Human complement receptor type 2 (CR2/CD21) transgenic mice provide an in vivo model to study immunoregulatory effects of receptor antagonists
Human complement receptor type 2 (CR2/CD21) transgenic mice provide an in vivo model to study immunoregulatory effects of receptor antagonists
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DOI：
10.1016/j.molimm.2010.12.019
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发表时间：
2011-03-01
影响因子：
3.6
通讯作者：
Holers, V. Michael
中科院分区：
文献类型：
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作者：
Kulik, Liudmila;Chen, Kuan;Holers, V. Michael
我们发现，稳定表达细菌人工染色体（BAC）衍生的人补体受体2型（CR 2/CD 21）基因的转基因（tg）小鼠显示B细胞特异性hCR 2蛋白表达，正常B细胞发育，B细胞亚群无变化。为了确定这种BAC编码的人CR2（hCR 2）是否可以取代Cr2（-/-）小鼠中的小鼠CR2/CR 1并恢复对模型外源抗原（Ags）的体液免疫应答，我们产生了hCR 2（+/-）Cr2（-/-）tg小鼠并用绵羊红细胞（SRBC）免疫它们。我们发现，hCR 2（+/-）Cr2（-/-）小鼠表现出抗SRBC抗体（Ab）水平，最初与Cr2-/-小鼠在单次注射Ag后相当，但在第二次免疫后，抗SRBC IgM和IgC 1水平显着增加。用第二种模型Ag，NP-Ficoll发现了相同的结果。进一步证实与Cr2（-/-）小鼠相比，Ag特异性抗体产生的改善确实是由于hCR 2表达，并检查用抑制性抗hCR 2单克隆抗体（mAb）治疗hCR 2（+/-）Cr2（-/-）小鼠的效果体内。我们使用了mAb 171，一种抗hCR 2 mAb，我们已经证明它直接识别hCR 2上的C3 d配体结合位点。我们首先发现，mAb 171完全阻断hCR 2-tg B细胞通过抗BCR/C3 d复合物的hCR 2依赖性共活化，如通过细胞内钙内流在体外测量的。然后发现腹膜内注射1 mg mAb 171至少3周仅诱导hCR 2表面表达的部分丧失，而不改变B和T细胞数量或细胞的表观活化状态。用mAb 171处理hCR 2（+/-）Cr2（-/-）小鼠也基本上抑制了用Ag免疫后抗SRBC和抗NP Ab的形成。该模型系统的开发应该允许研究用潜在的治疗化合物在体内操纵hCR 2功能的效果。(C)2011爱思唯尔有限公司保留所有权利。
We found that transgenic (tg) mice stably expressing a bacterial artificial chromosome (BAC)-derived human complement receptor type 2 (CR2/CD21) gene demonstrate B cell specific hCR2 protein expression, normal B cell development and no changes in B cell subpopulations. To determine whether this BAC-encoded human CR2 (hCR2) can replace mouse CR2/CR1 in Cr2(-/-) mice and restore humoral immune responses to model foreign antigens (Ags), we generated hCR2(+/-)Cr2(-/-) tg mice and immunized them with sheep red blood cells (SRBC). We found that hCR2(+/-)Cr2(-/-) mice demonstrated anti-SRBC antibody (Ab) levels that were initially comparable to Cr2-/- mice after a single injection of the Ag, but then showed marked increases in anti-SRBC IgM and IgC1 levels after a second immunization. Identical results were found with a second model Ag, NP-Ficoll. To further confirm that this improvement in Ag-specific Ab production over Cr2(-/-) mice was indeed due to hCR2 expression, as well as to examine the effects of treating hCR2(+/-)Cr2(-/-) mice with an inhibitory anti-hCR2 monoclonal Ab (mAb) in vivo. we used mAb 171, an anti-hCR2 mAb that we have shown directly recognizes the C3d ligand binding site on hCR2. We first found that mAb 171 completely blocked hCR2-dependent co-activation of hCR2-tg B cells by anti-BCR/C3d complexes as measured in vitro by intracellular calcium influx. The i.p. injection of 1 mg of mAb 171 was then found to induce for at least three weeks only partial loss of hCR2 surface expression, without modifying B and T cell numbers or the apparent activation status of the cells. Treatment of hCR2(+/-)Cr2(-/-) mice with mAb 171 also substantially suppressed the development of anti-SRBC and anti-NP Abs following immunization with Ags. The development of this model system should allow the study of the effects of manipulating hCR2 function in vivo with potential therapeutic compounds. (C) 2011 Elsevier Ltd. All rights reserved.