Engineering and Testing of Biomimetic Stimulators for Therapeutic Applications

项目总结 T细胞是免疫系统的总称，为先天免疫细胞提供指令。 细胞和其他T细胞，以协调对非我或改变的自我抗原的有效反应。的目标是 这一探索性的提议是为了推进我们已经产生的一类新的可溶性T细胞结合分子 通过仿生工程，将CD4T细胞反应重定向用于治疗目的。正常情况下，CD4T 细胞反应产生于分子相互作用的整合，这些分子相互作用发生在 CD4T细胞和抗原提呈细胞(APC)。这些包括但不限于：产生的信号 对MHCII分子(PMHCII)提呈的抗原肽的反应 T细胞受体、三个信号模块(CD3δε、CD3γε、CD3ζζ)和辅助受体的作用 T细胞上的LFA-1和APC上的ICAM-1之间的相互作用，提供黏附和 有助于信号传递；CD28参与APC上的CD80或CD86，提供关键的共刺激 IL-2产生和增殖的信号；以及CTLA-4参与相同的共刺激配体 用来限制反应的幅度。本文提出的工作将探索仿生学的用途。 刺激物(BMiMS)可溶性试剂，其一端具有新的抗原靶向区域和CD4T 另一方面是细胞刺激区。BMiMS背后的想法是，它们可以用来制造目标细胞 看起来像一个APC，并激发生理的CD4T细胞反应。在这份提案中，我们将具体致力于：1) 优化BMiMS的生产；2)在体外探索它们的功能；以及，3)在 活着。拟议的工作将为我们提供申请更大提案所需的初步数据 进一步在体内测试和提炼BMiMS的功能，以用作治疗试剂。长期目标将是 启动临床试验以评估BMiMS作为治疗试剂的疗效。

PROJECT SUMMARY CD4+ T cells are the field generals of the immune system, providing instructions to innate immune cells, B cells, and other T cells to coordinate effective responses against non-self or altered-self antigens. The goal of this exploratory proposal is to advance a new class of soluble T cell engagers, which we have generated through biomimetic engineering, to redirect CD4+ T cell responses for therapeutic purposes. Normally, CD4+ T cell responses emerge from the integration of molecular interactions that occur at the interface between a CD4+ T cell and an antigen presenting cell (APC). These include but are not limited to: signals generated in response to antigenic peptides presented by MHCII molecules (pMHCII) that result from the coordinated actions of the T cell receptor (TCR), three signaling modules (CD3δε, CD3γε, CD3ζζ), and the coreceptor module CD4; interactions between LFA-1 on the T cell and ICAM-1 on the APC that provide adhesion and contribute to signaling; CD28 engagement of CD80 or CD86 on the APC that provides a critical costimulatory signal for IL-2 production and proliferation; and, CTLA-4 engagement of the same costimulatory ligands that serve to limit the magnitude of the response. The work proposed herein will explore the utility of biomimetic stimulators (BMiMS) – soluble reagents that have a novel antigen targeting region on one end and a CD4+ T cell stimulatory region on the other. The idea underlying BMiMS is that they can be used to make a target cell look like an APC and elicit physiological CD4+ T cell responses. In this proposal we will specifically work to: 1) optimize the production of BMiMS; 2) explore their functionality in vitro; and, 3) explore their functionality in vivo. The proposed work will provide us with the preliminary data needed to apply for larger proposals to further test and refine BMiMS function in vivo for use as therapeutic reagents. The long-term goal will be to initiate clinical trials to evaluate the efficacy of BMiMS as therapeutic reagents.