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

基本信息

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
项目类别：
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

项目摘要

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）：通过荷尔蒙避孕药使用粘膜和系统性免疫的调节抽象的艾滋病毒大流行的女性化增加了对研究的更大需求，这将提高我们对促进HIV向女性传播的风险因素的理解。许多流行病学研究表明，激素避孕药使用和增强艾滋病毒易感性之间可能存在联系，但是我们建议的实质性研究局限性是基于孕激素的假设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在获取感染方面。该假设基于我们在病毒粘膜感染的鼠模型中的新型证明，即树突状细胞（DC）激活，病毒特异性T细胞膨胀和记忆T细胞在感染前抑制了小鼠施用的小鼠中的记忆T细胞发育。值得注意的是，我们的初步研究能够证明使用DMPA直接从女性中激活的抗原呈递细胞（APC）也具有降低的诱导同种异体T细胞增殖的能力。这些结果有助于为这一研究问题产生一种新的方法，该方法着重于DMPA，口服避孕药（OC）和左旋肺炎甲烷内部装置（LNG-IUD）的免疫调节作用，这些效果可能会影响针对病毒病原体的宿主反应。合并与我们初步研究中开发的方法相似的方法，我们将利用从妇女的血液和子宫颈（入学）和（1个月的随访访问）之后从妇女的血液和子宫颈中隔离的APC，它们会使用OC，DMPA或LNG-IUD来使用这些药物对APC的效果的影响，以确定这些药物对co eximule Morecules conter excimulity Merical conter的影响（征服）的效果（征服）。两次研究访问中从女性中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宫颈细胞与tollik-lik受体3刺激的宫颈细胞产生的炎症和抗病毒细胞因子产生（AIM 2）。在AIM 2中，我们还将确定OC，DMPA或LNG-IUD使用是否会引起宫颈上皮层厚度的任何降低或Langerhans细胞暴露于粘膜表面的任何增加。这些研究目标的完成将对OCP，DMPA和LNG-IUD的能力进行首次比较评估，以抑制打击生殖道感染所需的宿主反应，并且还将为医疗保健提供者提供有关HORMONAL避孕药最有知识的建议，以了解HIV风险的女性荷尔蒙避孕药。公共卫生相关性：越来越多的艾滋病毒流行的女性化要求更完整地描述了激素避孕药使用与艾滋病毒感染的易感性之间的关系。该项目研究了口服，可注射和宫内激素避孕药引起的系统性和生殖道免疫反应的变化，这些反应可能会损害女性对抗病毒感染的能力。该提案的完成将确定荷尔蒙避孕药和增加对艾滋病毒的易感性之间可疑关联的生物学合理性，并提供有关医疗保健提供者对艾滋病毒感染风险的妇女中适当的激素避孕选择的知识建议。