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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.

总结造血干细胞移植（HSCT）是一种治疗多种恶性肿瘤的有效方法和其他血液疾病，并且也有望用于治疗感染性疾病如HIV。然而，HSCT受到并发症（如移植失败）的高发病率和死亡率风险的限制（这导致对致命感染的高度易感性）和白血病复发。新的战略，以改善因此，造血移植的结果将具有显著的临床影响。该项目重点开发来自人类诱导多能干细胞（iPSC）的不变自然杀伤T（iNKT）细胞作为辅助HSCT细胞疗法，旨在促进成功的造血移植。在最近发表的初步研究，我们表明，加入同种异体人CD 4 + iNKT细胞，脐带血移植显著改善了免疫缺陷患者的造血植入，小鼠iNKT细胞的移植促进活性是由于它们与脐带血的相互作用单核细胞，导致产生几种有效的促造血因子，包括细胞因子 GM-CSF和IL-3（由iNKT细胞产生）和PGE 2（由单核细胞响应来自 iNKT细胞）。先前在小鼠模型中的研究已经确定，细胞因子程序和功能特性 iNKT细胞的增殖受两个关键转录因子PLZF和E4 BP 4控制。这些转录因子是如何影响人iNKT细胞的细胞因子谱尚不清楚，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提出以产生缺乏或过表达PLZF或E4 BP 4的人iPSC衍生的iNKT细胞。目标2将决定这些转录因子对iPSC衍生的iNKT细胞促进人类免疫应答的能力的影响。造血植入和移植物抗淋巴瘤（GVL）活性。通过这些研究， PLZF和E4 BP 4表达对iNKT功能特性的影响的高度新颖的见解，我们将建立产生具有修饰的转录因子表达的iPSC衍生的iNKT细胞的可行性用于稳定特定的功能程序。这将为设计iPSC衍生的iNKT奠定基础在转录上被调节以促进造血移植而不会不利地影响GVL的细胞。