice engrafted with human hematopoietic stem cells and developing functional human T-cell adaptive responses are in critical demand to test human-specific therapeutics. We previously showed that humanized mice immunized with long-lived induced-dendritic cells loaded with the pp65 viral antigen (iDCpp65) exhibited a faster development and maturation of T cells. Herein, we evaluated these effects in a long-term (36 weeks) nonclinical model using two stem cell donors to assess efficacy and safety. Relative to baseline, iDCpp65 immunization boosted the output of effector memory CD4 T cells in peripheral blood and lymph nodes. No weight loss, human malignancies, or systemic graft-versus-host (GVH) disease were observed. However, for one reconstitution cohort, some mice immunized with iDCpp65 showed GVH-like signs on the skin. Histopathology analyses of the inflamed skin revealed intrafollicular and perifollicular human CD4 cells near F4/80 mouse macrophages around hair follicles. In spleen, CD4 cells formed large clusters surrounded by mouse macrophages. In plasma, high levels of human T helper 2-type inflammatory cytokines were detectable, which activated in vitro the STAT5 pathway of murine macrophages. Despite this inflammatory pattern, human CD8 T cells from mice with GVH reacted against the pp65 antigen in vitro. These results uncover a dynamic cross-species interaction between human memory T cells and mouse macrophages in the skin and lymphatic tissues of humanized mice.
为了测试针对人类的疗法，迫切需要用人造血干细胞移植并产生功能性人类T细胞适应性反应的人源化小鼠。我们之前表明，用负载pp65病毒抗原的长寿诱导树突状细胞（iDCpp65）免疫的人源化小鼠表现出T细胞更快的发育和成熟。在此，我们在一个长期（36周）的非临床模型中使用两名干细胞供体评估了这些效应，以评估疗效和安全性。相对于基线，iDCpp65免疫增强了外周血和淋巴结中效应记忆CD4 T细胞的输出。未观察到体重减轻、人类恶性肿瘤或全身性移植物抗宿主（GVH）病。然而，对于一个重建队列，一些用iDCpp65免疫的小鼠在皮肤上出现了GVH样体征。对发炎皮肤的组织病理学分析显示，在毛囊周围的F4/80小鼠巨噬细胞附近有滤泡内和滤泡周围的人类CD4细胞。在脾脏中，CD4细胞形成了被小鼠巨噬细胞包围的大簇。在血浆中，可检测到高水平的人类辅助性T细胞2型炎性细胞因子，其在体外激活了小鼠巨噬细胞的STAT5途径。尽管有这种炎症模式，但来自患有GVH的小鼠的人类CD8 T细胞在体外对pp65抗原产生了反应。这些结果揭示了人源化小鼠皮肤和淋巴组织中人类记忆T细胞与小鼠巨噬细胞之间动态的跨物种相互作用。
