Lymphatic and systemic immunity changes in post-radiation lymphedema development

放射后淋巴水肿发展中的淋巴和全身免疫变化

• 批准号: 9267950
• 负责人: Melissa B Aldrich
• 金额: $ 35.61万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9267950
• 关键词: Address; Adipose tissue; Affect; Aftercare; Anatomy; Animals; Antibodies; Appearance; Architecture; Autoimmune Process; Autoimmunity; Axilla; Axillary Lymph Node Dissection; Biological Assay; Biological Markers; Blood specimen; Breast; Breast Cancer Patient; Breast-Conserving Surgery; Cancer Center; Cancer Survivor; Cancer Survivorship; Cell physiology; Cells; Cellulitis; Chronic; Collagen; Contralateral; Development; Diagnosis; Disease; Early treatment; Ensure; Etiology; Failure; Flow Cytometry; Fluorescence; Glean; Goals; Head and Neck Cancer; Human; Image; Imagery; Imaging technology; Immune; Immune response; Immunity; Immunohistochemistry; Impairment; Incidence; Infection; Inflammation; Inflammatory; Inherited; Interleukin-1 beta; Interleukin-6; Intervention; Keratin; Lead; Limb structure; Link; Localized Disease; Lymph; Lymphatic; Lymphatic vessel; Lymphedema; Lymphoid Tissue; Malignant Neoplasms; Mastectomy; Measures; Mediating; Mental Depression; Monitor; Morbidity - disease rate; Mus; Near-infrared optical imaging; Pain; Patients; Peripheral Blood Mononuclear Cell; Plasma; Population; Predisposition; Prevention; Preventive Intervention; Procedures; Production; Prophylactic treatment; Public Health; Pump; Radiation; Radiation therapy; Reporting; Role; Sampling; Swelling; Symptoms; TNF gene; Testing; Therapeutic; Therapeutic Intervention; Time; Toll-like receptors; Visual; Work; arm; cancer surgery; cancer therapy; chemotherapy; cytokine; ds-DNA; experience; experimental study; granulocyte; imaging study; immunological status; improved; in vitro Assay; lymphatic drainage; lymphatic pump; malignant breast neoplasm; novel; novel therapeutics; peripheral blood; phase 1 study; prevent; primary lymphedema; prospective; public health relevance; reproductive tract; skin fibrosis; therapeutic target; therapy development

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.

描述（由申请人提供）;淋巴水肿（LE）是一种致残性、毁容性疾病，可导致肢体肿胀、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），发达国家的大多数继发性LE病例是由癌症治疗引起的。并不是每个在癌症手术、化疗和放疗中幸存下来的人都会发生LE-40%的乳腺癌、10-20%的生殖道癌和75%的头颈癌幸存者会在治疗期间或治疗后的任何时候开始肿胀。癌症治疗后继发性LE的原因完全未知。有一个关键的未满足的需求，能够确定谁将发展LE癌症治疗后，因为早期LE诊断和治疗往往可以扭转肿胀，并防止长期发病，如皮肤纤维化和蜂窝织炎。此外，确定病因或相关的免疫参数可能会建议治疗干预策略，以阻止LE的发展。尽管最近的报道暗示了动物研究中炎症在LE中的作用，但迄今为止还没有研究比较了发生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态。鉴于这些发现，我们假设近红外荧光成像（NIRFLI）将允许可视化淋巴结构和功能的最早变化，因为LE的发展，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，可以驱动炎症细胞因子TNF-α，IL-1 β和IL-6的产生，以减缓淋巴泵，并允许LE的发展。这一假设将在以下具体目标的实验中得到解决：（1）检查NIRFLI是否可以检测晚期乳腺癌患者中淋巴管解剖结构和功能的最早LE相关变化，（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水肿的发展相关，和（3）评估淋巴管解剖学和功能的变化是否与自身免疫的血浆和免疫细胞标志物的出现相关。这项工作是一项前瞻性I期研究，旨在评估NIRFLI在检测淋巴管结构和泵送的最早变化方面的疗效，因为LE的发展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，并指导潜在治疗方法的选择。