人源化免疫缺陷小鼠是研究移植的人类细胞与预重建的人类免疫系统之间功能相互作用的关键模型。这些模型有助于分子和细胞致病机制的研究，并能够评估免疫疗法的功效和毒性，从而加速其临床前和临床开发。目前的策略依赖于 CD34 造血祖细胞的低效、长期/延迟造血重建或外周血单核细胞 (PB-MNC) 的短期重建，与移植物抗宿主病 (GvHD) 的高发生率和低效的代表性相关免疫细胞群。在这里，我们假设免疫学上幼稚的脐带血单核细胞（CB-MNC）可以作为一种更好的替代品，提供持久且功能有效的免疫重建。我们对非肥胖糖尿病（NOD）进行了全面比较。Cg-Prkdc∧ˆscid-IL2rg∧ˆtm1Wjl/SzJ (NSG) 和 NSG-Tg(CMV-IL3,CSF2,KITLG)∧ˆ1Eav/MloySzJ (NSGS) 免疫缺陷者PB-MNC 或 CB-MNC 人源化后的小鼠模型。我们评估了各种人类免疫细胞随时间的植入动态，并监测了两种模型中 GvHD 的发展。对于最有前途的模型，我们使用肉瘤和白血病异种移植物在体外和体内广泛评估了免疫细胞功能。用 CB-MNC 人性化 NSGS 小鼠可以快速、稳健和持续地表达多种功能性人类淋巴和骨髓细胞群，同时最大限度地减少 GvHD 发生率。在该模型中，人类免疫细胞群显着损害肉瘤和 B 细胞急性淋巴细胞白血病细胞的生长和植入，免疫细胞水平与肿瘤生长之间存在显着的负相关。这项研究为癌症免疫治疗的各种应用建立了一个快速、高效、可靠的体内平台，特别是在临床开发之前探索体内癌细胞、免疫细胞和肿瘤微环境之间的复杂相互作用。©作者（或其雇主）2024。根据 CC BY-NC 允许重复使用。禁止商业再利用。请参阅权利和权限。英国医学杂志出版。

Humanized immunodeficient mice serve as critical models for investigating the functional interplay between transplanted human cells and a pre-reconstituted human immune system. These models facilitate the study of molecular and cellular pathogenic mechanisms and enable the evaluation of the efficacy and toxicity of immunotherapies, thereby accelerating their preclinical and clinical development. Current strategies rely on inefficient, long-term/delayed hematopoietic reconstitution by CD34+ hematopoietic progenitors or short-term reconstitution with peripheral blood mononuclear cells (PB-MNCs) associated with high rates of graft-versus-host disease (GvHD) and an inefficient representation of immune cell populations. Here, we hypothesized that immunologically naïve cord blood mononuclear cells (CB-MNCs) could serve as a superior alternative, providing long-lasting and functionally effective immune reconstitution. We conducted a comprehensive comparison between the non-obese diabetic (NOD).Cg-Prkdc∧ˆscid-IL2rg∧ˆtm1Wjl/SzJ (NSG) and NSG-Tg(CMV-IL3,CSF2,KITLG)∧ˆ1Eav/MloySzJ (NSGS) immunodeficient mouse models following humanization with either PB-MNCs or CB-MNCs. We assessed the engraftment dynamics of various human immune cells over time and monitored the development of GvHD in both models. For the most promising model, we extensively evaluated immune cell functionality in vitro and in vivo using sarcoma and leukemia xenografts. Humanizing NSGS mice with CB-MNCs results in a rapid, robust, and sustained representation of a diverse range of functional human lymphoid and myeloid cell populations while minimizing GvHD incidence. In this model, human immune cell populations significantly impair the growth and engraftment of sarcoma and B-cell acute lymphoblastic leukemia cells, with a significant inverse correlation between immune cell levels and tumor growth. This study establishes a fast, efficient, and reliable in vivo platform for various applications in cancer immunotherapy, particularly for exploring the complex interactions between cancer cells, immune cells, and the tumor microenvironment in vivo, prior to clinical development.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.