Expansion of alloantigen reactive Tregs for transplantation tolerance

扩增同种抗原反应性 Tregs 以实现移植耐受

基本信息

批准号：
8079487
负责人：
Nagendra Singh
金额：
$ 18.19万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8079487
关键词：
Address Adverse effects Alloantigen Allogenic Animal Model Antibodies Antigens Apoptosis Apoptotic Binding CASP8 and FADD-like apoptosis regulating protein CD28 gene CD3 Antigens CD4 Positive T Lymphocytes Cell Culture Techniques Cell Death Cell Therapy Cells Clinic Disease Ectopic Expression Eragrostis Frequencies Graft Rejection Growth Human IL2RA gene Immune Tolerance Immunosuppressive Agents In Vitro Inbred BALB C Mice Ligation Link Longevity Mediating Methods Modeling Molecular Mus OVA 323-339 Organ Organ Transplantation Outcome Study Peptide/MHC Complex Pharmaceutical Preparations Population Procedures Regulatory T-Lymphocyte Role Signal Transduction Sirolimus Skin Transplantation Skin graft System T-Lymphocyte T-Lymphocyte Subsets Techniques Technology Testing Therapeutic Transgenic Mice Translating Transplantation Transplantation Tolerance Transplanted tissue base clinical application clinical efficacy density human disease improved knock-down novel peripheral blood public health relevance research study small hairpin RNA transcription factor

项目摘要

DESCRIPTION (provided by applicant): A small subset of T lymphocytes expresses FoxP3 and is called as regulatory T cells or Tregs. Transplantation of various organs is often required to treat many human diseases or disease-related complications. However, transplanted tissues need to survive rejection by host T lymphocytes. Host-derived donor-specific Tregs offer a natural way of suppressing rejection of transplanted organs without side effects or off targets associated with immunosuppressive drugs. Tregs are found at very low frequency and animal models have shown that large numbers of Tregs are required to achieve clinical efficacy; therefore elucidation of the mechanisms underlying the expansion of Tregs will facilitate the therapeutic application of this specific subset of T lymphocytes for induction of transplantation tolerance. We have found that sustained and clustered CD3 and CD28 signaling induces apoptosis of effector T cells and allows expansion of Tregs in less than 2 weeks. Unsorted human CD4 T cells (initially 6% FoxP3+ cells) cultured for 12 days under this condition were highly enriched for Tregs (>75% cells Foxp3+ cells at end of culture). Therefore, this procedure has great promise and potential for clinical application of Tregs. The proposed study will investigate in detail the expansion of donor reactive Tregs from mice and humans for induction of transplantation tolerance and elucidate the mechanism of selective Treg expansion in this system. Aim 1 will test the hypothesis that Treg specific transcription factor FoxP3 actively suppresses apoptosis in this system, allowing selective proliferation and expansion of Tregs. Aim 2 will employ MHC-peptide tetramers for induction of TCR ligation to test the hypothesis that sustained and clustered signaling by immobilized MHC-peptide tetramers and anti-CD28 selectively expand alloantigen specific functional Tregs from mice and humans. The outcome of these studies will greatly facilitate clinical application of Tregs to improve transplantation tolerance. PUBLIC HEALTH RELEVANCE: Regulatory T cells offer a natural way of inducing longevity of transplanted organs to recipients without side effects. Using a novel system, proposed study aims to expand alloreactive Tregs to facilitate the long term acceptance of transplanted tissue to mismatch recipients.

描述（由申请人提供）：一小部分T淋巴细胞表达FOXP3，称为调节性T细胞或Tregs。通常需要各种器官的移植来治疗许多人类疾病或与疾病有关的并发症。然而，移植的组织需要在宿主T淋巴细胞排斥下存活。宿主衍生的供体特异性Treg提供了一种自然的方式，可以抑制对没有副作用或与免疫抑制药物相关的无副作用的移植器官排斥的方式。发现Treg的频率非常低，动物模型表明，达到临床疗效需要大量Treg。因此，阐明Treg扩展的机制将有助于该特定T淋巴细胞的特定子集的治疗应用以诱导移植耐受性。我们发现，持续和聚集的CD3和CD28信号传导会诱导效应T细胞的凋亡，并在不到2周内扩大Treg。在这种情况下，未分类的人CD4 T细胞（最初为6％FOXP3+细胞）在这种情况下培养了12天的Treg（培养结束时> 75％的细胞Foxp3+细胞）。因此，此程序具有巨大的希望和临床应用的潜力。拟议的研究将详细研究小鼠和人类的供体反应性Treg的扩展，以诱导移植耐受性，并阐明该系统中选择性Treg扩展的机制。 AIM 1将检验以下假设：Treg特异性转录因子FOXP3主动抑制该系统中的凋亡，从而可以选择性增殖和treg的扩展。 AIM 2将采用MHC肽四聚体诱导TCR连接，以测试固定的MHC肽四聚体持续和聚集信号传导的假设，而抗CD28选择性地扩展了从小鼠和人类和人类中的同种抗原特异性功能性Treg。这些研究的结果将极大地促进Treg的临床应用以提高移植耐受性。公共卫生相关性：调节性T细胞提供了一种自然的方式，可以将移植器官延长到没有副作用的受体。拟议的研究使用新的系统旨在扩大同种异体反应性Treg，以促进移植组织对不匹配受体的长期接受。