Development of novel strategy for treatment of steroid refractory GVHD

 描述（由申请人提供）：移植物抗宿主病（GVHD）限制了异基因骨髓移植（BMT）的应用，BMT是许多血液恶性肿瘤和遗传性疾病的治愈性疗法。GVHD，当其一线疗法类固醇难治时，导致>70%的死亡率。已经尝试了多种策略来治疗类固醇难治性GVHD，但结果仍然一致致命。目前对生物学的理解表明，GVHD的严重程度是由致细胞病变的T效应细胞（Tefs）和细胞保护性调节性T细胞（Teff）之间的平衡决定的，并且这种平衡严重依赖于炎症水平。我们最近证明，人α 1-抗胰蛋白酶（AAT），主要的血清丝氨酸蛋白酶抑制剂，具有抗炎作用，这在很大程度上是迄今为止尚未认识到的。我们最近已经表明，AAT减少了几种促炎细胞因子，积极调节Teff：Treg平衡，预防和治疗多种鼠模型中的GVHD（PNAS，2012）。但其分子机制仍不清楚。我们产生的初步数据证明了唾液酸结合免疫球蛋白样凝集素-G（Siglec-G）在宿主细胞上减轻GVHD中的新作用（Blood，2014）。未发表的初步数据进一步表明，Siglec-G对AAT的抗炎作用至关重要。在本提案中，我们将以这些令人兴奋的数据为基础，将这些观察结果转化为概念验证，首先在FDA IND下的人类BMT临床试验中进行，并将其与AAT介导效应的分子机制的进一步探索相结合。最近启动了翻译试验，以评估AAT在类固醇难治性GVHD患者中的安全性和有效性（已累积8例患者）。总的来说，如果成功，我们的建议将导致一个全新的治疗策略的发展，同时提供新的生物学见解的致命条件，类固醇难治性 GVHD。该提案的具体目标（SA）是：SA 1：阐明AAT介导的炎症调节的细胞和分子机制。在本SA中，我们将检验以下假设：AAT与抑制性Siglec-G受体的结合对于调节炎症和Teff-T平衡至关重要。SA 2：进行初步临床试验，以确定是否给予 对激素难治性GVHD患者进行AAT可提高缓解率。我们将探讨这样的假设，即AAT的管理将提高反应率的第28天的患者是难治性类固醇GVHD。

 DESCRIPTION (provided by applicant): Graft-versus-host disease (GVHD) limits the application of allogeneic bone marrow transplantation (BMT), a curative therapy for many hematological malignancies and inherited diseases. GVHD, when refractory to its first line therapy, steroids, leads to >70% mortality. A multitude of strategies have been tried to treat steroid refractory GVHD, but as yet the outcomes remain uniformly fatal. Current understanding of the biology indicates that GVHD severity is determined by the balance between cytopathic T effector cells (Teffs) and the cytoprotective regulatory T cells (Tregs) and that this balance is critically dependent on the level of inflammation. We recently demonstrated that human alpha1-antitrypsin (AAT), the major serum serine- protease inhibitor possesses, anti-inflammatory effects that were heretofore largely unrecognized. We have recently shown that AAT reduced several pro-inflammatory cytokines, positively modulated the Teff:Treg balance, prevented and treated GVHD in multiple murine models (PNAS, 2012). But the molecular mechanisms remain unknown. Preliminary data generated by us demonstrate a novel role for sialic acid- binding immunoglobulin-like lectins-G (Siglec-G), on host cells in mitigating GVHD (Blood, 2014). Unpublished preliminary data further suggest that Siglec-G is critical for the anti-inflammatory effects of AAT. In this proposal we will build on these exciting data to translate these observations into a proof of concept, first in human BMT clinical trial under an IND from FDA and meld it with further exploration of the molecular mechanisms of AAT mediated effects. The translational trial has recently been launched to assess the safety and efficacy of AAT in patients with steroid refractory GVHD (already accrued eight patients). Collectively, if successful, our proposal will lead to the development of an entirely novel therapeutic strategy while simultaneously providing novel biological insights into a fatal condition, steroid refractory GVHD. The specific aims (SA) of the proposal are: SA 1: Elucidate the cellular and molecular mechanisms of AAT mediated regulation of inflammation. In this SA we will test the hypothesis that binding of AAT to the inhibitory Siglec-G receptors is critical for regulating inflammation an the Teff-Tregs balance. SA 2: Perform a pilot clinical trial to determine whether administration of AAT to patients with steroid refractory GVHD will improve response rates. We will explore the hypothesis that administration of AAT will improve the response rates by day 28 in patients that are refractory to steroids GVHD.