Modulation of Hormonal and Systemic Immunity by Hormonal Contraceptive Use

使用激素避孕药调节激素和全身免疫

• 批准号: 8318311
• 负责人: Thomas L. Cherpes
• 金额: $ 49.74万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-27 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318311
• 关键词: Agonist; Allogenic; Antigen-Presenting Cells; Antiviral Agents; Biological; Biopsy; Blood; CCL20 gene; CCL3 gene; CCL4 gene; CD40 Antigens; CD80 gene; CD8B1 gene; CXCL12 gene; Cells; Cervical; Cervix Uteri; Contraceptive Agents; Contraceptive Usage; Dendritic Cells; Dendritic cell activation; Dextrans; Enrollment; Epidemic; Epidemiology; Epithelial; Equilibrium; Evaluation; Exposure to; Feminization; Genital system; HIV; HIV Infections; Health Personnel; Hormonal; IL8 gene; Immune response; Immunity; Infection; Inflammatory; Injectable; Interferons; Interleukin-1; Interleukin-10; Interleukin-12; Interleukin-15; Interleukin-6; Intrauterine Devices; Investigation; Lactoferrin; Langerhans cell; Levonorgestrel; Measures; Medroxyprogesterone 17-Acetate; Memory; Methods; Modeling; Mucous Membrane; Mus; Natural Immunity; Oral; Oral Contraceptives; PI3 gene; Permeability; Pharmaceutical Preparations; Poly I-C; Predisposition; Production; Progestins; RANTES; Recommendation; Research; Response Elements; Risk; Risk Factors; Surface; Swab; T-Cell Development; T-Cell Proliferation; T-Lymphocyte; Testing; Thick; Tissues; Tumor Necrosis Factor-alpha; Up-Regulation; Viral; Virus; Virus Diseases; Visit; Woman; adaptive immunity; antileukoprotease; antimicrobial; base; beta-defensin-2; chemokine; combat; comparative; cytokine; dextran; follow-up; hormonal contraception; human SLPI protein; human TLR3 protein; improved; novel; novel strategies; pandemic disease; pathogen; receptor; response; transmission process

DESCRIPTION (provided by applicant): Modulation of mucosal and systemic immunity by hormonal contraceptive use ABSTRACT Growing feminization of the HIV pandemic has created an even greater need for research that will improve our understanding of risk factors promoting transmission of HIV to women. Many epidemiological investigations indicate there may be connections between hormonal contraceptive use and enhanced susceptibility for HIV acquisition, but substantial study limitations hypothesis of our proposal is that progestin-based hormonal contraceptives inhibit genital tract immune responses and tip the balance of protective immunity at genital mucosal surfaces towards acquisition of infection. This hypothesis is based on novel demonstration in our murine model of viral mucosal infection that dendritic cell (DC) activation, virus-specific T cell expansion, and memory T cell development are suppressed among mice administered depot-medroxyprogesterone acetate (DMPA) prior to infection. Notably, our preliminary studies were able to demonstrate that antigen presenting cells (APCs) activated directly ex vivo from women using DMPA also have a decreased ability to induce allogeneic T cell proliferation. These results helped generate a fresh approach to this research question that focuses on the immunomodulatory effects of DMPA, oral contraceptives (OC), and levonorgestrel-containng intrauterine devices (LNG-IUD) that may impair host responses against viral pathogens. Incorporating methods similar to ones developed in our preliminary investigations, we will utilize APCs isolated from the blood and cervixes of women before (enrollment) and after (1 month follow-up visit) they initiate use of OC, DMPA, or LNG-IUD in order to determine the effects of these drugs on APC ability to up-regulate co-stimulatory molecule expression and induce ex vivo T cell proliferation (Aim 1). Cervical secretions collected from women at both study visits will be used to compare concentrations of several innate immune response elements, while cervical tissue will also be used to compare inflammatory and antiviral cytokine production by cervical cells stimulated ex vivo with a Toll-lik receptor 3 agonist (Aim 2). In Aim 2, we will also determine if OC, DMPA, or LNG-IUD use elicits any decreases in cervical epithelial layer thickness or any increases in the exposure of Langerhans cells to the mucosal surface. Completion of these research aims would provide the first comparative evaluation of the capacity of OCP, DMPA, and LNG-IUD to suppress host responses needed to combat genital tract infection, and would also supply healthcare providers more informed recommendations regarding the most appropriate choices for hormonal contraception among women at risk for HIV. PUBLIC HEALTH RELEVANCE: Increasing feminization of the HIV epidemic demands more complete delineation of the relationships between hormonal contraceptive use and susceptibility to HIV infection. This project investigates changes to systemic and genital tract immune responses elicited by oral, injectable, and intrauterine hormonal contraceptives that may impair a woman's ability to combat viral infection. Completion of this proposal will determine biological plausibility of suspected associations between hormonal contraceptive and increased susceptibility to HIV, and supply healthcare providers more informed recommendations regarding apt hormonal contraceptive choices among women at risk for HIV infection.

描述（由申请人提供）：通过使用激素避孕药调节粘膜和全身免疫 摘要 HIV 流行病的女性化日益严重，对研究的需求更加迫切，以提高我们对促进 HIV 向女性传播的危险因素的理解。许多流行病学调查表明，激素避孕药的使用与艾滋病毒感染易感性增强之间可能存在联系，但我们提议的实质性研究局限性假设是基于孕激素的避孕药 激素避孕药会抑制生殖道免疫反应，并使生殖器粘膜表面的保护性免疫平衡向感染的方向倾斜。这一假设基于我们的病毒粘膜感染小鼠模型中的新证据，即在感染前给予长效醋酸甲羟孕酮 (DMPA) 的小鼠中，树突状细胞 (DC) 激活、病毒特异性 T 细胞扩增和记忆 T 细胞发育受到抑制。值得注意的是，我们的初步研究能够证明，使用 DMPA 从女性体内直接激活的抗原呈递细胞 (APC) 诱导同种异体 T 细胞增殖的能力也会降低。这些结果有助于为这一研究问题提供一种新的方法，重点关注 DMPA、口服避孕药 (OC) 和含左炔诺孕酮宫内节育器 (LNG-IUD) 的免疫调节作用，这些作用可能会损害宿主对病毒病原体的反应。结合与我们初步调查中开发的方法类似的方法，我们将在妇女开始使用 OC、DMPA 或 LNG-IUD 之前（入组）和之后（1 个月的随访），利用从妇女的血液和子宫颈中分离出的 APC。为了确定这些药物对 APC 上调共刺激分子表达和诱导离体 T 细胞增殖的能力的影响（目标 1）。在两次研究访问中从女性身上收集的宫颈分泌物将用于比较几种先天免疫反应元件的浓度，而宫颈组织也将用于比较用 Toll 样受体 3 激动剂离体刺激的宫颈细胞产生的炎症和抗病毒细胞因子（目标 2）。在目标 2 中，我们还将确定 OC、DMPA 或 LNG-IUD 的使用是否会导致宫颈上皮层厚度减少或朗格汉斯细胞暴露于粘膜表面的情况增加。这些研究目标的完成将为 OCP、DMPA 和 LNG-IUD 抑制宿主反应（对抗生殖道感染所需）的能力提供首次比较评估，并且还将为医疗保健提供者提供关于最合适的激素选择的更明智的建议。有感染艾滋病毒风险的妇女采取避孕措施。 公共卫生相关性：艾滋病毒流行的女性化程度不断提高，需要更完整地描述激素避孕药的使用与艾滋病毒感染易感性之间的关系。该项目研究口服、注射和宫内激素避孕药引起的全身和生殖道免疫反应的变化，这些变化可能会损害女性抵抗病毒感染的能力。该提案的完成将确定激素避孕药与艾滋病毒易感性增加之间可疑关联的生物学合理性，并为医疗保健提供者提供有关艾滋病毒感染风险女性适当激素避孕药选择的更明智的建议。