Development of novel strategies to modulate human NK cell response in xenotransplantation

开发在异种移植中调节人类 NK 细胞反应的新策略

基本信息

批准号：
10285145
负责人：
Ping Li
金额：
$ 23.78万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-21 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10285145
关键词：
Address African American Allografting Antibodies Asians Binding Binding Proteins CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene CRISPR/Cas technology Carbohydrates Cell Surface Proteins Cell physiology Cell-Mediated Cytolysis Cells Cessation of life Clinical Cytolysis Data Development Effector Cell Endothelial Cells Engineering Equilibrium Excision Family suidae Generations Genes Genetic Genetic Engineering Genetic study Goals HLA Antigens Hepatitis B e Antigens Heterophile Antigens Hispanics Histocompatibility Histocompatibility Antigens Class I Human Immune Immune Tolerance Immune response Immunoglobulins Immunomodulators Inflammatory Innate Immune System KLRD1 gene Killer Cells Lead Ligands Liver Mediating Methods Minority Modification NK Cell Activation Natural Killer Cells Organ Organ Transplantation Outcome Patients Pregnancy Production Property Public Health Receptor Cell Regulation Regulatory T-Lymphocyte Signal Pathway Signal Transduction T cell response Testing Tissues Transplantation Waiting Lists Xenograft procedure base chemokine clinical application cytokine cytotoxicity design experimental study fetal knockout gene novel strategies prevent receptor response trophoblast

项目摘要

PROJECT SUMMARY Xenotransplantation (i.e. cross-species transplantation using pig organ in human) offers a potential solution to address persistent organ shortage. Organ shortage more severely impacts minorities, such as African Americans, Asians, and Hispanics. However, pig-human incompatibility results in destructive human immune response and ultimate rejection of pig organs. The long-term goal of this proposal is to develop an effective and safe method to prevent the human immune response to transplanted pig cells, tissues, and organs. Human NK cell mediated-direct killing of porcine endothelial cells is one of the barriers in xenotransplantation. A balance of signals from porcine cell ligands and human NK cell receptors interaction determines human NK cell function. This proposal focuses on manipulation of porcine cell surface proteins to inhibit/block NK cells recognition and activation. In our preliminary data, we have demonstrated that expression of HLA-G on porcine cell inhibits NK cell activation and reduces pro-inflammatory cytokine production. An antibody mediated- blocking of NKG2D receptor can diminish NK cell activation. We hypothesize that manipulation of porcine ligands may abolish human NK cell-mediated cytotoxicity. Expression of inhibitory ligands and removal of activating ligands on porcine cells may induce NK cell tolerance and inhibition. The hypothesis will be addressed in the experiments of the following Specific Aims: 1) to determine the inhibition of human NK cell by co-expression of HLA class I molecules HLA-C, HLA-E, and HLA-G on porcine cells; and 2) to determine whether elimination of NKG2D porcine ligands blocks human NK cell recognition and activation. This exploratory study will expand our understanding of the mechanism of cross-species immune recognition and response, develop a novel approach to induce local immune tolerance/acceptance, and guide engineering of pigs to meet xenotransplantation needs.

项目概要异种移植（即使用猪器官进行人体跨物种移植）提供了一个潜在的解决方案解决持续的器官短缺问题。器官短缺对非洲等少数族裔影响更为严重美国人、亚洲人和西班牙人。然而，猪与人的不相容性会导致破坏性的人类免疫猪器官的反应和最终排斥。该提案的长期目标是制定有效的以及防止人体对移植的猪细胞、组织和器官产生免疫反应的安全方法。人NK细胞介导的对猪内皮细胞的直接杀伤是异种移植的障碍之一。猪细胞配体信号与人类 NK 细胞受体相互作用的平衡决定了人类 NK 细胞功能。该提案的重点是操纵猪细胞表面蛋白来抑制/阻断 NK 细胞识别和激活。在我们的初步数据中，我们已经证明 HLA-G 在猪上的表达细胞抑制 NK 细胞活化并减少促炎细胞因子的产生。抗体介导- 阻断 NKG2D 受体可以减少 NK 细胞的激活。我们假设对猪的操纵配体可以消除人类 NK 细胞介导的细胞毒性。抑制性配体的表达和去除激活猪细胞上的配体可能会诱导 NK 细胞耐受和抑制。假设将是在以下具体目标的实验中解决：1)确定对人NK细胞的抑制作用 HLA I 类分子 HLA-C、HLA-E 和 HLA-G 在猪细胞上的共表达； 2) 确定 NKG2D 猪配体的消除是否会阻碍人类 NK 细胞的识别和激活。这探索性研究将扩大我们对跨物种免疫识别机制的理解反应，开发一种新方法来诱导局部免疫耐受/接受，并指导工程猪以满足异种移植的需要。