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

• 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
• 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

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.

项目摘要 急性移植 - 抗宿主病（AGVHD）是同种异体造血的经常且致命的并发症 干细胞移植（Allo-HSCT），其中供体T细胞通过分泌而破坏HLA不匹配的宿主组织 炎性细胞因子（TNF-α和IFN-γ）和/或诱导的直接细胞毒性细胞反应。尽管最近 进步，AGVHD仍然是一个主要的临床问题，强调了进一步阐明其进一步的临床问题 然后制定新的治疗策略的机制。在此提案中，我们正在研究上皮 生长因子（例如7（EGFL7））作为AGVHD的潜在调节剂。 EGFL7是内皮细胞的复制品 激活在血管生成中起重要的身体作用。最近，它也已被记录 EGFL7通过反映内皮细胞激活在调节创新中起着重要作用 对炎性细胞因子（例如TNF-α）的反应。 EGFL7激活内皮细胞的表达 导致细胞粘附分子（例如ICAM-1，VCAM和E-选择素）的表达降低，这 导致炎症细胞降低和渗出到目标时机中。基于这些数据， 我们假设在Allo-HSCT之后增加EGFL7水平会降低AGVHD的严重性 干扰T细胞向目标时间迁移。我们的初步数据表明治疗 在两个不同的AGVHD鼠模型中，重组EGFL7（regfl7）降低了AGVHD的严重性和 同种异体移植相对于对照而不影响对照的同种异体移植后，提高受体小鼠的生存率 移植与白血病（GVL）效应。此外，我们表明regfl7治疗导致较高 Allo-HSCT后，受体小鼠的胸腺细胞T，B和树突状细胞。总体而言，我们的初步数据支持 EGFL7在AGVHD调制中的作用。在此提案中，我们想通过 EGFL7调节AGVHD并对免疫BM重建的影响并进行临床前研究 使用regfl7作为预防和治疗AGVHD的疗法。我们计划通过执行 以下目的：特定目的1：剖析EGFL7调节AGVHD和的机制 在此目标中，我们将系统地评估内皮细胞激活状态 EGFL7治疗后AGVHD的鼠模型中的T细胞表型。此外，我们将探索是否 EGFL7对T细胞功能和肠干细胞具有任何直接影响。最后，我们将调查EGFL7 对免疫重构的影响。特定目的2：使用Regfl7作为A进行临床前研究 预防和治疗AGVHD的治疗。在此目标中，我们想执行初始毒理学，药代动力学 和药效研究以选择最佳剂量和时间表来预防和治疗AGVHD。此外， 我们想研究Regfl7治疗在类固醇难治性AGVHD鼠模型中是否有效。 影响：将EGFL7鉴定为GVHD的新疗法将受益于主要接受同类的患者 HSCT治疗血液学恶性肿瘤。