Immune Modulation/Hematopoietic Cell Transplantation

描述（由申请人提供）：免疫应答在决定异基因造血细胞移植（HCT）的结果方面至关重要。供体细胞针对宿主抗原的同种异体免疫应答导致移植物抗宿主病（GVHD）和移植物抗白血病（GVL）。相反，免疫应答的重建不足导致各种微生物和病毒病原体的机会性感染。新移植的供体免疫系统对残留肿瘤细胞的识别和破坏不足也会导致患者潜在恶性肿瘤的复发。准确理解异基因HSCT后的免疫重建对于设计和实施调节免疫反应的策略是必要的。希望通过这样做，可以增强抗肿瘤反应性，同时最大限度地减少GVHD和免疫缺陷等并发症。该计划项目将建立在移植后免疫功能的重建和操纵的中心主题上，我们在过去的计划资助周期中一直在大力追求这一主题。项目1将重点关注旨在刺激抗白血病免疫而不产生不加选择的同种异体反应的疫苗接种策略。基于在非移植环境中进行的研究（已证实安全性和诱导稳健的免疫活性），非清髓性同种异体移植后的高风险患者将接种经工程改造以分泌GM-CSF的肿瘤源性经辐照自体肿瘤细胞。T和B细胞对疫苗接种的反应的检查将有望导致鉴定新的基因和抗原，其可以作为未来疫苗接种策略的靶点。确定和建立最佳的环境环境，以最大限度地提高特异性免疫反应将是本项目成功的关键。调节性T细胞被认为在移植后同种异体免疫应答（GVH和GVL反应）的发展和控制中起重要作用，并且它们也可能影响对其他抗原的免疫应答。产生针对微生物病原体或残留肿瘤细胞的特异性免疫的尝试可能受到这些调节细胞的活性的深刻影响。项目2将重点关注调节性T细胞的特征及其与接受HCT的患者的GVHD和抗肿瘤免疫应答的相关性。项目3将开发实验小鼠模型，以研究外源性给予这些调节性T细胞对同种异体和肿瘤特异性反应的影响。这是一个高度互动的项目，将汇集实验动物模型，基于患者的临床试验和相关的实验室研究，以更好地了解免疫反应的调节，以便它们可以被调节以改善移植结果。

DESCRIPTION (provided by applicant): Immune responses are critical in determining the outcome of allogeneic hematopoietic cell transplantation (HCT). Allogeneic immune responses of donor cells against host antigens lead to both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL). In contrast, deficient reconstitution of immune responsiveness leads to opportunistic infections with a variety of microbial and viral pathogens. Inadequate recognition and destruction of residual tumor cells by a newly engrafted donor immune system also permits recurrence of a patient's underlying malignancy. An accurate understanding of immune reconstitution after allogeneic HSCT is necessary to design and implement strategies to regulate immune responsiveness. Hopefully, by so doing, anti-tumor reactivity can be enhanced while minimizing complications such as GVHD and immune deficiency. This Program Project will build on the central theme of reconstitution and manipulation of immune function post-transplant that we have pursued vigorously during the past funding cycles of the Program. Project 1 will focus on vaccination strategies designed to stimulate anti-leukemic immunity without producing an indiscriminate allogeneic response. Based upon studies performed in the non-transplant setting which have confirmed safety and induction of robust immunologic activity, vaccinations with recipient-derived irradiated autologous tumor cells engineered to secrete GM-CSF will be administered to high risk patients after non-myeloablative allogeneic transplantation. Examination of T and B cell responses to vaccination will hopefully lead to the identification of new genes and antigens which can serve as targets for future vaccination strategies. Determining and establishing the optimal environmental milieu to maximize a specific immune response will be critical to the success of this Project. Regulatory T cells are thought to play an important role in the development and control of allogeneic immune responses (GVH and GVL reactions) post-transplant, and it is likely they will impact on immune responses to other antigens as well. Attempts to generate specific immunity against microbial pathogens or residual tumor cells may be profoundly influenced by the activity of these regulatory cells. Project 2 will focus on the characterization of regulatory T cells and their correlation with GVHD and anti-tumor immune responses in patients undergoing HCT. Project 3 will develop experimental murine models to study the impact of exogenous administration of these regulatory T cells on allogeneic and tumor specific responses. This is highly interactive Program will bring together experimental animal models, patient based clinical trials, and correlative laboratory investigation to better understand the regulation of immune responses so that they may be modulated to improve transplant outcome.