Lack of acute xenogeneic graft-versus-host disease, but retention of T-cell function following engraftment of human peripheral blood mononuclear cells in NSG mice deficient in MHC class I and II expression
Lack of acute xenogeneic graft-versus-host disease, but retention of T-cell function following engraftment of human peripheral blood mononuclear cells in NSG mice deficient in MHC class I and II expression
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DOI：
10.1096/fj.201800636r
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发表时间：
2019-03-01
期刊：
影响因子：
4.8
通讯作者：
Shultz, Leonard D.
中科院分区：
文献类型：
--
作者：
Brehm, Michael A.;Kenney, Laurie L.;Shultz, Leonard D.
移植人外周血单核细胞（PBMC）的免疫缺陷小鼠支持人类病原体、同种异体移植排斥和人类T细胞功能的临床前研究。然而，PBMC植入的主要限制是由于人T细胞识别鼠主要组织相容性复合体（MHC）而导致急性异种移植物抗宿主病（GVHD）的发展。为了解决这一问题，我们创建了2个NOD-scid IL-2受体亚基（IL 2 rg）（null）（NSG）菌株，其缺乏鼠I类和II类MHC [NSG-2-微球蛋白（B2 M）（null）（IA IE）（null）和NSG-（K-b D-b）（null）（IA（null））]。我们在NSG-B2 M（null）（IA IE）（null）小鼠中观察到快速的人IgG清除，而在NSG-（K-b D-b）（null）（IA（null））小鼠和NSG小鼠中的清除是相当的。将人PBMC注射到两种菌株中使得人CD 4（+）和CD 8（+）T细胞能够长期植入而没有急性GVHD。移植的人T细胞功能通过人胰岛同种异体移植物的排斥反应来记录。通过腺相关病毒载体将人IL-2给予NSG-（K-b D-b）（null）（IA（null））小鼠增加了人CD 45（+）细胞的植入，包括人调节性T细胞的增加。然而，高IL-2水平也诱导GVHD的发展。这些数据证明，鼠MHC缺陷的NSG小鼠支持在不存在急性GVHD的情况下的人免疫研究，并且能够评价靶向人T细胞的人抗体治疗剂。一、肯尼湖L.，怀尔斯，M。五、低，B。E、蒂施河M.，Burzenski，L.，Mueller，C.，Greiner，D. L.，舒尔茨湖D.在MHC I类和II类表达缺陷的NSG小鼠中植入人外周血单核细胞后，没有出现急性异种移植物抗宿主病，但保留了T细胞功能。
Immunodeficient mice engrafted with human peripheral blood mononuclear cells (PBMCs) support preclinical studies of human pathogens, allograft rejection, and human T-cell function. However, a major limitation of PBMC engraftment is development of acute xenogeneic graft-versus-host disease (GVHD) due to human T-cell recognition of murine major histocompatibility complex (MHC). To address this, we created 2 NOD-scid IL-2 receptor subunit (IL2rg)(null) (NSG) strains that lack murine MHC class I and II [NSG--2-microglobulin (B2M)(null) (IA IE)(null) and NSG-(K-b D-b)(null) (IA(null))]. We observed rapid human IgG clearance in NSG-B2M(null) (IA IE)(null) mice whereas clearance in NSG-(K-b D-b)(null) (IA(null)) mice and NSG mice was comparable. Injection of human PBMCs into both strains enabled long-term engraftment of human CD4(+) and CD8(+) T cells without acute GVHD. Engrafted human T-cell function was documented by rejection of human islet allografts. Administration of human IL-2 to NSG-(K-b D-b)(null) (IA(null)) mice via adeno-associated virus vector increased human CD45(+) cell engraftment, including an increase in human regulatory T cells. However, high IL-2 levels also induced the development of GVHD. These data document that NSG mice deficient in murine MHC support studies of human immunity in the absence of acute GVHD and enable evaluation of human antibody therapeutics targeting human T cells.Brehm, M. A., Kenney, L. L., Wiles, M. V., Low, B. E., Tisch, R. M., Burzenski, L., Mueller, C., Greiner, D. L., Shultz, L. D. Lack of acute xenogeneic graft-versus-host disease, but retention of T-cell function following engraftment of human peripheral blood mononuclear cells in NSG mice deficient in MHC class I and II expression.