Modifying Regulatory T-cell signaling to enhance prevention of GVHD

修改调节性 T 细胞信号传导以加强 GVHD 的预防

• 批准号: 8921839
• 负责人: Cameron S McDonald-Hyman
• 金额: $ 3.61万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-02 至 2018-09-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8921839
• 关键词: Adenosine; Adoptive Transfer; Allogenic; Antigens; Apoptotic; Autoimmune Diseases; Autoimmunity; Biology; Blocking Antibodies; Clinical Research; Clinical Trials; Clinical Trials Cooperative Group; Complex; Data; Dependency; Development; Disease; Disease model; Distal; Dose; Eragrostis; Future; Gastrointestinal tract structure; Goals; Graft Rejection; Granzyme; Hematopoietic stem cells; Homing; Human; Immune; Immune response; Immunosuppression; In Vitro; Infection; Inflammatory; Infusion procedures; Interleukin-10; Knockout Mice; Laboratory Finding; Mediating; Mediator of activation protein; Modification; Morbidity - disease rate; Mus; Organ; Organ Transplantation; Patients; Play; Prevention; Protein Kinase C; Reagent; Recruitment Activity; Recurrence; Regimen; Regulatory T-Lymphocyte; Risk; Role; Signal Pathway; Signal Transduction; Solid; Stem cell transplant; Surface; System; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic immunosuppression; Treatment Efficacy; cancer recurrence; design; disorder prevention; graft vs host disease; improved; in vivo; inhibitor/antagonist; insight; mortality; novel; perforin; preclinical study; prevent; public health relevance; response; tumor

DESCRIPTION (provided by applicant): The efficacy of allogeneic hematopoietic stem cell transplant (HSCT) is limited by graft-versus-host disease (GVHD), a severe immune-mediated multi-organ inflammatory disease that is the leading cause of morbidity and mortality after HSCT. Current globally immunosuppressive therapies to prevent GVHD are incompletely effective, and have unwanted consequences, such as increasing cancer recurrence and infection risk. Thus, new treatments for GVHD are needed. Regulatory T-cells (Tregs) play an indispensible role in controlling autoimmunity and responses to foreign antigens, including the allo-antigens that drive GVHD. As a result, Tregs hold immense promise for the treatment of GVHD. O ur group conducted the first-in-human clinical trial using ex vivo expanded Tregs for GVHD prevention. While this trial demonstrated a significant reduction in GVHD, it was not eliminated. We determined that infused Tregs had variable suppressor potency, which limited consistent efficacy. Therefore, the overarching goal of this project is to improve Treg suppressive function so that we can better prevent GVHD. To accomplish this, the specific aims of this application build on our lab's finding that protein kinase C-theta (PKC-?), a key molecule necessary for Effector T-cell (Teff) activation and proliferation, negatively regulates Treg function. We are taking advantage of this finding by using a clinically available PKC-? inhibitor (AEB071) as a means to enhance Treg suppressive potency. We now find that ex vivo treatment of murine Tregs with AEB071 results in a 300% increase in Treg function in vitro, and increases Treg-mediated suppression of murine GVHD. However, in vitro, PKC-? inhibition enhances Treg suppressive potency in a dose-dependent manner, whereas in vivo, only low dose treatment augments GVHD suppression. This suggests that while PKC-? inhibition enhances Treg suppression in a dose-dependent manner, treatment with higher doses restrains Treg function in vivo. In order to overcome this limitation and further advance the efficacy of Treg therapies, the aims proposed in this application are designed to identify the downstream mechanisms by which PKC-? inhibition mediates these modifications to Treg functionality in vitro and in vivo. Aim 1 will focus on Treg suppression and test the hypothesis that PKC-? inhibition augments Treg function by up-regulating known contact-dependent and possibly secreted suppressive molecules in a dose-dependent manner. Aim 2 will focus on diminished in vivo efficacy with higher dose AEB071 treatment, and test the hypothesis that PKC-? inhibition reduces Treg proliferation and GI tract homing in vivo. These studies will provide novel insights into the mechanisms by which inhibiting a negative regulator of Treg function (PKC-?) alters Treg biology. These results will help us overcome the limitation to Treg therapeutic efficacy identified in our group's clinical trial and inform a new wave of clinical studies. Therefore, this proposal has broad implications not only for the treatment of GVHD, but also for transplant rejection and autoimmunity.

描述（由申请人提供）：同种异体造血干细胞移植（HSCT）的功效受到移植物抗宿主病（GVHD）的限制，移植物抗宿主病是一种严重的免疫介导的多器官炎症性疾病，是发病和死亡的主要原因造血干细胞移植后。目前全球用于预防 GVHD 的免疫抑制疗法并不完全有效，并且会产生不良后果，例如增加癌症复发和感染风险。因此，需要新的 GVHD 治疗方法。调节性 T 细胞 (Treg) 在控制自身免疫和对外源抗原（包括驱动 GVHD 的同种异体抗原）的反应中发挥着不可或缺的作用。因此，Tregs 在治疗 GVHD 方面具有巨大的前景。我们的团队利用离体扩增的 Tregs 进行了首次人体临床试验，用于预防 GVHD。虽然该试验证明 GVHD 显着降低，但并未消除。我们确定输注的 Tregs 具有可变的抑制效力，这限制了一致的功效。因此，该项目的总体目标是改善Treg抑制功能，以便更好地预防GVHD。为了实现这一目标，本应用的具体目标建立在我们实验室的发现之上，即蛋白激酶 C-theta (PKC-?) 是效应 T 细胞 (Teff) 激活和增殖所必需的关键分子，可负调节 Treg 功能。我们正在通过使用临床上可用的 PKC-? 来利用这一发现。抑制剂（AEB071）作为增强 Treg 抑制效力的手段。我们现在发现，用 AEB071 对小鼠 Treg 进行离体治疗，可导致体外 Treg 功能增加 300%，并增强 Treg 介导的对小鼠 GVHD 的抑制。然而，在体外，PKC-？抑制以剂量依赖性方式增强 Treg 抑制效力，而在体内，仅低剂量治疗即可增强 GVHD 抑制。这表明，虽然 PKC-？抑制以剂量依赖性方式增强Treg抑制，较高剂量的治疗会抑制体内Treg功能。为了克服这一局限性并进一步提高 Treg 疗法的功效，本申请提出的目标旨在确定 PKC-？抑制介导这些体外和体内 Treg 功能的修饰。目标 1 将重点关注 Treg 抑制并检验 PKC-？抑制通过以剂量依赖性方式上调已知的接触依赖性和可能分泌的抑制分子来增强 Treg 功能。目标 2 将重点关注较高剂量 AEB071 治疗的体内功效减弱，并检验 PKC-？抑制可减少体内 Treg 增殖和胃肠道归巢。这些研究将为抑制 Treg 功能负调节因子 (PKC-?) 改变 Treg 生物学的机制提供新的见解。这些结果将帮助我们克服我们小组临床试验中发现的 Treg 治疗功效的局限性，并为新一波的临床研究提供信息。因此，这 该提案不仅对 GVHD 的治疗，而且对移植排斥和自身免疫也具有广泛的影响。