Restoration of lymphatic function in postsurgical lymphedema with lymph node transfer

通过淋巴结转移恢复术后淋巴水肿的淋巴功能

• 批准号: 9185953
• 负责人: Babak J Mehrara
• 金额: $ 19.13万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9185953
• 关键词: Address; Adjuvant Therapy; Affect; Animals; Antibody Response; Architecture; Axillary Lymph Node Dissection; B-Lymphocytes; Biology; Breast Cancer Treatment; Breast cancer metastasis; Cancer Biology; Chronic; Clinical; Clinical Research; Defect; Dendritic Cells; Development; Diphtheria Toxin; Disease; Disease Management; Functional disorder; Growth; Immune; Immune System Diseases; Immune System and Related Disorders; Immune response; Impairment; Implant; Incidence; Infection; Infiltration; Inflammatory; Injury; Interleukin-6; Knowledge; Lead; Limb structure; Lymph Node Dissections; Lymph node excision; Lymphatic; Lymphatic System; Lymphatic vessel; Lymphedema; Lymphoid Tissue; Malignant Neoplasms; Mammary Neoplasms; Massage; Methods; Microscopic; Mission; Modeling; Molecular; Morbidity - disease rate; Mus; Natural regeneration; Neoplasm Metastasis; Obesity; Operative Surgical Procedures; Pathway interactions; Patients; Play; Positioning Attribute; Process; Radiation; Reaction; Recurrence; Regulatory T-Lymphocyte; Reporting; Resolution; Risk; Risk Factors; Role; Site; Source; Surgical Management; Swelling; T cell response; T-Lymphocyte; Tail; Techniques; Testing; Time; Tissues; Tumorigenicity; United States National Institutes of Health; aging population; base; cancer complication; cancer therapy; clinically relevant; design; environmental change; experimental study; high risk; immune function; immunoregulation; improved; improved outcome; innovation; lymph nodes; lymphatic circulation; macrophage; malignant breast neoplasm; migration; mouse model; multidisciplinary; novel; palliative; patient population; prevent; public health relevance; response to injury; restoration; tumor; tumor growth; tumorigenic

 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.

 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针对淋巴水肿的新疗法，淋巴水肿是癌症治疗的一种常见病态并发症，会导致慢性肿胀、反复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）至患肢后肿胀减少，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，并表明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，尽管这些结果令人鼓舞，但 LNT 后免疫功能是否恢复仍不清楚。我们的知识差距很重要，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空白，从而为淋巴水肿的治疗开辟新天地。我们的方法是创新的，因为我们开发了一种诱导性淋巴水肿小鼠模型，其中可以使用白喉毒素选择性消融组织淋巴管。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解决的中心假设。目标 1：确定 LNT 如何恢复免疫功能。这一目标将检验 LNT 后先天性和适应性免疫功能恢复的假设。这些研究的基本原理是基于以下事实：接受过淋巴结清扫术或患有淋巴水肿的患者抗体反应受损，感染风险增加。目标 2：确定 LNT 如何调节淋巴损伤引起的微环境变化和肿瘤复发。这一目标将检验 LNT 减少淋巴损伤后已知发生的致瘤微环境变化的激活这一假设。该假设基于以下基本原理：1）乳腺癌患者局部区域复发的风险较高； 2) 淋巴损伤增加致瘤途径的表达，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，淋巴损伤会增加乳腺癌的生长/转移。我们将测试我们的 LNT 小鼠模型以及显微原位和异位乳腺肿瘤植入物，以确定 LNT 恢复免疫反应如何调节局部复发的生长或新原发性癌症的发展。通过这些研究，我们希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。在拟议研究的结论中，我们希望了解调节免疫功能受损和促进淋巴损伤后致瘤环境变化的机制，以及 LNT 如何改变这些反应。因此，这些研究不仅对淋巴水肿患者不重要，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。