Developing novel therapies to improve blood stem cell transplantation outcomes

开发新疗法以改善造血干细胞移植结果

基本信息

批准号：
10458315
负责人：
Adrienne M. Dorrance
金额：
$ 78.4万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2022-11-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10458315
关键词：
Acute Graft Versus Host Disease Address Adhesions Affect Allogenic Apoptosis B-Lymphocytes Biology Blood Vessels Cell Adhesion Cell Adhesion Molecules Cell Proliferation Cell physiology Cells Clinical Complication Data Dendritic Cells Disease Disease model Dose E-Selectin Endothelial Cells Endothelium Epidermal Growth Factor Epithelial Extravasation Future Goals Growth Factor Hematologic Neoplasms Hematological Disease Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Homologous Transplantation Immune Inbred BALB C Mice Inflammation Inflammatory Intercellular adhesion molecule 1 Interferon Type II Intestines Large Intestine Liver Maximum Tolerated Dose Morbidity - disease rate Mus Outcome Patients Phenotype Physiological Play Proteins Publishing Recombinants Refractory Repression Role Schedule Severities Severity of illness Stem cell transplant Steroids T-Cell Activation T-Lymphocyte TNF gene Therapeutic Tissues Toxic effect Toxicology Transplantation Tumor-infiltrating immune cells Vascular Cell Adhesion Molecule-1 angiogenesis base cell motility cytokine cytotoxic graft vs leukemia effect immune reconstitution improved knockout animal loss of function migration mouse model novel therapeutic intervention novel therapeutics pharmacokinetics and pharmacodynamics preclinical study prevent reconstitution repaired response stem cells thymocyte treatment strategy vasculogenesis

项目摘要

PROJECT SUMMARY Acute Graft-versus-host disease (aGVHD) is a frequent and lethal complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in which donor T cells destroy HLA mismatched host tissues by secreting inflammatory cytokines (TNF-α and IFN-γ) and/or inducing direct cytotoxic cellular responses. Despite recent advances, aGVHD still remains a major clinical problem, underscoring the need to elucidate further its mechanisms to then develop novel therapeutic strategies. In this proposal, we are investigating epithelial growth factor like 7 (EGFL7) as a potential modulator of aGVHD. EGFL7 is a repressor of endothelial cell activation which plays an important physiological role in angiogenesis. Recently, it has also been documented that EGFL7 plays a significant role in regulating inflammation by repressing endothelial cell activation in response to the inflammatory cytokines such as TNF-α. The repression of endothelial cell activation by EGFL7 results in reduced expression of cellular adhesion molecules such as ICAM-1, VCAM, and E-Selectin, which results in reduced adhesion and extravasation of inflammatory cells into target tissues. Based on these data, we hypothesized that increasing EGFL7 levels after allo-HSCT will diminish the severity of aGVHD by interfering with the migration of T cells to the target tissues. Our preliminary data showed that treatment with recombinant EGFL7 (rEGFL7) in two different murine models of aGVHD decreases aGVHD severity and improves survival in recipient mice after allogeneic transplantation with respect to controls without affecting graft versus leukemia (GVL) effect. Furthermore, we showed that rEGFL7 treatment results in higher thymocytes, T, B and dendritic cells in recipient mice after allo-HSCT. Overall, our preliminary data support a role for EGFL7 in the modulation of aGVHD. In this proposal, we would like to dissect the mechanisms by which EGFL7 modulates aGVHD and impact on immune BM reconstitution and to perform preclinical studies using rEGFL7 as a therapy to prevent and treat aGVHD. We are planning to achieve these goals by performing the following aims: Specific Aim 1: To dissect the mechanisms by which EGFL7 modulates aGVHD and impact on immune reconstitution. In this aim, we will systematically assess endothelial cell activation status and T cell phenotypes in murine models of aGVHD after EGFL7 therapy. Furthermore, we will explore whether EGFL7 has any direct effects on T cell function and intestinal stem cells. Last, we will investigate the EGFL7 effects on immune reconstitution. Specific Aim 2: To perform preclinical studies using rEGFL7 as a therapy to prevent and treat aGVHD. In this aim, we would like to perform initial toxicology, pharmacokinetics and pharmacodynamic studies to select the best dose and schedule to prevent and treat aGVHD. In addition, we would like to investigate whether rEGFL7 therapy is effective in a steroid refractory aGVHD murine model. Impact: The identification of EGFL7 as new therapy for GVHD will benefit primarily patients undergoing allo- HSCT to cure hematologic malignancies.

项目概要急性移植物抗宿主病（aGVHD）是同种异体造血的常见且致命的并发症干细胞移植（allo-HSCT），供体 T 细胞通过分泌破坏 HLA 不匹配的宿主组织尽管最近出现了炎症细胞因子（TNF-α 和 IFN-γ）和/或诱导直接细胞毒性细胞反应。尽管取得了进展，aGVHD 仍然是一个主要的临床问题，强调需要进一步阐明其机制，然后开发新的治疗策略在本提案中，我们正在研究上皮细胞。生长因子样 7 (EGFL7) 作为 aGVHD 的潜在调节剂，是内皮细胞的抑制因子。最近，它也被证明在血管生成中起着重要的生理作用。 EGFL7 通过抑制内皮细胞活化在调节炎症中发挥重要作用对 TNF-α 等炎症细胞因子的反应 EGFL7 抑制内皮细胞活化。导致 ICAM-1、VCAM 和 E-Selectin 等细胞粘附分子表达减少，导致炎症细胞向靶组织的粘附和外渗减少。我们认为，allo-HSCT 后增加 EGFL7 水平会通过以下方式减轻 aGVHD 的严重程度：我们的初步数据表明，治疗会干扰 T 细胞向靶组织的迁移。在两种不同的 aGVHD 小鼠模型中使用重组 EGFL7 (rEGFL7) 可降低 aGVHD 的严重程度和与对照组相比，同种异体移植后受体小鼠的存活率提高，且不影响此外，我们还发现 rEGFL7 治疗可产生更高的移植物抗白血病 (GVL) 效应。总体而言，我们的初步数据支持 a 受体小鼠的胸腺细胞、T、B 和树突状细胞。 EGFL7 在 aGVHD 调节中的作用在本提案中，我们想通过以下方式剖析其机制。 EGFL7 调节 aGVHD 并影响免疫 BM 重建并进行临床前研究我们计划通过使用 rEGFL7 作为预防和治疗 aGVHD 的疗法来实现这些目标。具体目标 1：剖析 EGFL7 调节 aGVHD 和为了这个目的，我们将系统地评估内皮细胞的激活状态。 EGFL7 治疗后 aGVHD 小鼠模型中的 T 细胞和 T 细胞表型。 EGFL7对T细胞功能和肠道干细胞有什么直接影响最后，我们将研究EGFL7。具体目标 2：使用 rEGFL7 作为免疫重建的影响进行临床前研究。预防和治疗 aGVHD 的疗法为此，我们希望进行初步毒理学、药代动力学研究。和药效学研究，以选择预防和治疗 aGVHD 的最佳剂量和时间表。我们想研究 rEGFL7 疗法在类固醇难治性 aGVHD 小鼠模型中是否有效。影响：将 EGFL7 确定为 GVHD 的新疗法将主要使接受同种异体治疗的患者受益 HSCT 治疗血液系统恶性肿瘤。