ALLO SPECIFIC TOLERANCE BY TARGETING CD28

以 CD28 为靶点的 ALLO 特异性耐受

• 批准号: 6514265
• 负责人: Xue-Zhong Yu
• 金额: $ 13.48万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-15 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6514265
• 关键词: CD28 molecule; T lymphocyte; antileukocyte isoantibody; artificial immunosuppression; autologous transplantation; bone marrow transplantation; genetically modified animals; graft versus host disease; homologous transplantation; immune tolerance /unresponsiveness; interleukin 10; laboratory mouse; leukemia; monoclonal antibody; neoplasm /cancer immunology; transplant rejection; transplantation immunology

DESCRIPTION (Applicant's Description): Dr. Yu is a Research Associate with the Immunogenetics Program in the Clinical Research Division at Fred Hutchinson Cancer Research Center (FRCRC) and has investigated mechanisms of peripheral T cell tolerance in the laboratory of Dr. Claudio Anasetti. The FHCRC is a premier biomedical research center dedicated to the cause of eliminating cancer as a major form of human suffering. This Center provides an exceptional opportunity for the research and intellectual development of physician scientists. The long-term goal of this project is to develop a strategy [of] inducing specific tolerance of alloreactive T cells responsible for graft-versus-host disease (GVHD) and graft rejection, while preserving T cells responsible for pathogens or tumor antigens. Being successful in this research project, it is expected that Dr. Yu's research career will be greatly enhanced, and he will realize his career goal, [i.e.,] to become an independent investigator. S t u dies proposed in this application are expected to determine the immunosuppressive mechanism of CD28-ligation with its specific monoclonal antibody (mAb) in vivo, to disclose a new approach exploiting the function of CD28 in regulation of T cell response, which may be highly beneficial to patients with leukemia. The specific aims of this application are: 1) To determine whether treatment with anti-CD28 mAb can prevent GVHD and facilitate engraftment. Bone marrow and peripheral T cells from donors will be transplanted into irradiated MHC class I and class II-incompatible recipients, and the effects of treatment with anti-CD28 mAb on GVHD and graft rejection w i l l [ be] tested. 2) To determine whether anti-CD28 mAb induces immunosuppression in vivo by over-activating T cells, and/or promoting T cells to produce type-2 cytokines, especially IL-10. TCR transgenic 2C and DO11.10 mice will be used to test the hypothesis that anti-CD28 mAb facilitates, rather than inhibits, CD4 and CD8 T cell activation respectively. Neutralizing in mAb specific for mouse anti-IL-10 mAb will be used to neutralize IL-10 in vivo to assess the contribution of IL-10 in GVRD protection mediated by anti- CD28-treatment. 3) To determine whether treatment with anti-CD28 mAb can preserve GVL effects. The effects of anti-CD28 mAb on tumor rejection will be tested in syngeneic or allogenic hosts.

描述（申请人的描述）：Yu博士是一名研究合伙人 弗雷德临床研究部的免疫遗传学计划 Hutchinson癌症研究中心（FRCRC）研究了 Claudio Anasetti博士实验室中的外围T细胞耐受性。这 FHCRC是一个主要的生物医学研究中心 消除癌症是人类苦难的一种主要形式。这个中心提供了一个 研究和智力发展的杰出机会 医师科学家。 该项目的长期目标是开发 [诱导同种反应性T细胞的特定耐受性的策略 用于移植物抗宿主病（GVHD）和移植物的排斥反应，同时保留T 负责病原体或肿瘤抗原的细胞。在这方面取得成功 研究项目，预计Yu博士的研究职业将大大 增强了，他将意识到自己的职业目标，即 独立研究者。 预计在本申请中提出的s t u dies将确定 CD28结合及其特定单克隆的免疫抑制机制 体内抗体（MAB），以披露一种利用功能的新方法 CD28在调节T细胞反应中，这可能对 白血病患者。 此应用程序的具体目的是：1） 确定抗CD28 mAb处理是否可以防止GVHD并促进 植入。 供体的骨髓和外围T细胞将是 移植到受辐照的MHC I类和II类不兼容的接受者中 以及用抗CD28 mAb治疗对GVHD和移植排斥的影响 测试。 2）确定抗CD28 mAb是否诱导 通过过度激活T细胞和/或促进T细胞在体内免疫抑制 产生2型细胞因子，尤其是IL-10。 TCR转基因2C和DO11.10 小鼠将用于检验抗CD28 mAb促进的假设， CD4和CD8 T细胞活化而不是抑制。中和 在MAB中，特定于小鼠抗IL-10 mAb将用于中和IL-10 Vivo评估IL-10在抗 - 介导的GVRD保护中的贡献 CD28处理。 3）确定用抗CD28 mAb处理是否可以 保留GVL效果。抗CD28 mAb对肿瘤排斥的影响将是 在同源或同种异体宿主中测试。