PET Imaging of GVHD and GVL after treatment with Azacitidine

调节性T细胞有助于维持自身耐受性和减轻移植物抗宿主反应 疾病(GvHD)，异基因造血干细胞移植(HSCT)的主要并发症，而 保留有益的移植物抗白血病(GVL)效应。然而，罕见的Treg细胞的体外扩增 子集效率低、成本高、耗时长。Tregs的主调控子Foxp3的基因座是 未甲基化，仅在Tregs中表达。我们最近报道了去甲基化药物 氮杂胞苷(AzaC)在体内诱导Foxp3表达并增加Tregs，从而减轻GvHD而不是 在小鼠异基因移植模型中废除GVL。我们还开发了一种活体成像技术 追踪携带嵌合自杀基因(CD34-)的转基因T细胞的技术[18FJ-FHBG-PET TK75)。在这次更新中，我们将进一步定义AzaC诱导的免疫抑制的最佳条件 小鼠异基因移植模型(AIMI)，证实类似的效应可以在人类T细胞中表现出来 使用我们实验室开发的信息性异种移植GvHD/白血病模型(Aim 2)，并验证 AzaC在先导性临床试验中的作用(目标3)。在目标3建议的临床试验中，我们建议给予 HSCT后复发的AML或MDS患者接受含有T细胞的供体淋巴细胞输注 用我们的CD34-TK75自杀/成像基因转导；一半将用AzaC治疗。我们的假设是 AzaC会将T细胞转化为FoxP3树状细胞，从而控制同种异体反应性T细胞，从而减轻GvHD 而不会消除GVL效应。无创[~(18)F]-FHBG-PET显像测量心脏功能的能力 过继转移的CD34-TK75示踪T细胞在患者体内的重建、扩增和持续存在 对于提供GvHD和AzaC治疗效果的早期预测，可能具有重要的临床实用价值。 相关性(请参阅说明)： 如果成功，通过[18FJ-FHBG-PET成像观察到的GvHD轮廓将预示着 严重的GvHD和开始GvHD预防的必要性。相反，观察到“无GvHD”的个人资料 将预测可以忽略到有限的GvHD，并允许继续观察接受者而不是 免疫抑制药物，从而允许更持久的GVL效应。

Regulatory T cells (Tregs) contribute to the maintenance of self-tolerance and mitigate graft-versus-host disease (GvHD), a major complication of allogeneic hematopoietic stem cell transplantation (HSCT), while preserving the beneficial graft-versus-leukemia (GvL) effect. However, in vitro expansion of the rare Treg cell subset is inefficient, costly, and time-consuming. The locus of Foxp3, the master regulator of Tregs, is unmethylated and expressed only in Tregs. We have recently reported that the hypomethylating agent azacitidine (AzaC) induces Foxp3 expression and increases Tregs in vivo, thereby mitigating GvHD without abrogating GvL in a murine allogeneic transplant model. We have also developed an in vivo imaging technique, [18FJ-FHBG-PET, to track genetically-modified T cells carrying a chimeric suicide gene (CD34- TK75). In this renewal, we will further define the optimal conditions for AzaC-induced immune suppression in murine allogeneic transplant models (Aimi), confirm that similar effects can be demonstrated in human T cells using informative xenograft GvHD/leukemia models developed in our lab (Aim 2), and validate the effects of AzaC in a pilot clinical trial (Aim 3). In the clinical trial proposed in Aim 3, we propose to give patients with relapsed AML or MDS after HSCT a donor lymphocyte infusion containing T cells that are transduced with our CD34-TK75 suicide/imaging gene; half will be treated with AzaC. Our hypothesis is that AzaC will convert the T cells into FoxP3+ Tregs that will control the alloreactive T cells thus mitigating GvHD without abrogating GvL effects. The ability of non-invasive [18F]-FHBG-PET imaging to measure the reconstitution, expansion and persistence of adoptively transferred CD34-TK75+ tracer T cells in patients may have significant clinical utility for providing early predictions of GvHD and AzaC treatment efficacy. RELEVANCE (See instructions): If successful, the observation of a "GvHD profile" by [18FJ-FHBG-PET imaging would herald the onset of severe GvHD and the need for initiation of GvHD prophylaxis. In contrast, observation of a "No GvHD" profile would predict negligible to limited GvHD and permit the continued observation of recipients without immunosuppressive medications, thereby permitting a more sustained GvL effect.