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力

• 批准号: 8659112
• 负责人: Thomas L. Cherpes
• 金额: $ 18.65万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-20 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8659112
• 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.

摘要：随着艾滋病毒流行的女性化，对研究的需求越来越大，这将提高我们对促进艾滋病毒向妇女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易感性的增强之间可能存在联系，但我们提出的大量研究局限性假设是基于黄体酮