Immune Modulation/Hematopoietic Cell Transplantation

描述（由申请人提供）：免疫反应是决定同种异体造血细胞移植（HCT）结果的关键。供体细胞对宿主抗原的异体免疫反应可导致移植物抗宿主病（GVHD）和移植物抗白血病（GVL）。相反，免疫反应性重构缺陷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余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。准确理解同种异体造血干细胞移植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。该项目将以移植后免疫功能的重建和操纵为中心主题，这是我们在过去的项目资助周期中大力追求的。项目1将侧重于旨在刺激抗白血病免疫而不产生不分青红皂白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，这些研究已经证实了安全性和诱导强大的免疫活性，将对非清髓性同种异体移植后的高风险患者使用受体来源的经辐照的自身肿瘤细胞接种疫苗，使其分泌GM-CSF。检查T细胞和B细胞对疫苗接种的反应将有望导致鉴定新的基因和抗原，这些基因和抗原可以作为未来疫苗接种策略的目标。确定和建立最佳的环境环境，以最大限度地提高特定的免疫反应将是这个项目成功的关键。调节性T细胞被认为在移植后同种异体免疫反应（GVH和GVL反应）的发展和控制中发挥重要作用，并且它们也可能影响对其他抗原的免疫反应。对微生物病原体或残留肿瘤细胞产生特异性免疫的尝试可能受到这些调节细胞活性的深刻影响。项目2将重点研究调节性T细胞的特征及其与HCT患者GVHD和抗肿瘤免疫反应的相关性。项目3将开发实验性小鼠模型，研究外源性调节性T细胞对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，以便调节它们以改善移植结果。

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.