Role of Dendritic Cells in Mixed Chimerism and Tolerance

 描述（由申请人提供）：我们的临床研究已经证明，给予肾和造血细胞联合移植的患者接受全淋巴照射（TLI）和抗胸腺细胞球蛋白的预处理，在HLA匹配的患者中可靠地诱导混合嵌合体和对移植肾的耐受，从而能够完全停用抗排斥药物，而不会出现血细胞减少、移植物抗宿主病或其他严重并发症。有前途的临床研究表明，这种方法也诱导持久的混合嵌合体在HLA单倍型匹配的患者，虽然抗排斥药物的撤回尚未尝试在这些嵌合体患者。拟议研究的目标是通过在充分表征的小鼠模型中进行研究，确定TLI和抗胸腺细胞血清（ATS）诱导耐受诱导的细胞和分子基础。我们先前在小鼠中的实验表明，由TLI/ATS诱导的稳定的混合嵌合和耐受依赖于CD 8+抗原交叉致敏的髓样DC和I型不变NKT细胞两者的存在，因为在Batf 3-/-和Ja 18-/-受体中不能诱导耐受，所述受体分别特异性地缺乏交叉致敏的DC和不变NKT细胞。此外，预处理方案改变了免疫细胞的平衡，有利于CD 8 + DC和NKT细胞，并导致其活化。研究旨在阐明TLI/ATS调节对髓样DC亚群和NKT细胞的表面标志物、细胞因子分泌模式和功能的影响，以及这些影响如何影响DC和NKT细胞之间促进耐受性的相互作用。我们还将分析供体骨髓DCs在TLI/ATS耐受诱导中的作用，考虑到浆细胞样DCs亚群抑制同种免疫应答的能力。拟议的研究将导致详细了解的机制，负责耐受诱导TLI/ATS为基础的空调，从而使增强的临床协议的发展，实现HLA不匹配的器官和造血细胞移植的耐受性。

 DESCRIPTION (provided by applicant): Our clinical studies have demonstrated that conditioning patients given combined kidney and hematopoietic cell transplants with total lymphoid irradiation (TLI) and anti-thymocyte globulin reliably induces mixed chimerism and tolerance to the transplanted kidney in HLA matched patients, enabling complete withdrawal of anti-rejection medications without cytopenias, graft versus host disease or other serious complications. Promising clinical studies indicate that this approach also induces persistent mixed chimerism in HLA haplotype matched patients, although withdrawal of anti-rejection medications has not yet been attempted in these chimeric patients. The goal of the proposed research is to determine the cellular and molecular basis for tolerance induction induced by TLI and anti-thymocyte serum (ATS) through studies in well-characterized mouse models. Our previous experiments in mice indicate that stable mixed chimerism and tolerance induced by TLI/ATS is dependent on the presence of both CD8+ antigen cross-priming myeloid DCs and type I invariant NKT cells, since tolerance cannot be induced in Batf3-/- and Ja18-/- recipients, which specifically lack cross priming DCs and invariant NKT cells, respectively. In addition, the conditioning regimen changes the balance of immune cells to favor CD8+ DCs and NKT cells, and results in their activation. Studies are designed to elucidate the effect of TLI/ATS conditioning on surface markers, cytokine secretion patterns and functions of the myeloid DC subsets and NKT cells, and how these effects impact the interactions between the DCs and NKT cells that promote tolerance. We will also analyze the role of donor bone marrow DCs in TLI/ATS tolerance induction, given the capacity of a subset of plasmacytoid DCs to suppress alloimmune responses. The proposed studies will lead to a detailed understanding of the mechanisms responsible for tolerance induction in TLI/ATS based conditioning, and thereby enable the development of enhanced clinical protocols for achieving tolerance in HLA mismatched organ and hematopoietic cell transplants.