Immunomodulation Requirements for Treg Immunotherapy for autoimmune diabetes

自身免疫性糖尿病 Treg 免疫治疗的免疫调节要求

基本信息

批准号：
8707637
负责人：
Allison Lorayne Bayer
金额：
$ 36.07万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-15 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8707637
关键词：
Address Adoptive Transfer Alloantigen Allogeneic Bone Marrow Transplantation Allogenic Allografting Antibodies Antigens Autoimmune Diabetes Autoimmune Diseases Autoimmune Process Autoimmunity Autologous Biological Cell Count Cell Therapy Cell physiology Cells Chronic Clinical Clinical Data Clinical Trials Complex Complication Cyclophosphamide Data Dependence Diabetes Mellitus Disease Donor person Dose Engraftment Eragrostis Future Goals Graft Rejection Human Immune response Immune system Immunosuppression Immunotherapy Inbred NOD Mice Infusion procedures Injection of therapeutic agent Insulin Insulin-Dependent Diabetes Mellitus Interleukin-2 Islets of Langerhans Transplantation Laboratories Life Longevity Longitudinal Studies Lymphocyte Depletion Modeling Mus Neonatal Pancreas Pancreas Transplantation Patients Peripheral Pharmaceutical Preparations Population Pre-Clinical Model Prevention Process Production Reagent Recurrence Recurrent disease Regimen Regulatory T-Lymphocyte Research Research Proposals Self Tolerance Signal Transduction Sirolimus Specificity Testing Therapeutic Therapeutic Effect Therapeutic Uses Thymus Gland Tissues Transplantation Transplantation Tolerance Transplanted tissue Treatment Efficacy Treatment Protocols Work base clinically relevant combinatorial design graft vs host disease immunoregulation in vivo insulin secretion interest microorganism novel peripheral tolerance pre-clinical prevent research study response skin allograft success

项目摘要

DESCRIPTION (provided by applicant): Our work focuses on T regulatory (Treg) cells, which inhibit both self and allogeneic immune responses making these cells attractive for novel cell-based therapy approaches to promote tolerance and control autoimmune diseases, including type 1 diabetes. However, the use of these cells for therapy is hindered by the inability to generate the sufficient number of cells required to inhibit the desired immune response(s) and achieve stable engraftment of the donor Treg cell inoculums. Furthermore, the constant production of Treg cells from the thymus creates a continuous, competitive barrier that our laboratory has demonstrated must be overcome in order to successfully use Treg cells for therapy. Previous studies from our laboratory demonstrate that the single adoptive transfer of Treg cells into neonatal IL-2R¿-/- mice, which have impaired IL-2 signaling and Treg cell function, fully prevents severe autoimmunity that would otherwise be lethal for these mice in a matter of a few weeks. Therapy with wild-type Treg cells allows these mice to remain autoimmune-free and to have a normal life span, and is accompanied by life-long donor Treg cell engraftment. Importantly, we show that allo-Treg cells also engraft which confers tolerance to skin allografts and restores self-tolerance. These findings show that under the right biological conditions adoptive transfer of even a small, unmanipulated number of Treg cells is very effective at achieving tolerance and results in long-term engraftment. This IL-2R¿-/- model offers some clues to the mechanisms that may be required for successful therapy. The overall goals of this proposal are: 1) to elucidate the mechanisms that regulate successful Treg therapy and 2) to develop clinically translatable protocols for the treatment of T1D, using preclinical models to investigate if clinically applicable Treg therapy can be achieved for the prevention or reversal of autoimmune diabetes or to suppress graft rejection of islet cell transplantation for the treatment of diabetes. The present research proposal is designed to test the hypothesis that stable donor Treg engraftment requires immunomodulation and that there is in vivo biological selection by antigen for therapeutic Tregs leading to successful immunotherapy. Based on this hypothesis, the specific aims of this proposal are: 1) to identify mechanisms that promote stable donor Treg engraftment in NOD mice through immunomodulation with clinically translatable combinatorial regimens. and 2) to determine whether selection and expansion of antigen (Ag)-specific donor Tregs occurs following aCD3 and Treg infusion. This research will generate novel data that are required for the design of successful therapies based on Treg cells. Further, the demonstration of therapeutic synergy with agents that have been or are being used in clinical trials for new onset diabetes will provide impetus and needed pre-clinical data for the design of future clinical trials that combine adoptive Treg transfer with immunomodulation, and perhaps antigen-specific therapies.

描述（由适用提供）：我们的工作着重于调节性（TREG）细胞，这些细胞抑制了自我和同种异体免疫调查，使这些细胞对基于新型细胞的治疗方法有吸引力，以促进耐受性和控制自身免疫性疾病，包括1型糖尿病。然而，由于无法产生抑制所需的免疫响应所需的足够数量的细胞并实现供体Treg细胞接种物的稳定参与所需的足够数量的细胞，因此阻碍了这些细胞进行治疗。此外，胸腺的treg细胞持续产生会产生一个连续的竞争障碍，我们的实验室证明必须克服，以便成功使用Treg细胞进行治疗。我们实验室的先前研究表明，将Treg细胞的单一继产传递到新生儿IL-2R = - / - 小鼠中，这些小鼠损害了IL-2信号传导和Treg细胞功能，完全阻止了严重的自身免疫性，否则这些小鼠在几周内对这些小鼠来说是致命的。用野生型Treg细胞的治疗使这些小鼠保持无自身免疫性并具有正常的寿命，并伴有终身供体Treg细胞植入。重要的是，我们表明Allo-Treg细胞还植入了传达对皮肤同种异体移植物的耐受性并恢复自我耐受性的细胞。这些发现表明，在正确的生物学下条件即使是少数未经操纵的Treg细胞的适应性转移也非常有效地实现耐受性并导致长期植入。该IL-2R�-/ - 模型为成功治疗所需的机制提供了一些线索。该提案的总体目标是：1）阐明调节成功Treg治疗的机制，以及2）使用临床上的模型开发用于临床转换的T1D治疗方案，以研究是否可以为预防或反向进行临床适用的Treg治疗自身免疫性糖尿病或仅抑制胰岛细胞移植的谷物排斥以治疗糖尿病。本研究建议旨在检验以下假设：稳定的供体Treg植入需要免疫调节，并且抗原对治疗性TREG有体内生物学选择，从而成功进行免疫疗法。基于这一假设，该提案的具体目的是：1）确定通过临床翻译的组合方案的免疫调节来促进NOD小鼠中稳定的供体Treg植入的机制。 2）确定在ACD3和Treg输注后，是否会选择和扩展抗原（Ag）特异性供体Treg。这项研究将生成基于Treg细胞成功疗法设计所需的新数据。此外，与已在临床试验中使用或已在新发作糖尿病中使用的药物的热协同作用将提供动力和所需的临床前数据，以设计将来的临床试验，这些试验将适应性Treg转移与免疫调节和可能的抗原特异性疗法相结合。