Transplant Models

正如本项目的目标和目的所指出的，该项目旨在创建新的模型，以检验不同的假设，并为通过造血干细胞移植治疗淋巴瘤、骨髓瘤、白血病、乳腺癌和肾癌的新策略的开发提供新的理解。这些疾病的造血干细胞移植治疗通常会导致淋巴细胞减少和免疫功能受损。在人类中，有能力在癌症治疗相关的淋巴细胞减少症的背景下上调胸腺功能的观察已经被转化为小鼠模型。我们已经开始了四项平行的努力，以确定胸腺功能的控制点。在使用IGF-1的实验中，我们观察到，虽然胸腺细胞前体池的大小和参与迁移的分子受到影响，但关键控制点是为传入的胸腺细胞扩大成熟生态位的水平。停止雄激素信号，也会导致胸腺活性增加，涉及CCL25分子的上调，这反过来又促进胸腺细胞前体细胞进入胸腺。在这种情况下，CCL25被发现是胸腺功能上调所必需的。在癌症治疗的背景下，这两种提高胸腺功能并进而增强T细胞免疫重建的方法都可以应用于临床试验。

As noted in the goals and objectives stated for this project, it aims to create new models that test distinct hypotheses and provide new understandings for development of novel strategies in the treatment of lymphoma, myeloma, leukemia, breast cancer and renal cancer by hematopoietic stem cell transplantation. Hematopoietic stem cell transplant treatment of these diseases generally results in lymphopenia and immune compromise. The observation that in humans there is the ability to upregulate thymus function in the setting of cancer therapy-associated lymphopenia has been translated to murine models. We have initiated four parallel efforts to identify points of control in thymus function. In experiments utilizing IGF-1, which was found to upregulate thymus activity, we observed that while thymocyte precursor pool size and molecules involved in migration are affected, the critical control point was at the level of expanding maturational niches for incoming thymocytes. Cessation of androgen signaling, which also results in increased thymus activity, involved upregualtion of the molecule CCL25 which in turn enhanced immigation of thymocyte precusors into the thymus. CCL25 was found to be necessary for upregulation of thymus function in this setting. Both of these approaches for increasing thymus function and in turn enhancing T cell immune reconstitution in the setting of cancer therapy can be applied to clinical trials.