Inducing antigen specific B cell tolerance

描述(由申请人提供)：该项目将调查我们最近的发现的可能性，即通过给予与Siglec配体修饰的纳米颗粒偶联的抗原，可以在动物中诱导抗原特异性B细胞耐受[Duong等人。(2010)J.Exp.地中海医院。184,4183]。这种应用的动机源于这样一种认识，即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。如果能诱导出对致病抗原的耐受性，可能会获得显著的治疗效果。我们的目标是开发一种模块化平台，Siglec配体耐受脂质体(STL)，用于方便地连接各种医学相关抗原，并证明它可以用于在体内诱导强大的抗原特异性B细胞耐受。初步数据显示，同时显示CD22的糖链配体和抗原的STL给药小鼠，可诱导对随后仅用抗原攻击的强大的抗原特异性耐受。CD22是免疫球蛋白(Ig)受体Siglec家族中B细胞特异性的成员，它识别含有唾液酸的多糖为自身配体，并作为辅助受体参与细胞信号的调节。到目前为止的证据表明，耐受是由STL诱导的，导致CD22与B细胞受体(BCR)连接，产生凋亡信号，选择性地耗尽识别抗原的B细胞，放大CD22维持外周B细胞耐受的自然功能。该项目的主要目标是1)优化用于展示抗原和Siglec配体以诱导耐受的模块化STL平台，2)评估另一主要B细胞信号CD22和Siglec-G的特定配体诱导耐受的相对能力，3)评估STL对抗原特异性记忆B细胞的耐受能力，以及4)展示STL在诱导对一组不同医学上重要抗原的耐受方面的作用，并在EAE和过敏性哮喘模型中减少抗原反应性B细胞介导的病理改变。如果成功，STL平台可以为治疗自身免疫性其他抗原介导的疾病提供一种B细胞耗竭疗法的替代方案，通过去除抗原特异性B细胞，而保持其余B细胞群体和免疫记忆不变，代表着一种外科手术般的打击。

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.