Targeting y-secretase in GVHD

移植物抗宿主病（GVHD）是造血干细胞移植（HSCT）的一种严重并发症，是导致HSCT失败的主要原因。目前GVHD的治疗最常涉及使用免疫抑制药物，因此使受体处于免疫功能低下状态。 允许HSCT而不发生GVHD并发症的策略将为更广泛地使用HSCT治疗几种恶性血液病提供可能性。常规使用HSCT的主要障碍是GVHD可能发生的严重并发症。众所周知，GVHD是由活化的T细胞介导的，因此早期的方法是在转移之前从供体细胞群中完全删除T细胞。虽然这种方法消除了GVHD，但它也严重抑制了有效的植入以及治疗性移植物抗白血病（GVL）反应的发展。因此，目前的方案包括供体细胞群中的T细胞。这导致接受HSCT的成人中GVHD的高发病率。我们的初步数据，在本申请中，支持γ-分泌酶的底物在GVHD中的作用。我们的数据清楚地表明，γ-分泌酶的底物在GVHD中起着重要作用，GSI受体的治疗可抑制GVHD。我们还表明，GVHD伴随着Notch 1在供体T细胞中的激活，这表明GVHD中GSI的一个重要靶点是Notch 1。最后，我们对Notch缺陷型T细胞的研究牢固地确立了Notch是这些实验中GSI的一个相关靶标。本项目中的实验旨在验证γ-分泌酶抑制剂在治疗GVHD同时维持移植物抗白血病（GVL）方面可能具有显著临床效用的假设。然后，我们提出了一系列的实验，以确定γ-分泌酶抑制剂的功能，以阻止GVHD的机制，并建议这样的理解可能会导致合理的机制为基础的方法来治疗GVHD。

Graft-versus-host-disease (GVHD) is a life threatening complication of hematopoietic stem cell transfer (HSCT) and is the major factor in failure of HSCT. Current treatment of GVHD most commonly involves the use of immunosuppressive drugs and hence places the recipient in an immunocompromised state. Strategies that allow HSCT without the complication of GVHD would open the possibility of broader use of HSCT in the treatment of several hematologic malignancies. The major obstacle for routine use of HSCT is the profound complications that can occur from GVHD. It is well known that GVHD is mediated by activated T cells therefore an early approach was to completely delete T cells from the donor cell population prior to transfer. While this approach eliminated GVHD, it also profoundly inhibited effective engraftment as well as development of the therapeutic graft-versus-leukemia (GVL) response. Therefore current protocols include T cells in the donor cell population. This results in a high incidence of GVHD in adults receiving HSCT. Our preliminary data, presented in this application, supports a role for substrates of y-secretase in GVHD. Our data clearly demonstrate that substrates of y-secretase play an important role in GVHD and treatment of recipients with GSI inhibits GVHD. We also show that GVHD is accompanied by activation of Notch1 in donor T cells, suggesting that an important target of GSI in GVHD is Notch1. Lastly our studies with Notch deficient T cells firmly establish that Notch is one relevant target of GSI in these experiments. The experiments in this project are designed to test the hypothesis that y-secretase inhibitors may have significant clinical utility in the treatment of GVHD while maintaining graft-versus-leukemia (GVL). We then propose a series of experiments to determine the mechanisms by which y-secretase inhibitors function to block GVHD and suggest that such an understanding may lead to rational mechanistic based approach to the treatment of GVHD.