Regulatory T cells in allogeneic transplantation

同种异体移植中的调节性T细胞

• 批准号: 9065603
• 负责人: Robert S Negrin
• 金额: $ 52.2万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9065603
• 关键词: Acute; Adoptive Transfer; Allogenic; Animal Model; Animals; Antigens; Asthma; Autoimmune Diseases; Autoimmune Process; Biological; Biological Models; Biological Response Modifiers; Blood Cells; Bone Marrow Transplantation; CD34 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Calcineurin inhibitor; Cell Separation; Cell Therapy; Cells; Chronic; Clinic; Clinical; Clinical Protocols; Clinical Trials; Diabetes Mellitus; Disease; Dose; Drug usage; Funding Opportunities; Goals; Graft Rejection; Graft-Versus-Tumor Induction; Health; Hematologic Neoplasms; Hematopoietic; Hereditary Disease; Histocompatibility; Homologous Transplantation; IL2RA gene; IL7R gene; Immune; Immune response; Immunosuppressive Agents; Inflammatory Bowel Diseases; Infusion procedures; Institutional Review Boards; Interleukin-7; Intervention; Laboratories; Laboratory Study; Malignant - descriptor; Minor; Modality; Multiple Sclerosis; Mus; Organ Transplantation; Patients; Phase; Play; Population; Reaction; Recovery; Recurrence; Regulation; Regulatory T-Lymphocyte; Research; Risk; Role; Sirolimus; Solid; Speed; Staging; T-Cell Depletion; T-Lymphocyte; Technology; Testing; Time; Tissues; Toxic effect; Translating; Translations; Transplantation; Transplantation Tolerance; Treatment Protocols; base; bone marrow failure syndrome; cell preparation; chronic graft versus host disease; conditioning; effective therapy; graft vs host disease; hematopoietic cell transplantation; high risk; improved; improved outcome; mouse model; peripheral blood; pre-clinical; receptor; reconstitution; response; study population; transcription factor

DESCRIPTION (provided by applicant): Immune regulation is critical in health and disease. Nowhere is this clearer than following allogeneic hematopoietic cell transplantation where dysregulated immune responses result in graft-versus-host disease (GVHD) and effective immune recognition results in control of the underlying disease, termed graft-versus- tumor effects. In this proposal, we will study the key regulators of immune reactions, namely CD4+CD25+CD127loFoxP3+ regulatory T cells (Treg) which have been demonstrated to have profound effects on control of GVHD in murine models, yet allow for GVT responses. Due to the suppression of the deleterious alloimmune effects which can also impact immune tissues, the use of Treg at defined doses along with conventional CD4 and CD8 cells (Tcon) has also resulted in more effective immune recovery. Further, it has been suggested by a number of studies that Treg can also be used to treat chronic GVHD. Therefore, the aims of this proposal are to directly translate the biological concepts developed in preclinical animal studies to test te hypothesis that the adoptive transfer of highly purified Treg will result in control of GVHD, yet promote accelerated immune reconstitution, as well as treat chronic GVHD. The Proposal involves two clinical trials both utilizing highly purified populations of Treg isolated by high-sped cell sorting through IRB and IND approved clinical protocols. The studies will directly translate important biological concepts from the laboratory to the clinic. If successful the studies could have a major impact on the field of allogeneic hematopoietic cell transplantation and could also set the stage for new treatments of autoimmune disorders and induction of solid organ transplantation tolerance.

描述（由申请人提供）：免疫调节在健康和疾病中至关重要。没有什么比异基因造血细胞移植更清楚的了，在异基因造血细胞移植中，失调的免疫应答导致移植物抗宿主病（GVHD），有效的免疫识别导致控制潜在疾病，称为移植物抗肿瘤效应。在这个提议中，我们将研究免疫反应的关键调节因子，即CD4+CD25+CD127loFoxP3+调节性T细胞（Treg），其已被证明在小鼠模型中对GVHD的控制具有深远的影响，但允许GVT应答。由于抑制了也可影响免疫组织的有害同种免疫效应，以限定剂量沿着使用Treg以及常规CD 4和CD 8细胞（Tcon）也导致了更有效的免疫恢复。此外，许多研究表明Treg也可用于治疗慢性GVHD。因此，本提案的目的是直接转化临床前动物研究中开发的生物学概念，以验证高度纯化Treg的过继转移将导致GVHD控制，但促进加速免疫重建以及治疗慢性GVHD的假设。该提案涉及两项临床试验，均使用通过IRB和IND批准的临床方案通过高速细胞分选分离的高度纯化的Treg群体。这些研究将直接将重要的生物学概念从实验室转化为临床。如果成功，这些研究可能对异基因造血细胞移植领域产生重大影响，也可能为自身免疫性疾病的新治疗和诱导实体器官移植耐受奠定基础。