Induction Acquired Thymic Tolerance by Regulatory APCs

通过监管 APC 诱导获得胸腺耐受

• 批准号: 6534344
• 负责人: IRVING GOLDSCHNEIDER
• 金额: $ 21.75万
• 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/6534344
• 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（申请人提供）：获得的胸腺耐受性似乎 在抑制自动反应性和同种异体T细胞中起关键作用 通过出口免疫调节性胸腺细胞（THYREG）向周围。 我们最近证明了由NKT介导的获得的胸腺耐受性 可以通过腔内（i.c.）注射外国或 自动抗原进入眼睛的前室。我们也证明了 该免疫调节环的传入肢体由F4/80+介导 I.C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（可能是未成熟的树突状 细胞通过诱导前腔室相关的免疫偏差（ACAID） 将抗原运送到百里香，并诱导形成和出口 蒂格。因为在存在抗原和 TGF_或其他细胞因子，我们进一步假设应该有可能 通过需求诱导自动或同种特异性的获得性胸腺耐受性 I.V.从自体（或同步）APC中输注APCREG生成的APCREG 在血液或骨髓中。为了检验这些假设，来自血液的F4/80+ APC 注射的小鼠的表征将以表型为特征，它们的能力 用荧光示踪剂标记后，将确定迁移到胸腺 并且将测试一系列用于生成类似apcreg的协议 并优化。另外，获得的胸腺耐受性 预防或改善鼠EAE，IDDM和皮肤同种异体移植抑制作用将是 由I.T.确认和I.C.注射自动抗原或同种抗原。角色 然后，在此过程中的APCREG将通过i.v.测试。 in I.C.注射供体的血液中的体内生成的APCREG；并通过i.v.转移 幼稚的血液，BM或腹膜渗出液的过体生成的APCREG 捐助者。这些实验的成功不仅会记录 APCREG诱导获得的胸腺耐受性，但会证明潜力 自身免疫性中体内生成的APCREG的临床实用性和 同种异体移植。