Induction Acquired Thymic Tolerance by Regulatory APCs

通过监管 APC 诱导获得胸腺耐受

• 批准号: 6352513
• 负责人: IRVING GOLDSCHNEIDER
• 金额: $ 21.63万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-15 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6352513
• 关键词: T lymphocyte; anterior chamber; antigen presenting cell; autoantigens; autoimmune disorder; autologous transplantation; cell migration; dendritic cells; experimental allergic encephalomyelitis; immune tolerance /unresponsiveness; insulin dependent diabetes mellitus; isoantigen; laboratory mouse; skin transplantation; thymus; tissue /cell culture; transplant rejection

DESCRIPTION (provided by applicant): Acquired thymic tolerance appears to play a key role in the suppression of autoreactive and alloreactive T cells through the export of immunoregulatory thymocytes (THYreg) to the periphery. We have recently demonstrated that acquired thymic tolerance mediated by NKT cells can be induced by intracameral (i.c.) injection of foreign or autoantigens into the anterior chamber of the eye. We have also demonstrated that the afferent limb of this immunoregulatory loop is mediated by F4/80+ regulatory APCs that appear in the blood shortly after i.c.-injection of antigen. We therefore postulate that APCreg (presumably immature dendritic cells induce anterior chamber-associated immune deviation (ACAID) by transporting antigen to the thymus and inducing the formation and export of THYreg. As APCreg can also be generated ex vivo in the presence of antigen and TGF_or other cytokines, we further postulate that it should be possible to induce auto- or alloantigen-specific acquired thymic tolerance on demand by i.v. infusion of APCreg generated ex vivo from autologous (or syngeneic) APCs in blood or bone marrow. To test these hypotheses, the F4/80+ APCs from blood of i.c.-injected mice will be characterized phenotypically, their ability to migrate to thymus will be determined after labeling with fluorescent tracers, and a series of protocols for generating similar APCreg ex vivo will be tested and optimized. In addition, the ability of acquired thymic tolerance to prevent or ameliorate murine EAE, IDDM and skin allograft rejection will be confirmed by i.t. and i.c. injection of autoantigens or alloantigens. The role of APCreg in this process will then be tested by i.v. transfer of in vivo-generated APCreg from blood of i.c.-injected donors; and by i.v. transfer of ex vivo-generated APCreg from blood, BM or peritoneal exudate of naive donors. Success in these experiments would not only document the ability of APCreg to induce acquired thymic tolerance, but would demonstrate potential clinical utility of ex vivo-generated APCreg in autoimmunity and allotransplantation.

描述（由申请人提供）：获得性胸腺耐受性似乎 在抑制自身反应性和同种反应性 T 细胞中发挥关键作用 通过将免疫调节胸腺细胞（THYreg）输出到外周。 我们最近证明了由 NKT 介导的获得性胸腺耐受 细胞可以通过前房内（i.c）注射外源或 自身抗原进入眼前房。我们还展示了 该免疫调节环路的传入肢是由 F4/80+ 介导的 注射后不久出现在血液中的调节性 APC 抗原。 因此，我们假设 APCreg（大概是未成熟的树突 细胞通过以下方式诱导前房相关免疫偏差（ACAID） 将抗原转运至胸腺并诱导抗原的形成和输出 THYreg。由于 APCreg 也可以在抗原存在的情况下离体产生，并且 TGF_或其他细胞因子，我们进一步假设应该有可能 根据需要诱导自身或同种异体抗原特异性获得性胸腺耐受 静脉注射输注由自体（或同基因）APC 离体产生的 APCreg 在血液或骨髓中。为了检验这些假设，来自血液的 F4/80+ APC 注射的小鼠的表型特征将被表征，它们的能力 迁移至胸腺将在用荧光示踪剂标记后确定， 并且将测试一系列用于离体生成类似APCreg的协议 并进行了优化。此外，获得性胸腺耐受的能力 预防或改善小鼠 EAE、IDDM 和皮肤同种异体移植排斥反应 经 i.t. 证实和 i.c.注射自身抗原或同种异体抗原。角色 然后，将通过 i.v. 测试此过程中的 APCreg。的转移 从注射供体的血液中体内产生的 APCreg；并通过静脉注射转移 从幼稚动物的血液、BM 或腹膜渗出物中体外产生的 APCreg 捐助者。这些实验的成功不仅证明了 APCreg 诱导获得性胸腺耐受，但显示出潜力 离体生成的 APCreg 在自身免疫和免疫治疗中的临床应用 同种异体移植。