T Progenitor and Thymic Epithelial Cell Replacement Post Transplant

免疫缺陷导致造血细胞移植（HCT）受者的显著发病率和死亡率。当利用高剂量的细胞毒性预处理、HLA不匹配或含有少量成熟T淋巴细胞的供体HSC来源时，临床意义尤其明显，如脐带血（UCB）移植的情况。我们已经观察到在脐带血移植受者中严重或致命的细胞内和DNA病毒（CMV; EBV; HHV 6;腺病毒）感染的高发病率。一个主要原因是胸腺生成能力的丧失，以及由于年龄、放化疗或移植物抗宿主病而导致的T细胞恢复受损。胸腺生成依赖于胸腺基质衍生受体和配体的相互作用。移植前条件作用对胸腺上皮细胞（TEC）的损伤会损害移植后成熟T细胞的生成，并使受体易于感染。我们的中心假设是，胸腺微环境损伤是主要的限制因素， 在UCB移植受者中缓慢的T细胞重建和功能，由晚期感染的易感性指示。TEC的分化、增殖和存活受到细胞内在和外在因素的控制。胸腺细胞前体和TEC参与“串扰”，使得由胸腺细胞和TEC提供的双向信号传导机制对于它们的相互增殖和存活是必不可少的。我们在小鼠中的初步数据表明，成熟胸腺细胞和TEC的数量之间存在直接相关性，特别是位于胸腺髓质中的TEC，其作为阴性选择和胸腺进入外周的主要部位。 有效的胸腺生成的恢复速度受到无效的TEC串扰（目的1）和逃避调节方案的内源性TEC的相对缺乏（目的1，2）的限制。我们将追求两种方法（具体目标），以克服在胸腺生成TEC支持的定量和定性缺陷。目标1.确定TEC再生和胸腺生成恢复是否受到HSCT后胸腺细胞前体和TEC之间不充分串扰的限制。目标二。设计和测试新的TEC替代策略的基础上TEC的发展线索和使用诱导多能干细胞技术。

Immune deficiency causes significant morbidity and mortality in hematopoietic cell transplant (HCT) recipients. The clinical significance is especially evident when utilizing high doses of cytotoxic conditioning, donor HSC sources that are HLA-mismatched or contain low numbers of mature T lymphocytes, as would be the case with umbilical cord blood (UCB) transplants. We have observed a high incidence of severe or fatal intracellular and DNA viral (CMV; EBV; HHV6; adenovirus) infections in UCB transplant recipients. A major cause is loss of thymopoietic capacity, and impaired T cell recovery as a result of age, chemoradiotherapy or graft-versus-host-disease. Thymopoiesis depends on the interaction of the thymic stroma-derived receptors and ligands. Damage to thymic epithelial cells (TECs) by pre-transplant conditioning impairs the generation of mature T cells following transplant and predisposes the recipient to infections. Our central hypothesis is that thymic microenvironmental injury is the major limiting factor for slow T cell reconstitution and function in UCB transplant recipients, indicated by the predisposition for late infections. TEC differentiation, proliferation, and survival are controlled by both cell intrinsic and extrinsic factors. Thymocyte precursors and TECs engage in "cross-talk" such that bidirectional signaling mechanisms provided by and to both thymocytes and TECs are essential for their mutual proliferation and survival. Our preliminary data in mice indicate that there is a direct correlation between the number of mature thymocytes and TECs, especially those located in the thymic medulla, which serves as the primary site of negative selection and thymic egress into the periphery. With the operational hypothesis that the rapidity of recovery of effective thymopoiesis is limited both by ineffective :TEC cross-talk (aim 1) and the relative paucity of endogenous TECs that escape conditioning regimens (aims 1, 2). We will pursue two approaches (specific aims) to overcome the quantitative and qualitative defect in TEC support of thymopoiesis. Aim 1. To determine whether TEC regeneration and thymopoietic recovery is limited by inadequate cross-talk between thymocyte precursors and TECs post-HSCT. Aim 2. To devise and test novel TEC replacement strategies based upon TEC developmental cues and using inducible pluripotent stem cell technology.