Estrogen Receptor Modulators and Dendritic Cell Function

描述（由申请人提供）：预防或治疗乳腺癌的方案包括通过选择性雌激素受体调节剂（SERM）部分阻断全身雌激素反应。他莫昔芬和雷洛昔芬（星星）的研究是目前NCI乳腺癌预防试验，涉及用这两种SERM治疗乳腺癌高危女性。免疫细胞表达雌激素受体（ER）;然而，SERM对人类或小鼠对病原体或肿瘤的抗原特异性免疫应答的潜在影响在很大程度上没有记录。抗原特异性T细胞应答依赖于树突状细胞（DC）在先天性和适应性免疫启动期间的功能。活化的DC通过应答病原体相关分子和分泌炎性细胞因子来促进天然免疫应答。DC还显示高水平的MHC结合抗原和共刺激分子，导致初始T细胞的活化和分化。在小鼠离体培养系统中，我们已经表明，在从骨髓前体分化DC的过程中需要雌二醇，而他莫昔芬和雷洛昔芬抑制DC分化。我们最初的体外研究表明，在SERM存在下分化的少数DC在LPS活化后表现出MHCII和CD 86的表面表达降低。因此，我们假设全身性SERM治疗对免疫系统的影响可能是：1）淋巴器官中DC数量减少; 2）在发展的DC中抗原呈递功能受损。本文提出的实验将检查DC的数量和功能，以及由此产生的CD 4 + T细胞反应，在体内暴露于SERM后，在完整的和卵巢切除的小鼠。目的1：观察SERM对DC数量和表型的影响。目的2：研究SERM处理的DC在体内刺激初始CD 4 + T细胞的能力。目的3：用SERM暴露的DC检测体内辅助性T细胞的极化。了解SERM对DC功能的影响将是重要的，在评估这些药物在降低乳腺癌风险方面的疗效。

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.