Lymphatic and systemic immunity changes in post-radiation lymphedema development

描述（由申请人提供）；淋巴水肿（LE）是一种致残、毁容的疾病，导致肢体肿胀、疼痛、感染发生率增加、皮肤纤维化和抑郁。LE可能是遗传性的（原发性）或获得性的（继发性），在发达国家，大多数继发性LE是由癌症治疗引起的。并非所有癌症手术、化疗和放射治疗的幸存者都会患上LE-40%的乳腺癌、10-20%的生殖道癌和75%的头颈癌幸存者在治疗期间或之后的任何时候都会出现肿胀。癌症治疗后继发LE的原因完全未知。由于早期LE诊断和治疗通常可以逆转肿胀并预防皮肤纤维化和蜂窝组织炎等长期发病率，因此确定癌症治疗后谁会发生LE是一个关键的未满足需求。此外，确定致病或相关的免疫参数可能提出治疗干预策略，以阻止LE的发展。尽管最近的报道在动物实验中暗示了炎症在LE中的作用，但迄今为止还没有研究比较发生LE的癌症幸存者和未发生LE的癌症幸存者的全身宿主免疫状况。鉴于这些发现，我们假设近红外荧光成像（NIRFLI）将允许可视化LE发展过程中淋巴结构和功能的最早变化，这些变化可能与外周血免疫细胞中toll样受体（TLR）活性的改变相关，TLR活性可以驱动炎症细胞因子TNF-α、IL-1ß和IL-6的产生，从而减缓淋巴泵入并允许LE发展。这一假设将在以下具体目标的实验中得到解决：(1)研究NIRFLI是否能检测晚期乳腺癌患者早期与le相关的淋巴管解剖和功能变化；(2)确定血浆细胞因子水平和外周血单核细胞（PBMC）和粒细胞功能的变化是否与淋巴水肿的发生有关；(3)评估淋巴管解剖和功能的变化是否与血浆和自身免疫的免疫细胞标志物的出现有关。这项工作是一项前瞻性I期研究，旨在评估NIRFLI在LE发展过程中检测淋巴血管结构和泵血早期变化的功效，这些变化与外周血免疫状态相关。从这项研究中收集的信息可以帮助预测LE发展的易感性，确保早期治疗和预防，并指导选择潜在的治疗方法。

DESCRIPTION (provided by applicant); Lymphedema (LE) is a disabling, disfiguring disease that results in limb swelling, pain, increased incidence of infections, skin fibrosis, and depression. LE may be hereditary (primary) or acquired (secondary), with most cases of secondary LE in the developed world resulting from cancer treatment. Not everyone who survives cancer surgery, chemotherapy, and radiation treatment develops LE-40% of breast cancer, 10-20% of reproductive tract cancer, and 75% of head and neck cancer survivors experience swelling, starting anytime during or after treatment. The cause of secondary LE after cancer treatment is completely unknown. There is a critical unmet need to be able to determine who will develop LE after cancer treatment, because early LE diagnosis and treatment can often reverse swelling and prevent long-term morbidities such as skin fibrosis and cellulitis. Additionally, identifying causative or correlative immune parameters may suggest therapeutic intervention strategies to arrest LE development. Despite recent reports implying a role for inflammation in LE in animal studies, no studies to date have compared the status of systemic host immunity in cancer survivors who develop LE and those who do not. Given these findings, we hypothesize that near-infrared fluorescence imaging (NIRFLI) will allow visualization of the earliest changes in lymphatic architecture and function as LE develops, and these changes can be correlated to alterations in toll-like receptor (TLR) activity in peripheral blood immune cells that can drive production of the inflammatory cytokines TNF-α, IL-1ß, and IL-6 to slow lymph pumping and allow LE development. This hypothesis will be addressed in the experiments of the following Specific Aims: (1) to examine if NIRFLI can detect the earliest LE-related changes to lymphatic vessel anatomy and function in advanced breast cancer patients, (2) to determine if changes in plasma cytokine levels and peripheral blood mononuclear cell (PBMC) and granulocyte function associate with development of lymphedema, and (3) to assess if changes to lymphatic vessel anatomy and function correlate to the appearance of plasma and immune cell markers of autoimmunity. This work is a prospective Phase I study to evaluate the efficacy of NIRFLI in detecting the earliest changes in lymphatic vessel architecture and pumping as LE develops, correlated to peripheral blood immune status. The information gleaned from this study could help to predict susceptibility to development of LE, ensure early treatment and perhaps prevention, and guide selection of potential therapeutics.