Modulation of hormonal and systemic immunity by hormonal contraceptive use

说明（申请人提供）：激素避孕药对粘膜和全身免疫的调节摘要HIV流行的女性化趋势日益增长，这就更需要进行研究，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，但大量的研究局限性 我们建议假设是孕激素为基础的 激素避孕药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倾向于获得感染。这一假设是基于我们的病毒粘膜感染小鼠模型中的新证据，即在感染前给予醋酸甲羟孕酮（DMPA）的小鼠中，树突状细胞（DC）活化、病毒特异性T细胞扩增和记忆性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，直接从使用DMPA的女性体内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。这些结果有助于产生一个新的方法来解决这个研究问题，重点是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，可能会损害宿主对病毒病原体的反应。与我们的初步研究中开发的方法类似的方法，我们将利用在开始使用OC、DMPA或LNG-IUD之前（登记）和之后（1个月随访）从妇女的血液和宫颈分离的APC，以确定这些药物对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（目的1）。在两次研究访视时从女性收集的宫颈分泌物将用于比较几种先天免疫应答元件的浓度，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（Aim 2）。在目标2中，我们还将确定OC、DMPA或LNG-IUD是否会导致宫颈上皮层厚度减少或粘膜表面朗格汉斯细胞暴露增加。这些研究目标的完成将提供OCP，DMPA和LNG-IUD抑制对抗生殖道感染所需的宿主反应的能力的第一次比较评估，并且还将为医疗保健提供者提供关于HIV风险妇女中激素避孕的最适当选择的更明智的建议。

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.