Improving Immune Reconstitution via Cytokine-Mediated Expansion of Transplanted

通过细胞因子介导的移植物扩增改善免疫重建

• 批准号: 8260367
• 负责人: KENNETH I WEINBERG
• 金额: $ 30.52万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8260367
• 关键词: Adoptive Transfer; Aging; B-Lymphocytes; Biological; Bone Marrow Transplantation; CD34 gene; Cells; Clinical Research; Commit; Common Lymphoid Progenitor; Cytokine Signaling; Cytomegalovirus Infections; Development; Evaluation; Funding; Gene Expression; Generations; Goals; Grant; Growth; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Immune; Immunity; In Vitro; Infection; Interleukin 7 Receptor; Interleukin-7; Kinetics; Lead; Ligands; Lymphocyte; Lymphoid; Marrow; Mature B-Lymphocyte; Measures; Mediating; Murid herpesvirus 1; Mus; Myelogenous; Pathway interactions; Population; Prevention; Recovery; Relative (related person); Resistance; Risk; Signal Transduction; Stem Cell Factor; T-Cell Depletion; T-Cell Development; T-Lymphocyte; Testing; Therapeutic Uses; Thymus Gland; Transplantation; Work; cytokine; graft vs host disease; immune function; improved; in vivo; leukemia/lymphoma; progenitor; reconstitution; response

Following hematopoietic stem cell transplantation (HSCT), there are twopathways forI lymphocyte reconstitution. Transplantation of pre-formed T lymphocytes can result in adoptive transfer of competent donor-derived T lymphocytes, albeit with a restricted repertoire and the potential for alloreactivity and the risk of graft-versus-host disease (GVHD). Transplantation of hematopoietic stem cells (HSC) or committed lymphoid progenitors can result in generation of donor-derived T lymphocytes, which have a broad repertoire and were selected by the host thymus, resulting in host tolerance. When the donor graft has been highly enriched for HSC by CD34 selection and/or T cell depletion, post-HSCT immune reconstitution is dependent on the latter thymus-dependent pathway for T lymphocyte development. Post-HSCT T cell development is inherently delayed because of normally slow ontogeny and microenvironmental damage caused by pre- HSCT chemoradiotherapy, aging, and GVHD, Strategies to overcome these problems include transplantation of committed lymphoid progenitors as well as HSC, replacement of microenvironmental signals, or prevention of microenvironmental damage. Common lymphoid progenitors (CLP) are a phenotypically defined population of marrow cells capable of giving rise to T, NK, and B lymphocytes, but not myeloid lineages. CLP express receptors for interleukin-7 (IL-7), Kit ligand (KL, aka stem cell factor [SCF]), and FltS ligand (FLT3L). In vivo, CLP are highly proliferative, which is in distinct contrast to HSC. Studies performed in the last funding period have shown that transplantation of CLP in addition to HSC results in greater resistance to peri-transplant murine cytomegalovirus (MCMV) infection. Previous work has shown that administration of IL-7 to murine HSCT recipients results in rapid reconstitution of the thymus as well as increased mature B cells. The goal of this grant is to understand the cytokine signals that regulate the development of lymphoid progenitors in order to develop a strategy for enhancement of post-HSCT immune reconstitution by combining transplantation of CLP and therapeutic use of cytokines to enhance the development of lymphocytes from the transplanted CLP. The studies will test the hypothesis that IL-7, KL, and FltSL are the complementary cytokines which regulate the proliferation, survival and differentiation of CLP in vivo. The effects of IL-7, KL, and FltSL on transplanted CLP will be characterized to better understand whether and how expansion of transplanted CLP occurs after transplantation. The effects of IL-7, KL, and/or FltSL on immune reconstitution from CLP will be tested, including the evaluation of functional immunity to MCMV. Gene expression by CLP stimulated with IL-7, KL, and FltSL will be characterized and compared. Together, the studies will advance the understanding of CLP and lead to clinical studies to induce the rapid development of a broad immunological repertoire after HSCT.

造血干细胞移植（HSCT）后，I淋巴细胞有两条途径 重组预形成的T淋巴细胞的移植可以导致有能力的T淋巴细胞的过继转移。 供者来源的T淋巴细胞，尽管具有有限的库和潜在的同种异体反应性和风险 移植物抗宿主病（GVHD）造血干细胞（HSC）移植或定向 淋巴祖细胞可导致产生供体来源的T淋巴细胞，其具有广泛的库 并被宿主胸腺选择，从而产生宿主耐受性。当供体移植物高度 通过CD34选择和/或T细胞耗竭富集HSC，HSCT后免疫重建依赖于 对T淋巴细胞发育的胸腺依赖性途径。HSCT后T细胞发育是 由于通常缓慢的个体发育和由预- HSCT放化疗、衰老和GVHD，克服这些问题的策略包括 定向淋巴祖细胞以及HSC的移植，微环境的替代， 信号或防止微环境损害。共同淋巴祖细胞（CLP）是一种 表型确定的骨髓细胞群，能够产生T、NK和B淋巴细胞，但不能 骨髓谱系CLP表达白细胞介素-7（IL-7）、Kit配体（KL，又名干细胞因子[SCF]）的受体， 和FltS配体（FLT3L）。在体内，CLP是高度增殖的，这与HSC形成鲜明对比。研究 上一个资助期进行的研究表明，除了HSC之外，还移植CLP会导致 对移植前后鼠巨细胞病毒（MCMV）感染的抵抗力更强。以前的工作表明 向小鼠HSCT接受者施用IL-7导致胸腺的快速重建， 成熟B细胞增多。这项资助的目标是了解调节细胞因子信号的细胞因子。 开发淋巴祖细胞，以开发增强HSCT后 通过将CLP移植和细胞因子的治疗性应用相结合来进行免疫重建， 促进来自移植CLP的淋巴细胞的发育。这些研究将测试 假设IL-7、KL和FltSL是调节增殖的互补细胞因子， CLP在体内存活和分化。IL-7、KL和FltSL对移植的CLP的作用将被评估。 其特征在于更好地理解移植的CLP在移植后是否以及如何发生扩张。 移植将测试IL-7、KL和/或FltSL对来自CLP的免疫重建的影响， 包括对MCMV的功能性免疫的评价。通过用IL-7、KL刺激的CLP的基因表达， 和FltSL将被表征和比较。这些研究将有助于加深对中电的了解， 并引导临床研究以诱导HSCT后广泛免疫谱系的快速发展。