CAREER: Engineering Therapeutic Immune Responses with Artificial Antigen-Presenting Cells

0747577 Fahmy这个职业项目将开发一种新型的人工抗原提呈细胞样装置(AAPC)，增强免疫系统对疾病的反应。提高机体对病原体甚至肿瘤的免疫应答能力是免疫治疗的主要目标。由于T淋巴细胞在这一增强中起着核心作用，实现这一目标的进展是通过抗原免疫刺激体内抗原特异性T细胞免疫反应，或通过在称为过继免疫疗法的过程中重新转移大量体外扩张的T细胞来实现的。在主动和过继治疗中，迫切需要一种可靠和有效的抗原呈递策略来刺激足够数量的T细胞。虽然天然抗原提呈细胞是体内最强大的抗原提呈细胞，但它们在这些应用中的用途受到它们的可用性、分离细胞的质量、数量和与分离相关的劳动力的限制。然而，关于它们向T细胞展示抗原的策略已经了解了很多，这些新的生物学信息应该对设计新的、合理的人工抗原呈递技术具有指导意义。PI的方法结合了生物相容聚合物颗粒中对T细胞刺激重要的信号。这些系统集成了有效刺激T细胞所需的所有信号。这类设备在靶向不同类型的T细胞方面提供了易用性和灵活性，使其能够针对各种疾病状态进行扩展。拟议的工作将导致新一代治疗系统制备方面的最先进水平的改进。通过重述设计人造抗原呈递装置所需的生物学要求，该项目将有助于系统剖析聚合物颗粒与T细胞的相互作用及其在调节免疫反应中的作用。拟议的研究计划将探索创造影响免疫系统功能的仿生可降解颗粒的新方法。人们对免疫在健康和疾病中的作用知之甚少，但缺乏将这种理解与新材料技术相结合。该项目将提供一个关键机会，将生物学和工程学结合起来，以恢复对具有挑战性的疾病的免疫能力。拟议的研究将导致更好地理解和更好地设计解决生物学中的重要挑战所需的材料。与依赖于使用工程重组抗体或药物的方法不同，这里的策略应该产生一种稳定、易于制造的产品，可能会用作癌症免疫治疗的现成设备。该项目团队将在一个教育和推广计划的背景下处理一个重要的技术问题，该计划旨在培训年轻科学家和工程师在一个与社会和公共利益直接相关的跨学科科学的新领域：工程免疫。此外，这一科学项目解决了一个具有生物医学意义的问题，通过完善和成功的外联和教育计划，提供了一个机会来吸引大纽黑文地区的年轻人和教育工作者的注意。

0747577FahmyThis CAREER project will develop a new class of artificial antigen presenting cell-like devices (aAPC) that enhance immune system responses against disease. Enhancing the capacity of the immune response to pathogens and even tumors is a major goal in immunotherapy. Because T lymphocytes play a central role in this enhancement, progress towards that goal is accomplished by stimulating the antigen-specific T cell immune response in vivo through antigen immunization, or by re-transfer of large numbers of T cells expanded outside the body in a process called adoptive immunotherapy. In both active and adoptive therapy, there is a critical need for a reliable and effective antigen-presentation strategy to stimulate sufficient numbers of T cells. While natural antigen-presenting cells are the most potent cells in the body for antigen-presentation, their utility for these applications are limited by their availability, quality of isolated cells, quantity and labor associated with their isolation. Yet much has been learned about their strategies for antigen-display to T cells and this new biological information should be instructive for designing new, rational technologies for artificial antigen-presentation. The PI's approach incorporates signals important for T cell stimulation in biocompatible polymer particulates. These systems integrate all the signals needed for efficient T cell stimulation. Devices as such offer ease and flexibility over targeting different types of T cells enabling their expansion for a variety of disease states.The proposed work will lead to improvements in the state of the art in the preparation of a new generation of therapeutic systems. By recapitulating the biological requirements needed to engineer an artificial antigen-presenting device, this project will facilitate a systematic dissection of the interactions of polymer particles with T cells and their effect in modulating immune responses. The proposed research program will explore new methods for creation of biomimetic degradable particles that impact immune system function. Much is known about immunity in health and disease, yet integration of this understanding with new materials technology has been lacking. The project will facilitate a key opportunity to synergize biology and engineering for the purpose of restoring immune competence in challenging diseases. The studies proposed will lead to a better understanding and better design of materials needed to address important challenges in biology. Unlike approaches relying on the use of engineered recombinant antibodies or drugs the strategies here should produce a stable, easy to fabricate product that might be useful as an off-the-shelf device for cancer immunotherapy. The project team will approach an important technological problem within the context of an educational and outreach program that seeks to train young scientists and engineers in a new area of interdisciplinary science that is of immediate societal relevance and public interest: engineering immunity. In addition, this science project, which addresses a problem of biomedical significance, provides an opportunity to attract the attention of young people as well as educators in the greater New Haven area through well-established and successful outreach and education programs.