Development of iPSC-derived iNKT cells to promote hematopoietic engraftment

开发 iPSC 衍生的 iNKT 细胞以促进造血植入

基本信息

批准号：
10632065
负责人：
Jenny E. Gumperz
金额：
$ 19.44万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
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：
2022-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10632065
关键词：
Ablation Adjuvant Adult Affect Allogenic Antigen Presentation B-Lymphocytes Bone Marrow Cell Transplantation Bone Marrow Transplantation CD1d antigen CD34 gene Cell Line Cell Therapy Cell physiology Cells Cellular immunotherapy Clinical Cytotoxic T-Lymphocytes Development Dinoprostone Disease E4BP4 Engineering Engraftment Foundations Gene Expression Profiling Genetic Diseases Genetic Transcription Graft vs Tumor Effect Granulocyte-Macrophage Colony-Stimulating Factor HIV Hematological Disease Hematopoietic Hematopoietic Stem Cell Transplantation Human Human Herpesvirus 4 IL17 gene IL3 Gene Immune Immune System Diseases Immunodeficient Mouse Infection Inflammation Inflammatory Interferon Type II Interleukin-10 Interleukin-13 Interleukin-4 Knock-in Knock-out Left Lymphoma Lymphomagenesis Malignant Neoplasms Mediating Modeling Mononuclear Morbidity - disease rate Mus Output Pathologic Patients Predisposition Procedures Production Property Protocols documentation Publishing Signal Transduction System T-Lymphocyte Testing Therapeutic Toxic effect Transplantation Transplantation Conditioning Tumor Burden Umbilical Cord Blood Umbilical Cord Blood Transplantation ZNF145 gene combat conditioning curative treatments cytokine design differential expression factor A graft failure hematopoietic engraftment hematopoietic transplantation high risk improved improved outcome induced pluripotent stem cell induced pluripotent stem cell technology infectious disease treatment insight leukemia relapse monocyte mortality mouse model novel novel therapeutic intervention novel therapeutics overexpression programs response segregation success therapy design transcription factor

项目摘要

Summary Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for a variety of malignancies and other hematological disorders, and also holds promise for treatment of infectious diseases such as HIV. However, HSCT is limited by high risks of morbidity and mortality from complications such as graft failure (which leads to high susceptibility to lethal infections) and leukemic relapse. New strategies to improve outcomes of hematopoietic transplantation would thus have a significant clinical impact. This project focuses on developing invariant Natural Killer T (iNKT) cells derived from human induced pluripotent stem cells (iPSCs) as an adjunct HSCT cellular therapy designed to promote successful hematopoietic engraftment. In recently published preliminary studies, we showed that addition of allogeneic human CD4+ iNKT cells to human umbilical cord blood transplants led to dramatically improved hematopoietic engraftment in immunodeficient mice. The engraftment-promoting activity of iNKT cells was due to their interactions with cord blood monocytes that resulted in production of several potently pro-hematopoietic factors, including the cytokines GM-CSF and IL-3 (produced by iNKT cells), and PGE2 (produced by monocytes in response to signals from iNKT cells). Prior studies in murine models have established that cytokine programs and functional properties of iNKT cells are controlled by two key transcription factors, PLZF and E4BP4. How these transcription factors influence the cytokine profiles of human iNKT cells remains unclear, and specifically, their impact on iNKT cell production of GM-CSF and IL-3 and interactions with monocytes is not known. Aim 1 of this project proposes to generate human iPSC-derived iNKT cells lacking or over-expressing PLZF or E4BP4. Aim 2 will determine the impact of these transcription factors on the ability of iPSC-derived iNKT cells to promote human hematopoietic engraftment and on graft-versus-lymphoma (GVL) activity. Through these studies we will gain highly novel insight into the impact of PLZF and E4BP4 expression on iNKT functional properties, and we will establish the feasibility of generating iPSC-derived iNKT cells with modified transcription factor expression designed to stabilize specific functional programs. This will lay a foundation for designing iPSC-derived iNKT cells that are transcriptionally tuned to promote hematopoietic engraftment without adversely affecting GVL.

概括造血干细胞移植（HSCT）是各种恶性肿瘤的潜在治疗方法和其他血液学疾病，还具有治疗诸如艾滋病毒之类的传染病的希望。但是，HSCT受到诸如移植失败等并发症的高风险和死亡率的高风险（这导致对致命感染的敏感性很高）和白血病复发。改进的新策略因此，造血移植的结果将产生重大的临床影响。这个项目集中在在开发不变的自然杀伤（Inkt）细胞时，源自人类诱导的多能干细胞（IPSC）作为辅助性HSCT细胞疗法，旨在促进成功的造血植入。在最近发表的初步研究，我们表明将同种异体人CD4+ inkt细胞添加到人脐带血移植导致免疫缺陷的造血植入大大改善老鼠。 Inkt细胞的植入促进活动是由于它们与脐带血的相互作用单核细胞导致产生多种有效的促山地大学因素，包括细胞因子 GM-CSF和IL-3（由Inkt细胞产生）和PGE2（由单核细胞生产，以响应来自的信号 inkt细胞）。鼠模型中的先前研究已经确定了细胞因子程序和功能特性 inkt细胞的控制受两个关键转录因子PLZF和E4BP4的控制。这些转录因素如何影响人Inkt细胞的细胞因子特征尚不清楚，具体而言，它们对inkt细胞的影响 GM-CSF和IL-3的产生以及与单核细胞的相互作用尚不清楚。该项目的目标1提出为了产生缺乏或过表达PLZF或E4BP4的人IPSC衍生的Inkt细胞。 AIM 2将确定这些转录因子对IPSC衍生的Inkt细胞促进人的能力的影响造血植入和移植物与淋巴瘤（GVL）活性。通过这些研究，我们将获得对PLZF和E4BP4表达对Inkt功能特性的影响的高度新颖洞察力，我们将建立具有修饰转录因子表达的IPSC衍生的Inkt细胞的可行性旨在稳定特定的功能程序。这将为设计IPSC衍生的inkt奠定基础经转录调整以促进造血植入的细胞而不会不利影响GVL。