Role of Dendritic Cells in Mixed Chimerism and Tolerance

树突状细胞在混合嵌合和耐受中的作用

• 批准号: 9127921
• 负责人: EDGAR G. ENGLEMAN
• 金额: $ 39.89万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9127921
• 关键词: Antithymoglobulin; Bone Marrow; Bone Marrow Transplantation; CD8 Antigens; CD8B1 gene; Cell Communication; Cell Transplants; Cells; Chimerism; Clinical Protocols; Clinical Research; Complex; Cross-Priming; Dendritic Cells; Development; Engraftment; Equilibrium; Goals; Haplotypes; Health; Hematopoietic; ITGAM gene; ITGAX gene; Immune; Immune Tolerance; Immune system; Interleukin-10; Interleukin-4; Kidney; Kidney Transplantation; Knock-out; Lead; Lymphatic Irradiation; Lymphoid Tissue; Maintenance; Mediating; Molecular; Mus; Myelogenous; Organ; Organ Transplantation; Patients; Pattern; Pharmaceutical Preparations; Play; Population; Process; Receptor Signaling; Regimen; Regulatory T-Lymphocyte; Reporting; Research; Research Design; Role; Serum; Signal Pathway; Suppressor-Effector T-Lymphocytes; Surface; System; T-Lymphocyte; Withdrawal; base; cell type; conditioning; cytokine; cytopenia; design; genetic manipulation; graft vs host disease; killer T cell; mouse model; research study; response; thymocyte

 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.

 描述（由适用提供）：我们的临床研究表明，将肾脏和造血细胞移植的结合患者与总淋巴样辐射（TLI）和抗心理细胞球蛋白可靠地诱导的混合嵌合体和抗肾脏的容忍度相结合的患者，不带HLA匹配的肾脏抗拒的药物抗拒的肾脏，并诱发了混合嵌合式的携带，并诱发了混合的嵌合体。严重的并发症。有希望的临床研究表明，这种方法还诱导HLA单倍型与患者相匹配的持续混合嵌合体，尽管尚未尝试在这些嵌合患者中戒断抗排斥药物。拟议的研究的目的是通过在特征良好的小鼠模型中进行研究来确定TLI和抗心理细胞血清（ATS）诱导的耐受性诱导的细胞和分子基础。我们先前在小鼠中进行的实验，此外，调节方案改变了免疫细胞的平衡，以偏爱CD8+ DC和NKT细胞，并导致其激活。研究旨在阐明TLI/ATS调节对髓样DC亚群和NKT细胞的细胞因子分泌模式以及功能的影响，以及这些影响如何影响DCS和NKT细胞之间的相互作用，从而促进公差。鉴于浆细胞样DC的子集抑制同种免疫反应，我们还将分析供体骨髓DC在TLI/ATS耐受诱导中的作用。拟议的研究将导致对负责耐受性诱导基于TLI/ATS的调节的机制的详细理解，从而使增强的临床方案得以发展，以实现HLA不匹配的器官和血小质细胞移植剂的耐受性。