Improving Immune Reconstitution via Cytokine-Mediated Expansion of Transplanted

造血干细胞移植(HSCT)后，淋巴细胞有两种途径 重建。移植预先形成的T淋巴细胞可以导致过继转移 供者来源的T淋巴细胞，尽管有限制的谱系和同种异体反应的可能性和风险 移植物抗宿主病(GVHD)。造血干细胞(HSC)移植或已承诺移植 淋巴祖细胞可以产生供者来源的T淋巴细胞，这种T淋巴细胞具有广泛的谱系 并被寄主胸腺选择，产生寄主耐受性。当供者的移植物已经高度 CD34选择和/或T细胞耗尽对HSC的富集性依赖于HSCT后的免疫重建 T淋巴细胞发育的胸腺依赖途径。HSCT后T细胞发育是 由于正常缓慢的个体发育和预激反应造成的微环境破坏而固有的延迟 HSCT化疗、放射治疗、衰老和GVHD，克服这些问题的策略包括 承诺的淋巴祖细胞和造血干细胞的移植，微环境的替代 信号，或防止微环境破坏。常见淋巴祖细胞(CLP)是一种 表型定义的能够产生T、NK和B淋巴细胞的骨髓细胞群，但不能 髓系血统。CLP表达白介素7(IL-7)、Kit配体(KL，又名干细胞因子[SCF])受体， 和Flts配体(Flt3L)。在体内，CLP高度增殖，这与HSC形成鲜明对比。研究 在上一个资助期内进行的研究表明，移植中电和造血干细胞会导致 对移植围术期小鼠巨细胞病毒(MCMV)感染有更强的抵抗力。以前的工作已经表明 给小鼠HSCT受者注射IL-7会导致胸腺的快速重建以及 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 发展淋巴祖细胞以制定增强HSCT后免疫功能的策略 CLP移植联合细胞因子治疗的免疫重建 促进移植的CLP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在体内的存活和分化。IL-7、KL和FltSL对移植的CLP的影响 其特点是更好地了解移植的CLP是否以及如何在 移植。将测试IL-7、KL和/或FltSL对CLP免疫重建的影响。 包括对MCMV的功能免疫评价。IL-7、KL、IL-7刺激的CLP基因表达 和FltSL进行了表征和比较。这些研究将有助加深对中电的认识。 并导致临床研究，以诱导HSCT后广泛的免疫学谱系的快速发展。

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.