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（由申请人提供）：我们的工作重点是调节性 T (Treg) 细胞，它抑制自身和同种异体免疫反应，使这些细胞对新型细胞治疗方法具有吸引力，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，由于无法产生足够数量的细胞来抑制所需的免疫反应并实现供体 Treg 细胞接种物的稳定植入，因此使用这些细胞进行治疗受到阻碍。胸腺持续产生 Treg 细胞会产生持续的、竞争性的障碍，我们的实验室已经证明，为了成功地使用 Treg 细胞进行治疗，必须克服这一障碍。 2R?? -/- IL-2 信号传导和 Treg 细胞功能受损的小鼠可以完全预防严重的自身免疫，否则这些小鼠会在几周内致命。用野生型 Treg 细胞治疗可以使这些小鼠保持自身免疫。 -自由且具有正常的寿命，并且伴随着终生供体Treg细胞植入。重要的是，我们表明同种异体Treg细胞也植入，这赋予了皮肤同种异体移植物的耐受性和恢复。这些发现表明，在正确的生物学条件下。在这种IL-2R的条件下，即使是少量、未经操作的Treg细胞的过继转移也能非常有效地实现耐受并导致长期植入。 -/- 模型为成功治疗可能需要的机制提供了一些线索，该提案的总体目标是：1) 阐明调节成功的 Treg 治疗的机制；2) 开发用于治疗 T1D 的临床可转化方案。，使用临床前模型来研究是否可以实现临床适用的 Treg 疗法来预防或逆转自身免疫性糖尿病或抑制用于治疗糖尿病的胰岛细胞移植的排斥反应本研究计划旨在检验以下假设：稳定的供体 Treg 植入需要免疫调节，并且通过抗原对治疗性 Treg 进行体内生物选择，从而导致成功。基于这一假设，该提案的具体目标是：1）确定通过临床可转化的组合方案进行免疫调节促进 NOD 小鼠中稳定供体 Treg 植入的机制。 2) 确定aCD3和Treg输注后是否会发生抗原(Ag)特异性供体Treg的选择和扩增。这项研究将产生设计基于Treg细胞的成功疗法所需的新数据。与已经或正在用于新发糖尿病临床试验的药物的协同作用将为未来临床试验的设计提供动力和所需的临床前数据，这些临床试验将过继性 Treg 转移与免疫调节以及可能的抗原特异性疗法相结合。