T Progenitor and Thymic Epithelial Cell Replacement Post Transplant

在造血细胞移植(HCT)受者中，免疫缺陷会导致显著的发病率和死亡率。当使用高剂量的细胞毒条件处理，供者的HSC来源是不匹配的或含有少量成熟T淋巴细胞时，临床意义尤其明显，就像脐带血(UCB)移植一样。我们观察到，在脐带血移植受者中，严重或致命的细胞内和DNA病毒(CMV；EBV；HHV6；腺病毒)感染的发生率很高。一个主要的原因是胸腺生成能力的丧失，以及由于年龄、化疗或移植物抗宿主病而导致的T细胞恢复受损。胸腺的生成依赖于胸腺基质来源的受体和配体之间的相互作用。移植前条件处理对胸腺上皮细胞(TECs)的损伤会损害移植后成熟T细胞的生成，并使受体容易受到感染。我们的中心假设是胸腺微环境损伤是 脐带血移植受者T细胞重建和功能缓慢，表现为后期感染的易感性。TEC的分化、增殖和存活受细胞内在和外在因素的控制。胸腺细胞前体细胞和TECs参与“串话”，胸腺细胞和TECs提供的双向信号机制对它们的相互增殖和生存是必不可少的。我们在小鼠身上的初步数据表明，成熟胸腺细胞的数量与TEC之间存在直接的相关性，尤其是位于胸腺髓质的胸腺髓质，它是否定选择和胸腺进入外围的主要部位。 在操作假设下，有效的胸腺生成的恢复速度受到无效的TEC串扰(目标1)和逃脱条件反射方案的内源性TECs的相对缺乏(目标1，2)的限制。我们将寻求两种方法(特定目标)来克服TEC支持胸腺生成的数量和质量上的缺陷。目的1.探讨HSCT后胸腺细胞前体细胞与TECs之间的相互作用是否限制了TEC的再生和胸腺细胞的恢复。目的2.根据TEC发育线索，利用可诱导的多能干细胞技术，设计和测试新的TEC替代策略。

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.