Modulation of T Cell Responses with Cytokines

用细胞因子调节 T 细胞反应

• 批准号: 8224082
• 负责人: Charles D. Surh
• 金额: $ 46.9万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-22 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8224082
• 关键词: Address; Adult; Adverse effects; Autoimmune Diseases; Binding; Biological; Biology; Blood Vessels; Cells; Characteristics; Complex; Development; Dose; Employee Strikes; Exposure to; Family; Grant; Half-Life; Homeostasis; Immune response; In Vitro; Infectious Agent; Injection of therapeutic agent; Interleukin 2 Receptor Gamma; Interleukin-15; Interleukin-2; Interleukin-4; Interleukin-7; Interleukin-9; Investigation; Lead; Life; Link; Longevity; Lymphocyte Function; Lymphoid Tissue; Mature T-Lymphocyte; Measures; Molecular Weight; Monoclonal Antibodies; Mus; Natural Killer Cells; Population; Recombinant Fusion Proteins; Regulatory T-Lymphocyte; Research; Role; Syndrome; T cell response; T memory cell; T-Cell Development; T-Cell Proliferation; T-Lymphocyte; Techniques; Therapeutic; Tissues; Visit; Work; autocrine; cancer therapy; cytokine; design; improved; in vivo; neonatal Fc receptor; neoplastic cell; novel; paracrine; pathogen; receptor; tumor

The survival and function of T cells in vivo is controlled by a spectrum of different cytokines, especially by those that interact with receptors associated with the common gamma chain (?c) such as IL-2, IL-7 and IL-15. Contact with these cytokines is especially important for controlling the formation of T cells and maintaining T cell homeostasis in adult life. Exposure to??c cytokines is also crucial for mounting strong immune responses to pathogens and for eliminating tumor cells. It has been known for several years that the lifespan of??c cytokines can be extended by association with specific anti-cytokine monoclonal antibodies (mAb). Recently, formation of IL-2/IL-2 mAb complexes was found to markedly enhance the biological activity of IL-2. Thus, massive expansion of T cells and NK cells occurred after short-term injection of IL-2/IL-2 mAb complexes. Similar effects occurred with injection of mAbs bound to IL-4 or IL-7. A striking finding is that, especially for IL-2, the strong enhancing effect of mAb binding on cytokine function is conspicuous in vivo but largely absent in vitro. Precisely why cytokine/mAb complexes have such potent activity in vivo is still largely obscure, although extending cytokine half-life by FcRn and presentation of the complexes by FcR+ cells appear to be important. These issues will be probed in depth, especially by examining the stimulatory function of the cytokine-mAb complexes in mice lacking FcRn, one or more types of FcR, and both types of receptors. The possibility that the cytokine/mAb complexes function in part by extending cytokine half-life will be assessed by various approaches, including the use of techniques designed to reduce or improve half-life. Elucidating the mechanisms by how cyotkine/mAb complexes display strong biological activity could lead to development of better approaches for treatment of cancer and autoimmune diseases. ?? ?? ?? ?? ARRA JIT Submission: Grant # 1 R01 AI075164-01A2; PI: Surh

T 细胞在体内的存活和功能由一系列不同的细胞因子控制，特别是那些与共同伽马链 (?c) 相关的受体相互作用的细胞因子，例如 IL-2、IL-7 和 IL-15。与这些细胞因子的接触对于控制 T 细胞的形成和维持成人生活中的 T 细胞稳态尤其重要。接触细胞因子对于对病原体产生强烈的免疫反应和消除肿瘤细胞也至关重要。多年来人们已经知道，通过与特异性抗细胞因子单克隆抗体（mAb）结合可以延长细胞因子的寿命。最近，发现IL-2/IL-2 mAb复合物的形成可显着增强IL-2的生物活性。因此，短期注射 IL-2/IL-2 mAb 复合物后，T 细胞和 NK 细胞发生大量扩增。注射与 IL-4 或 IL-7 结合的 mAb 也会产生类似的效果。一个惊人的发现是，特别是对于 IL-2，mAb 结合对细胞因子功能的强烈增强作用在体内很明显，但在体外基本上不存在。尽管 FcRn 延长细胞因子半衰期和 FcR+ 细胞呈递复合物似乎很重要，但细胞因子/mAb 复合物在体内具有如此强大活性的确切原因仍然很大程度上不清楚。这些问题将得到深入探讨，特别是通过检查细胞因子-mAb 复合物在缺乏 FcRn、一种或多种类型的 FcR 以及两种类型受体的小鼠中的刺激功能。细胞因子/单克隆抗体复合物部分通过延长细胞因子半衰期发挥作用的可能性将通过各种方法进行评估，包括使用旨在缩短或改善半衰期的技术。阐明细胞因子/单克隆抗体复合物如何表现出强大的生物活性的机制可能会导致开发出更好的治疗癌症和自身免疫性疾病的方法。 ?? ?? ?? ?? ARRA JIT 提交：Grant # 1 R01 AI075164-01A2； PI：苏尔