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Generation of Potent Mouse Monoclonal Antibodies to Self-Proteins Using T-Cell Epitope 'Tags'

机译：使用T细胞表位“标签”产生效率小鼠单克隆抗体对自我蛋白质“标签”

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Immunisation of mice or rats with a "non-self” protein is a commonly used method to obtain monoclonal antibodies, and relies on the immune system's ability to recognise the immunogen as foreign. Immunisation of an antigen with 100% identity to the endogenous protein, however, will not elicit a robust immune response. To develop antibodies to mouse proteins, we focussed on the potential for breaking such immune tolerance by genetically fusing two independent T cell epitope-containing sequences (from tetanus toxin (TT) and diphtheria toxin fragment A (DTA)) to a mouse protein, mouse ST2 (mST2). Wild-type CD1 mice were immunised with three mST2 tagged proteins (Fc, TT and DTA) and the specific serum response was determined. Only in mice immunised with the T-cell epitope-containing antigens were specific mST2 serum responses detected, hybridomas generated from these mice secreted highly sequence-diverse IgGs that were capable of binding mST2 and inhibiting the interaction of mST2 with its' ligand, mouse IL-33 (mIL-33). Of the hundreds of antibodies profiled we identified five potent antibodies that were able to inhibit IL-33 induced IL-6 release in a mast cell assay, notably one such antibody was sufficiently potent to suppress IL-5 release and eosinophilia infiltration in an Alternaria alternata challenge mouse model of asthma. This study has demonstrated, for the first time, that T-cell epitope-containing tags have the ability to break tolerance in wild-type mice to 100% conserved proteins and provide a compelling argument for the broader usage of this approach to generate antibodies against any mouse protein or conserved orthologue.
机译：小鼠或大鼠与“非自身”蛋白的免疫接种是一种常用的方法，以获得单克隆抗体，并依赖于免疫系统的免疫原，与100％的同一性的抗原的外国。免疫识别内源蛋白质的能力，但是，将不能引起强烈的免疫应答。为了开发抗体小鼠蛋白质，我们集中于潜能通过遗传融合两个独立含有T细胞表位的序列（来自破伤风毒素（TT）和白喉毒素片段A打破这种免疫耐受（DTA））给小鼠蛋白，小鼠ST2（MST2）。野生型CD1小鼠进行免疫具有三个MST2标记的蛋白（FC，TT和DTA）和特定的血清反应进行了测定。只有在小鼠免疫与T-细胞含有表位的抗原是特异性的血清MST2响应检测到的，来自这些小鼠的分泌即能够结合MST2和抑制与它的MST2的相互作用高度序列多样化的IgG产生杂交瘤配体，小鼠IL-33（MIL-33）。数百抗体的异型我们确定了能够抑制在肥大细胞测定中的IL-33诱导的IL-6释放5点有效的抗体，特别是一种这样的抗体是充分有效的，以抑制在链格孢IL-5释放和嗜酸性粒细胞浸润哮喘的挑战小鼠模型。这项研究表明，在第一次，即T细胞含有表位的标签具有在野生型小鼠中，以破坏耐受性为100％保守的蛋白和用于这种方法产生针对抗体的更广泛的使用提供了令人信服的理由的能力任何小鼠蛋白或保守直向同源物。

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