Restoration of lymphatic function in postsurgical lymphedema with lymph node transfer

 描述（由申请人提供）：该提案意义重大，因为我们的目标是开发治疗水肿的新疗法，水肿是癌症治疗的常见和病态并发症，导致慢性肿胀，复发性感染和免疫功能障碍。最近的临床研究报告称，淋巴结转移（LNT）到患肢后，肿胀减轻，症状缓解。为了研究这一过程的机制，我们开发了LNT小鼠模型，并显示淋巴结的淋巴管自发地与受体部位的淋巴管重新连接，从而恢复淋巴循环。然而，尽管这些结果是有希望的，但仍不清楚LNT后免疫功能是否恢复。我们知识中的这一差距很重要，因为了解LNT调节免疫功能和微环境变化的机制是改善这些结果的必要步骤。我们提出的研究将解决这一差距，因此将开辟新的地面治疗水肿。我们的方法是创新的，因为我们已经开发了一种可诱导的小鼠水肿模型，其中可以使用白喉毒素选择性地消融组织炎症。这使我们能够在临床相关模型中研究LNT后的免疫功能，并测试LNT后淋巴再生恢复免疫功能并促进致瘤微环境变化的解决的中心假设。目的1：确定LNT如何恢复免疫功能。这一目标将检验先天性和适应性免疫功能在LNT后恢复的假设。这些研究的基本原理是基于这样一个事实，即接受淋巴结清扫术或患有水肿的患者抗体应答受损，感染风险增加。目的2：确定LNT如何调节淋巴损伤诱导的微环境变化和肿瘤复发。这一目标将测试的假设，即LNT减少激活的致瘤微环境的变化，已知发生在淋巴损伤后。该假设基于以下基本原理：1）乳腺癌患者局部复发风险高; 2）淋巴损伤增加了致瘤途径的表达，包括白细胞介素6以及巨噬细胞和Treg浸润; 3）先前的动物研究表明，淋巴损伤增加了乳腺癌的生长/转移。我们将测试我们的LNT小鼠模型以及显微镜原位和异位乳腺肿瘤植入物，以确定LNT如何恢复免疫应答，调节局部复发或新原发性癌症的发展。作为这些研究的结果，我们期望进一步了解淋巴损伤调节肿瘤生长/扩散的机制以及LNT如何调节这些变化。在拟议的研究的结论，我们希望了解的机制，调节受损的免疫功能，促进淋巴损伤后的致瘤环境变化，以及如何改变这些反应LNT。因此，这些研究不仅对水肿患者很重要，而且还将增加我们对淋巴系统如何调节肿瘤生长的一般理解。

 DESCRIPTION (provided by applicant): This proposal is significant because we aim to develop novel treatments for lymphedema, a common and morbid complication of cancer treatment that results in chronic swelling, recurrent infections, and immune dysfunction. Recent clinical studies have reported decreased swelling and symptomatic relief after lymph node transfer (LNT) to the affected limb. To study the mechanisms of this process, we have developed a mouse model of LNT and have shown that the lymphatic vessels of the lymph node spontaneously reconnect with the lymphatics of the recipient site thereby restoring lymphatic circulation. However, although these results are promising, it remains unclear if immunologic function is restored after LNT. This gap in our knowledge is important because understanding the mechanisms by which LNT regulates immune function and microenvironmental changes is a necessary step for improving these outcomes. Our proposed study will address this gap and will therefore break new ground in the treatment of lymphedema. Our approach is innovative because we have developed an inducible mouse model of lymphedema in which tissue lymphatics can be selectively ablated using diphtheria toxin. This enables us to study immune function after LNT in a clinically relevant model and test the central hypothesis that lymphatic regeneration after LNT restores immune function and promotes resolution of tumorigenic microenvironmental changes. Aim 1: Determine how LNT restores immune function. This aim will test the hypothesis that innate and adaptive immune function is restored after LNT. The rationale for these studies is based on the fact that patients who have undergone lymph node dissection or suffer from lymphedema have impaired antibody response and are at increased risk for infections. Aim 2: Determine how LNT regulates lymphatic injury induced microenvironmental changes and tumor recurrence. This aim will test the hypothesis that LNT decreases activation of tumorigenic microenvironmental changes known to occur after lymphatic injury. This hypothesis is based on the rationale that 1) Patients with breast cancer are at high risk for loco-regional recurrence; 2) Lymphatic injury increases expression of tumorigenic pathways including interleukin 6 as well as macrophages and Treg infiltration; and 3) Previous animal studies have shown that lymphatic injury increases the growth/metastasis of breast cancers. We will test our mouse model of LNT together with microscopic orthotopic and heterotopic breast tumor implants to determine how restoration of immune responses by LNT regulate growth of local recurrence or development of a new primary cancer. As a result of these studies, we expect to further our understanding of the mechanisms by which lymphatic injury regulates tumor growth/spread and how these changes are modulated by LNT. At the conclusion of the proposed study we expect to understand the mechanisms that regulate impaired immune function and promote tumorigenic environmental changes after lymphatic injury and how these responses are altered by LNT. These studies are therefore not only important not to patients with lymphedema but will also increase our general understanding of how the lymphatic system can regulate tumor growth.