Estrogen Receptor Modulators and Dendritic Cell Function

雌激素受体调节剂和树突状细胞功能

基本信息

批准号：
7140540
负责人：
Susan Kovats
金额：
$ 18.57万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-01 至 2008-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7140540
关键词：
antigen presentation cell differentiation cellular polarity cytokine dendritic cells estrogen receptors flow cytometry fluorescent dye /probe genetically modified animals helper T lymphocyte immunopharmacology inflammation laboratory mouse leukocyte activation /transformation monoclonal antibody ovariectomy pharmacokinetics selective estrogen receptor modulators

项目摘要

DESCRIPTION (provided by applicant): Regimens for prevention or treatment of breast cancer involve partial blockade of systemic estrogen responses via selective estrogen receptor modulators (SERM). The study of tamoxifen and raloxifene (STAR) is a current NCI breast cancer prevention trial involving treatment of women at high risk for breast cancer with these two SERM. Immune cells express estrogen receptors (ER); however, the potential effects of SERM on human or murine antigen-specific immune responses to pathogens or tumors are largely undocumented. Antigen specific T cell responses are dependent on the function of dendritic cells (DC) during the initiation of both innate and adaptive immunity. Activated DC promote innate immune responses by responding to pathogen associated molecules and secretion of inflammatory cytokines. DC also display high levels of MHC-bound antigens and costimulatory molecules, leading to the activation and differentiation of naive T cells. In a murine ex vivo culture system, we have shown that estradiol is required during DC differentiation from bone marrow precursors, while tamoxifen and raloxifene inhibit DC differentiation. Our initial in vitro studies show that the few DC that do differentiate in the presence of SERM exhibit decreased surface expression of MHCII and CD86 after LPS activation. Thus, we hypothesize that the consequences of systemic SERM treatment on the immune system might be: 1) reduced numbers of DC in lymphoid organs; and 2) impaired antigen presenting function in those DC that do develop. Experiments proposed here will examine DC numbers and function, and resulting CD4+ T cell responses, in intact and ovariectomized mice after in vivo exposure to SERM. Aim 1: Determine the effects of SERM on DC numbers and phenotype in vivo. Aim 2: Investigate the capacity of SERM treated DC to stimulate naive CD4+ T cells in vivo. Aim 3: Determine T helper cell polarization by SERM exposed DC in vivo. Knowledge of the effects of SERM on DC function will be important during evaluation of the efficacy of these drugs in breast cancer risk reduction.

描述（由申请人提供）：预防或治疗乳腺癌的方案涉及通过选择性雌激素受体调节剂（SERM）的全身性雌激素反应的部分阻断。他莫昔芬和雷洛昔芬（Star）的研究是当前的NCI乳腺癌预防试验，涉及对这两种Serm治疗患有乳腺癌的高风险的女性。免疫细胞表达雌激素受体（ER）；但是，SERM对病原体或肿瘤的人类或鼠类抗原特异性免疫反应的潜在影响在很大程度上没有证明。抗原特异性T细胞反应取决于启动先天和适应性免疫期间树突状细胞（DC）的功能。活化的直流通过对病原体相关分子的反应和炎症细胞因子的分泌来促进先天免疫反应。 DC还显示了高水平的MHC结合抗原和共刺激分子，从而导致幼稚T细胞的激活和分化。在鼠的离体培养系统中，我们表明在与骨髓前体的DC分化过程中需要雌二醇，而他莫昔芬和roxifene则抑制DC分化。我们的最初体外研究表明，在Serm存在下具有区分的少数DC在LPS激活后表现出MHCII和CD86的表面表达降低。因此，我们假设系统性SERM治疗对免疫系统的后果可能是：1）淋巴器官中DC数量减少； 2）在确实发展的DC中，抗原表现功能受损。此处提出的实验将检查DC数量和功能，并在体内暴露于Serm后完整和卵巢切除小鼠的CD4+ T细胞反应。 AIM 1：确定SERM对DC数字和体内表型的影响。 AIM 2：研究SERM处理的DC的能力，以刺激体内幼稚的CD4+ T细胞。 AIM 3：通过体内Serm暴露的DC确定T辅助细胞极化。在评估这些药物在降低乳腺癌风险中的功效时，了解SERM对DC功能的影响将很重要。