Inducing antigen specific B cell tolerance

描述（由申请人提供）：该项目将研究我们最近发现的抗原特异性B细胞耐受性可以通过施用偶联至siglec配体修饰的纳米颗粒的抗原在动物中诱导的潜力[Duong等人（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变态反应分别由B细胞对自身和非自身抗原的应答引起。如果可以诱导对攻击性抗原的耐受性，则可能实现显著的治疗益处。我们的目标是开发一种模块化平台，siglec配体耐受原性脂质体（STL），用于各种医学相关抗原的简易缀合，并证明其可用于诱导体内稳健的抗原特异性B细胞耐受。初步数据显示，向小鼠施用同时展示CD 22的聚糖配体和抗原的STL诱导了对随后仅用抗原攻击的稳健的抗原特异性耐受。CD 22是免疫球蛋白（IG）受体的siglec家族的B细胞特异性成员，其识别含有唾液酸的聚糖作为自身配体，并作为共受体参与细胞信号传导的调节。迄今为止的证据表明，耐受性由STL诱导，导致CD 22与B细胞受体（BCR）连接，产生凋亡信号并选择性耗尽识别抗原的B细胞，扩增CD 22的天然功能以维持外周B细胞耐受性。该项目的主要目的是1）优化用于展示抗原和siglec配体以诱导耐受性的模块化STL平台，2）评估CD 22和Siglec-G（另一种主要B细胞siglec）的特异性配体诱导耐受性的相对能力，3）评估STL耐受抗原特异性记忆B细胞的能力，和4）证明STL在EAE和过敏性哮喘模型中诱导对一组不同医学上重要的抗原的耐受性和减少由抗原反应性B细胞介导的病理的效用。如果成功的话，STL平台可以为B细胞耗竭疗法提供一种替代方案，用于治疗自身免疫性其他抗原介导的疾病，代表通过消融抗原特异性B细胞而留下其余的B细胞群和免疫记忆完整的“手术”打击。 公共卫生相关性：该项目旨在开发一种新的方法来选择性地消耗导致自身免疫性疾病和过敏性哮喘的白色血细胞（B细胞）。如果成功的话，它将成为目前耗尽所有B细胞的药物的替代品，使患者失去免疫系统的重要部分。

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. PUBLIC HEALTH RELEVANCE: This project is aimed at developing a novel approach to selectively deplete the white blood cells (B cells) that cause autoimmune diseases and allergic asthma. If successful, it will be an alternative to current drugs that deplete all B cells, leavinga patient without an important segment of the immune system.