Induction of allogeneic tolerance with bioengineered thymus organoids

用生物工程胸腺类器官诱导同种异体耐受

基本信息

批准号：
9082794
负责人：
YONG FAN
金额：
$ 38.36万
依托单位：
ALLEGHENY-SINGER RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-15 至 2019-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9082794
关键词：
3-Dimensional Address Adult Adverse effects Aging Alloantigen Allogenic Antigens Autoantigens Autoimmune Diabetes Autoimmune Diseases Autoimmune Process Autoimmunity Beta Cell Biomedical Engineering Cell Culture Techniques Cell Lineage Cell Transplants Cells Chronic Data Development Diabetic mouse Disease Embryo Extracellular Matrix Genetic Goals Graft Rejection Growth Homing Human Hydrogels Immune Immune Tolerance Immune system Immunization Immunosuppressive Agents In Vitro Individual Infection Insulin Insulin-Dependent Diabetes Mellitus Invaded Investigation Lymphocyte Lymphopoiesis Major Histocompatibility Complex Malignant Neoplasms Modeling Modification Molecular Nude Mice Organ Organ Donor Organ Transplantation Organoids Ovalbumin Peptides Pharmaceutical Preparations Pharmacotherapy Population Population Heterogeneity Prevention Property Regenerative Medicine Research Research Project Grants Self Tolerance Signal Pathway Skin graft Solid Source Stem cells Stromal Cells Structure of beta Cell of islet System T-Cell Development T-Lymphocyte Techniques Technology Thymic epithelial cell Thymus Gland Translating Transplantation Vascularization adaptive immunity allograft rejection autoreactive T cell base central tolerance clinical application design driving force improved in vivo innovation irradiation islet islet allograft pathogen postnatal prevent progenitor public health relevance research study response scaffold skin allograft transplantation medicine

项目摘要

DESCRIPTION: Chronic rejection of allografts remains a major hurdle in organ transplantation and regenerative medicine. While immunosuppressive drugs can prevent graft rejection to a certain degree, their efficacies are limited and often associate with severe side effects. The underlying problem is that new T-cells reactive to alloantigens are continuously generated from the thymus. While numerous efforts have been made to modulate thymic function to induce donor-specific immune tolerance, manipulating the thymus proves to be difficult. One major challenge is to reproduce its unique extracellular matrix microenvironment that is critical for the survival and function of thymic epithelial cells (TECs), the predominant population of thymic stromal cells that are essential for the development of T-cells and for defining the "immunological self" of an individual (the capability to distinguish self from non-self molecules i the body and respond accordingly). Here, we propose an innovative bioengineering approach to modulate the thymus function. We have recently developed a thymus decellularization technique, which allows us to reconstruct a functional thymus organoid de novo with isolated TECs. Athymic mice engrafted with the bioengineered thymus are able to develop strong humoral responses against model antigen ovalbumin and promptly reject skin allografts. Conversely, tolerance to allogeneic skin grafts can be achieved by transplanting thymus organoids co-expressing both donor and recipient's major histocompatibility complex (MHC) molecules. Based on these observations, we hypothesize that the bioengineered thymus organoid can recapitulate the function of a thymus in vivo, and are able to redefine the "immunological self" of the adaptive immune system. Given that the major translational experimental focus in our group is on Type 1 diabetes (T1D), in which the insulin-secreting beta cells of the pancreas becomes targets of autoimmune destruction due to loss of self-tolerance, we will focus our investigation on whether the bioengineered thymus organoids can re-establish immune tolerance to beta-cells. Furthermore, we will investigate whether we can simultaneously induce donor-specific immune tolerance to islet allografts with the thymus bioengineering technology. Experiments in Aim 1 will optimize the construction of the thymus organoids from decellularized thymic scaffolds in vitro. Our focus in Aim 2 is to optimize the long-term survival and function of the bioengineered thymus organoids in vivo. Experiments in Aim 3 is to demonstrate that the bioengineered thymus constructed with insulin- expressing allogeneic TECs can effectively modulate the adaptive immune system to reverse insulin-autoimmunity, one of the primary driving forces for T1D progression, and to establish immune tolerance of islet allografts. The long-term goal of the research project is to translate the thymus bioengineering technique into clinical applications.

描述：同种异体移植的慢性拒绝仍然是器官移植和再生医学的重大障碍。虽然免疫抑制药物可以在一定程度上防止等级排斥，但其有效性是有限的，并且通常与严重的副作用有关。潜在的问题是，新的T细胞对同种抗原的反应是由胸腺不断产生的。尽管已做出了许多努力来调节胸腺功能以诱导供体特异性免疫耐受性，但操纵胸腺被证明很困难。一个主要挑战是复制其独特的细胞外基质微环境，这对于胸腺上皮细胞（TEC）的存活和功能，TECS是胸腺基质细胞的主要种群，这些细胞对T细胞的发展至关重要，并确定一个个体的“免疫学自我”（将自我与非自身分子与身体I区分开并做出相应反应的能力）。在这里，我们提出了一种创新的生物工程方法来调节胸腺功能。我们最近开发了一种胸腺脱细胞技术，这使我们能够用孤立的TEC重建功能性的胸腺类器官。植入生物工程胸腺的无胸腺小鼠能够针对模型抗原卵巢蛋白产生强烈的体液反应，并迅速拒绝皮肤同种异体移植物。相反，可以通过移植胸腺器官共同表达供体和受体的主要组织相容性复合物（MHC）分子来实现对同种层皮肤移植物的耐受性。基于这些观察结果，我们假设生物工程的胸腺类细胞器可以概括体内胸腺的功能，并能够重新定义适应性免疫学系统的“免疫学自我”。鉴于我们小组中的主要翻译实验重点是1型糖尿病（T1D），其中胰腺的分泌胰岛素分泌β细胞成为自身免疫性破坏的靶标，因此我们将由于失去自我耐受性而将研究重点放在生物加工的胸腺素质体是否可以重建免疫耐受性上，以便重新建立免疫耐受性。此外，我们将研究是否可以通过胸腺生物工程技术轻松地诱导对胰岛同种异体移植物的特异性免疫耐受性。 AIM 1中的实验将优化体外脱细胞胸腺支架的胸腺器官的结构。我们在目标2上的重点是优化体内生物工程胸腺类器官的长期生存和功能。目标3中的实验是证明，用表达胰岛素的同种异体TEC构建的生物工程性胸腺可以有效地调节适应性免疫学系统，以逆转胰岛素自动免疫性，这是T1D进展的主要驱动力之一，并建立了Islet同型同型同症的免疫学耐受性。研究项目的长期目标是将胸腺生物工程技术转化为临床应用。