Inducing antigen specific B cell tolerance

描述（由申请人提供）：本项目将研究我们最近发现的潜力，即通过给药抗原偶联到sigleg配体修饰的纳米颗粒，可以在动物体内诱导抗原特异性B细胞耐受[Duong et al. (2010) J. Exp. Med. 184,4183]。这种应用的动机源于认识到许多自身免疫性疾病和过敏分别是由B细胞对自身和非自身抗原的反应引起的。如果能诱导对致病抗原产生耐受性，可能会取得显著的治疗效果。我们的目标是开发一个模块化平台，sigle配体耐受脂质体（STL），用于各种医学相关抗原的简单结合，并证明它可以用于诱导体内抗原特异性B细胞耐受。初步数据显示，STL同时显示CD22的聚糖配体和抗原，可诱导小鼠对随后的抗原攻击产生强大的抗原特异性耐受。CD22是免疫球蛋白（Ig）受体siglec家族的B细胞特异性成员，可识别含有聚糖的唾液酸作为自配体，并作为辅助受体参与细胞信号传导的调节。迄今为止的证据表明，STL可诱导耐受性，导致CD22与B细胞受体（BCR）连接，产生凋亡信号并选择性地消耗识别抗原的B细胞，从而增强CD22维持外周B细胞耐受性的自然功能。该项目的主要目标是1)优化模块化STL平台，用于展示抗原和siglec配体以诱导耐受性，2)评估CD22和siglec - g（另一种主要的B细胞siglec）特异性配体诱导耐受性的相对能力，3)评估STL对抗原特异性记忆B细胞的耐受性能力，4)证明STL在诱导对多种医学上重要抗原的耐受性方面的实用性。减少EAE和过敏性哮喘模型中抗原反应性B细胞介导的病理变化。如果成功，STL平台可以为B细胞消耗疗法提供一种替代疗法，用于治疗自身免疫性其他抗原介导的疾病，代表了一种“手术”打击，通过消融抗原特异性B细胞，同时保留其余的B细胞群和免疫记忆完整。

DESCRIPTION (provided by applicant): This project will investigate the potential of our recent discovery that antigen specific B cell tolerance can be induced in an animal by administering an antigen coupled to siglec ligand decorated nanoparticles [Duong et al. (2010) J. Exp. Med. 184, 4183]. The motivation for this application stems from the recognition that many autoimmune diseases and allergies result from a B cell response to self and non-self antigens, respectively. If tolerance can be induced to the offending antigen, significant therapeutic benefit might be achieved. Our goal is to develop a modular platform, siglec ligand toleragenic liposomes (STL), for facile conjugation of various medically relevant antigens, and demonstrate that it can be used to induce robust antigen specific B cell tolerance in vivo. Preliminary data show that administration to mice of STL simultaneously displaying a glycan ligand of CD22 and an antigen, induces robust antigen specific tolerance to subsequent challenge with antigen only. CD22 is a B cell specific member of the siglec family of immunoglobulin (Ig) receptors that recognize sialic acid containing glycans as self-ligands and participates as a co-receptor in regulation of cell signaling. Evidence to date suggests that tolerance is induced by STL, resulting in ligation of CD22 to the B cell receptor (BCR), producing an apoptotic signal and selective depletion of the B cells that recognize the antigen, amplifying a natural function of CD22 for maintenance of peripheral B cell tolerance. The major objectives of the project are 1) to optimize the modular STL platform for display of antigen and siglec ligands for inducing tolerance, 2) to assess the relative ability of specific ligands of CD22 and Siglec-G, the other major B cell siglec, to induce tolerance, 3) to assess the ability of STL to tolerize antigen speciic memory B cells, and 4) to demonstrate the utility of STL for inducing tolerance to a panel of diverse medically important antigens, and reduce the pathology mediated by antigen reactive B cells in models of EAE and allergic asthma. If successful, the STL platform could provide an alternative for B cell depletion therapies for treatment of autoimmune other antigen mediated diseases, representing a 'surgical' strike by ablating antigen specific B cells while leaving the rest of the B cell population and immunological memory intact.