LIMITED B-CELL REPERTOIRE IN SEVERE COMBINED IMMUNODEFICIENT MICE ENGRAFTED WITH PERIPHERAL-BLOOD MONONUCLEAR-CELLS DERIVED FROM IMMUNODEFICIENT OR NORMAL HUMANS
LIMITED B-CELL REPERTOIRE IN SEVERE COMBINED IMMUNODEFICIENT MICE ENGRAFTED WITH PERIPHERAL-BLOOD MONONUCLEAR-CELLS DERIVED FROM IMMUNODEFICIENT OR NORMAL HUMANS
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DOI：
10.1172/jci115043
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发表时间：
1991-02-01
影响因子：
15.9
通讯作者：
BRAUN, J
中科院分区：
文献类型：
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作者：
SAXON, A;MACY, E;BRAUN, J
将人PBMC或胎儿组织免疫细胞移植到严重联合免疫缺陷(SCID)小鼠体内的能力产生了对这些系统的表征及其在疾病模型中的应用的需要。我们证明，用PBMC重组的SCID小鼠支持有限的一组B细胞的生长和分化。尽管血清半衰期只有12天，但人的免疫球蛋白水平通常达到1-2 mg/ml(相当于正常人血清水平的10-20%)。免疫球蛋白水平在50天左右达到峰值，免疫球蛋白的产生维持在100天。免疫球蛋白是85%的免疫球蛋白，但仍能检测到一些免疫球蛋白M、免疫球蛋白A、免疫球蛋白D，甚至是免疫球蛋白E。然而，经等电聚焦和使用kappa/lambda轻链分析，Hu-PBL-SCID小鼠产生的人免疫球蛋白是少克隆的。使用一种新的基于聚合酶链式反应的分析，能够监测单个VH家族的利用，我们发现移植的B细胞显示出扭曲和限制了人类VH亚家族的利用。在早期(21-50d)和晚期(100d)由相同供体细胞群体重组的Hu-PBL-SCID小鼠中，这些参数都有明显的变化。用B细胞终末分化阻断的常见变异型免疫缺陷患者的细胞构建的HU-PBL/CVI-SCID小鼠产生的人免疫球蛋白应答与来自正常供者的HU-PBL-SCID小鼠产生的人Ig应答在数量上相同。使用PBMC的Hu-PBL-SCID系统可能会导致少量B细胞的生长和Ig的产生，并导致B细胞库的限制。
The ability to engraft human PBMC or fetal tissue immune cells in the severe combined immunodeficient (SCID) mouse has created a need for characterization of these systems and their application to disease models. We demonstrate that SCID mice reconstituted with PBMC support the growth and differentiation of a restricted set of B cells. Human IgG levels of 1-2 mg/ml (10-20% of normal human serum levels) were routinely achieved in spite of a serum half life of only 12 d. Ig levels peaked around 50 d and Ig production was maintained for > 100 d. The Ig was > 85% IgG though some IgM, IgA, IgD, and even IgE could be detected. However, the human IgG produced in hu-PBL-SCID mice was pauci-clonal when analyzed by isoelectric focusing and by kappa/lambda light chain usage. Using a new polymerase chain reaction based analysis capable of monitoring individual VH family utilization, we found that the engrafted B cells showed skewed and restricted human VH subfamily utilization. These parameters were markedly variable among hu-PBL-SCID mice reconstituted from the same donor cell population at both early (21-50 d) and late stages (> 100 d). Hu-PBL/CVI-SCID mice constructed with cells from patients with common variable immunodeficiency with an in vitro block in terminal B cell differentiation produced human Ig responses that were quantitatively the same as those produced by hu-PBL-SCID mice from normal donors. The hu-PBL-SCID system using PBMC appears to lead to growth and Ig production by a small number of B cells and results in a restricted B cell repertoire.