Regulatory T cells in allogeneic transplantation

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。 公共卫生相关性：调节免疫反应在许多不同的疾病状态中起着重要作用。在实验室研究中已经认识到，T细胞群体具有调节这些免疫应答的能力（称为调节性T细胞），并且可以深刻地影响这些疾病实体。该提案旨在通过使用高度纯化的调节性T细胞在骨髓移植的情况下治疗患者，将这些概念从实验室直接转化到临床。我们选择这种临床环境，因为我们相信这是证明调节细胞可以改善移植的最直接的方法，移植是恶性血液病和某些遗传性疾病患者的重要治疗方式。如果成功，这些研究可以改善骨髓移植，并为更广泛地使用调节性T细胞群治疗各种疾病打开大门。

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. PUBLIC HEALTH RELEVANCE: Regulated immune responses play a major role in a number of different disease states. It has been recognized in laboratory studies that populations of T cells have the ability to regulate these immune responses (termed regulatory T cells) and can profoundly impact these disease entities. This proposal aims to directly translate these concepts from the laboratory to the clinic by using highly purified regulatory T cells to treat patients in he setting of bone marrow transplantation. We have chosen this clinical setting since we believe it is the most direct way to demonstrate that the regulatory cells can improve transplantation which is an important treatment modality for patients with hematologic malignancies and certain genetic disorders. If successful, these studies could improve bone marrow transplantation and open the door to more general use of regulatory T cell populations for the treatment of a variety of diseases.