Immune reconstitution: how it should work, what's broken, and why it matters.
Immune reconstitution: how it should work, what's broken, and why it matters.
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DOI：
10.1016/j.bbmt.2009.10.003
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发表时间：
2010-01
影响因子：
4.3
通讯作者：
Drobyski, William R.
中科院分区：
文献类型：
--
作者：
Gress, Ronald E.;Emerson, Stephen G.;Drobyski, William R.
在造血干细胞移植（HSCT）的背景下进行重建的多个细胞系，本概述将集中在免疫系统的T细胞臂的重建。在临床HSCT中，自体设置不受对同种异体抗原的反应所施加的限制，但缺乏标志物来区分来自转移细胞的重建与残留在宿主中的干细胞或祖细胞。在同种异体移植中，情况正好相反：可以确定重建群体的干细胞来源，但这种重建的生物学被伴随的同种异体反应所混淆。由于这些限制，T细胞免疫重建的基本生物学首先在小鼠模型中描绘，其中同源株的可用性允许在不存在混杂同种异体反应的情况下研究重建细胞群体的干细胞起源。T细胞再生的两种途径被确定：来自骨髓祖细胞的新T细胞的胸腺依赖性成熟，以及成熟外周T细胞的胸腺非依赖性扩增[1]。这些初步的研究也确定了没有其他途径可以产生大量的外周T细胞群，并且还建立了一种通过分析白细胞共同抗原CD45的同种型的表达来研究人类T细胞重建的方法，作为与再生途径相关的幼稚和记忆群体的标志物。他们还证明了在淋巴细胞减少的宿主中发生成熟T细胞的稳态扩增。对这种扩张的研究形成了稳态的核心概念：T细胞水平是通过消耗细胞因子的细胞和支持T细胞成熟、增殖扩增和存活的稳态细胞因子之间的平衡来维持的[2]。在将这些小鼠发现转化为人类时，最初跟踪了在化疗治疗后严重淋巴细胞减少的儿科患者中CD4+ T细胞的恢复（图1）。在短短6个月后，总CD4+ T细胞数量的恢复与初始CD45RA+CD45ROJ CD4+ T细胞的恢复之间存在强相关性[3]。此外，幼稚CD4+细胞的恢复与胸腺体积的显著扩张相关，这与胸腺的动态调节一致。最后，年龄和外周血（PB）中CD4+ T细胞的早期恢复之间呈负相关。这些数据支持以下结论：胸腺依赖性T细胞的产生是年轻患者治疗相关急性T细胞耗竭后PB CD4+ T细胞再增殖的主要原因。最重要的是，这项工作证实了利用CD4+ T细胞上的CD45同种型表达的方法，如从鼠基础研究中建立的，可用于研究人类的免疫重建。为了评估胸腺依赖性和非依赖性途径在成人中的作用，对化疗后CD4+ T细胞表达的CD45亚型进行了表征[4]。与儿科患者人群中的观察结果相反，淋巴细胞减少的成人（年龄超过30岁）在治疗后第一年内产生很少的新CD45RA+ CD4+细胞。相反，CD45RO+ CD4+细胞数量迅速增加，大多数CD4+ T细胞在化疗后的前3个月内恢复到治疗前水平[5]。因此，这些研究确立了人类CD4+ T细胞再生的早期第二主要途径的存在，即以T细胞生成为标志的胸腺非依赖性外周扩增途径。
Of the multiple cell lineages undergoing reconstitution in the setting of hematopoietic stem cell transplantation (HSCT), this overview will focus on reconstitution of the T cell arm of the immune system. In clinical HSCT, the autologous setting is free of constraints imposed by reactions to allogeneic antigens, but markers are lacking to distinguish reconstitution from transferred cells versus stem or progenitor cells left residual in the host. In allogeneic transplants, the converse is true: the stem cell origins of the reconstituted populations can be determined, but the biology of such reconstitution is confounded by concomitant allogeneic responses. Because of these constraints, the basic biology of T cell immune reconstitution was first delineated in mouse models in which the availability of congenic strains allowed stem cell origins of reconstituted cell populations to be investigated without the presence of confounding allogenic reactions. Two pathways of T cell regeneration were identified: the thymic-dependent maturation of new T cells from marrow progenitors, and thymicindependent expansion of mature peripheral T cells [1]. These initial studies also determined that no other pathways existed by which substantial peripheral populations of T cells were generated, and also established a means for investigating T cell reconstitution in humans by analyzing the expression of isoforms of the leukocyte common antigen CD45 as markers of naıve and memory populations that correlated with the pathway of regeneration. They also demonstrated that homeostatic expansion of mature T cells occurred in lymphopenic hosts. Studies of such expansion have formed central concepts of homeostasis: that T cell levels are maintained by a balance between cytokineconsuming cells and homeostatic cytokines that support the maturation, proliferative expansion, and survival of T cells [2].In translating these murine findings to humans, the recovery of CD4+ T cells in pediatric patients who were severely lymphopenic following chemotherapy treatment were initially tracked (Figure 1). There was a strong correlation between the recovery of total CD4+ T cell numbers and the recovery of naive, CD45RA+CD45ROJ CD4+ T cells after as few as 6 months [3]. Furthermore, recovery of naive CD4+ cells was associated with a marked expansion of thymus volume, consistent with a dynamic regulation of the thymus. Finally, an inverse correlation was observed between age and early recovery of CD4+ T cells in the peripheral blood (PB). These data supported the conclusion that thymic-dependent T cell production was primarily responsible for the repopulation of PB CD4+ T cells in young patients following acute T cell depletion associated with therapy. Most importantly, this work confirmed that the approach of utilizing CD45 isoform expression on CD4+ T cells, as established from murine basic research, could be used to investigate immune reconstitution in humans. To assess the contributions of thymus-dependent and-independent pathways in adults, CD45 isoforms expressed by CD4+ T cells following chemotherapy were characterized [4]. In contrast to observations in pediatric patient populations, lymphopenic adults (aged over 30 years) generated few new CD45RA+ CD4+ cells during the first year posttherapy. Instead, CD45RO+ CD4+ cells increased rapidly in number, recovering the majority of CD4+ T cells to pretreatment levels within the first 3 months after chemotherapy [5]. Thus, these studies established the existence of an early second primary pathway of CD4+ T cell regeneration in humans, namely, a thymus independent, peripheral expansion pathway marked by production of T …
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影响因子：
32.4
作者：
Ernst, B;Lee, DS;Surh, CD
通讯作者：
Surh, CD
影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
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20.3
作者：
Heitger, A;Neu, N;Fink, FM
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Fink, FM
影响因子：
45.3
作者：
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Bishop, Michael R.
影响因子：
20.3
作者：
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通讯作者：
Gress, RE