Regulatory T cells in allogeneic transplantation

描述(申请人提供)：免疫调节对健康和疾病至关重要。这一点在异基因造血细胞移植后表现得尤为明显，在异基因造血细胞移植后，免疫反应失调会导致移植物抗宿主病(GVHD)，而有效的免疫识别会控制潜在的疾病，即移植物抗肿瘤效应。在这个方案中，我们将研究免疫反应的关键调节因子，即CD4CD25 CD127loFoxP3调节性T细胞(Treg)，它们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反应。由于抑制了有害的同种异体免疫效应，这也会影响免疫组织，所以在一定剂量下，Treg与常规的CD4和CD8细胞(Tcon)一起使用也能导致更有效的免疫恢复。此外，许多研究表明，Treg也可以用于治疗慢性GVHD。因此，该建议的目的是直接将临床前动物研究中发展起来的生物学概念转化为TE假设，即过继转移高纯度Treg将导致GVHD的控制，同时促进加速免疫重建，以及治疗慢性GVHD。该提案涉及两项临床试验，两项试验都利用了通过IRB和IND批准的临床方案进行高速细胞分选分离的高度纯化的Treg群体。这些研究将把重要的生物学概念从实验室直接转化为临床。如果成功，这些研究可能会对异基因造血细胞移植领域产生重大影响，并可能为自身免疫性疾病的新疗法和诱导实体器官移植耐受奠定基础。

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.