T Progenitor and Thymic Epithelial Cell Replacement Post Transplant

免疫缺陷导致造血细胞移植（HCT）受者显著的发病率和死亡率。当使用高剂量的细胞毒性调节、hla不匹配或成熟T淋巴细胞含量低的供体HSC来源（如脐带血（UCB）移植）时，其临床意义尤其明显。我们观察到UCB移植受者中严重或致命的细胞内病毒和DNA病毒（CMV、EBV、HHV6、腺病毒）感染的发生率很高。一个主要原因是由于年龄、放化疗或移植物抗宿主病导致的胸腺生成能力丧失和T细胞恢复受损。胸腺生成依赖于胸腺基质来源的受体和配体的相互作用。移植前调节对胸腺上皮细胞（TECs）的损伤会损害移植后成熟T细胞的产生，并使受体易受感染。我们的中心假设是胸腺微环境损伤是主要的限制因素

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.