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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细胞（Treg），其抑制自身和同种异体免疫应答，使这些细胞对基于细胞的新型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，由于不能产生抑制所需免疫应答和实现供体Treg细胞接种物的稳定植入所需的足够数量的细胞，这些细胞用于治疗的用途受到阻碍。此外，从胸腺持续产生Treg细胞产生了一个持续的竞争性障碍，我们的实验室已经证明必须克服这个障碍才能成功地使用Treg细胞进行治疗。我们实验室以前的研究表明，Treg细胞单次过继转移到新生IL-2 R-/-小鼠中，这些小鼠具有受损的IL-2信号传导和Treg细胞功能，完全防止了严重的自身免疫，否则这些小鼠在几周内就会致命。用野生型Treg细胞治疗允许这些小鼠保持无自身免疫并具有正常的寿命，并且伴随着终身供体Treg细胞移植。重要的是，我们表明同种异体Treg细胞也移植，这赋予对皮肤同种异体移植物的耐受性并恢复自身耐受性。这些发现表明，在正确的生物学条件下，在某些条件下，过继转移即使是小的、未操作数量的Treg细胞在实现耐受性方面也是非常有效的，并导致长期植入。这种IL-2 R-/-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Treg治疗的机制，和2）开发用于治疗T1 D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治疗以预防或逆转T1 D。自身免疫性糖尿病或抑制移植排斥的胰岛细胞移植用于治疗糖尿病。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，并且治疗性Treg的抗原存在体内生物选择，从而导致成功的免疫治疗。基于这一假设，该提议的具体目的是：1）鉴定通过用临床上可转化的组合方案进行免疫调节来促进NOD小鼠中稳定的供体Treg植入的机制。和2）确定aCD 3和Treg输注后是否发生抗原（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。此外，与已经或正在用于新发糖尿病的临床试验中的药剂的治疗协同作用的证明将为设计未来的临床试验提供动力和所需的临床前数据，所述临床试验将联合收割机过继性Treg转移与免疫调节以及可能的抗原特异性疗法组合。