Ovariectomy Induced T Cell Inflammatory Cytokines/Bone Loss in Young & Old Mice

卵巢切除术诱导年轻人 T 细胞炎症细胞因子/骨质流失

• 批准号: 7906811
• 负责人: ROBERTO PACIFICI
• 金额: $ 29.55万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7906811
• 关键词: Age; Aging; Aging-Related Process; Antigen Presentation; Antigens; Attenuated; Bone Formation Stimulation; Bone Marrow; Bone Resorption; CD8B1 gene; Castration; Cells; Clinical; Data; Disease; Estrogens; Home environment; Homing; Immune Tolerance; Immune system; Inflammation Mediators; Inflammatory; Integrins; Knockout Mice; Lead; Link; Longevity; Lymphoid; Mediating; Mediator of activation protein; Menopause; Modeling; Mus; Nude Mice; Organ; Osteoclasts; Osteoporosis; Output; Ovarian; Ovariectomy; Peptide/MHC Complex; Peptides; Peripheral; Phenotype; Play; Postmenopausal Osteoporosis; Production; Public Health; Role; Source; T cell response; T memory cell; T-Lymphocyte; TNF gene; Testing; Up-Regulation; Woman; bone; bone loss; cytokine; design; disease characteristic; in vivo; new therapeutic target; prevent; reconstitution; senescence; stem; wasting; young adult

DESCRIPTION (provided by applicant): Postmenopausal osteoporosis (PMO) is a frequent disease of aging women stemming from the cessation of ovarian function at menopause. Studies in ovariectomized (ovx) mice, an established model of PMO, have disclosed that enhanced production of TNF by an expanded pool of activated T cells plays a key role in the mechanism of ovx induced bone loss. However, it is presently unknown if ovx causes bone loss by stimulating T cell TNF production exclusively in the BM (as opposed to enhancing T cell TNF production in all lymphoid organs). Thus, in aim 1 we will determine: a) if ovx alters the phenotype and the number of T cells which home to bone, b) whether the suppression of T cell homing to the BM (via treatment with anti- LFA-1a and anti-integrin a4 subunit) prevents ovx induced bone loss, and c) if ovx causes bone loss in mice lacking the secondary lymphoid organs. Our data show that estrogen (E) deficiency causes a rebound in thymic T cell output that contributes to the T cell pool expansion and the bone loss induced by ovx in young adult mice. The resurgence of thymic activity induced by E deficiency is attenuated in older mice and we hypothesize that such diminished rebound in thymic T cell export mitigates the capacity of ovx to induce bone loss in older mice. Thus, in Aim 2 we will utilize thymectomized/ovx mice to determine the contribution of thymic T cell output to ovx-induced bone loss in aging mice. Both aging and castration decrease immune tolerance. Accordingly, our data show that ovx increases MHC expression and antigen presentation, suggesting that ovx induces higher MHC mediated presentation of self peptides. We hypothesize that this enhanced T cell response to self-peptide/MHC is essential for ovx-induced bone loss. We will test this hypothesis by: a) determining the contribution of MHC expression to ovx induced bone loss, b) testing if the response of T cells to self-peptide/MHC changes after ovx, c) determining if there is a change in the T cell repertoire after ovx due to an oligoclonal expansion of self-reactive T cells, and d) investigating if ovx breaks tolerance to a defined antigen. The project fulfills the objective of this RFA, that is to solicits applications designed to determine either the causes of the changes in inflammatory mediators induced by aging (including studies on the source of the altered cytokine production), or the consequences of such changes in conditions and diseases characteristic of senescence. This project is also relevant for public health as may lead to a better characterization of the mechanism of action of E in bone at different ages, demonstrate a link between the immune system and bone, and identify novel therapeutic targets for osteoporosis.

描述（由申请人提供）：绝经后骨质疏松症（PMO）是一种常见于绝经期卵巢功能停止的老年妇女的疾病。在卵巢切除（ovx）小鼠（一种已建立的PMO模型）中的研究已经公开了通过活化T细胞的扩增池增强TNF的产生在ovx诱导的骨丢失的机制中起关键作用。然而，目前尚不清楚OVX是否通过刺激BM中的T细胞TNF产生而引起骨丢失（与增强所有淋巴器官中的T细胞TNF产生相反）。因此，在目的1中，我们将确定：a）OVX是否改变归巢至骨的T细胞的表型和数量，B）归巢至BM的T细胞的抑制（通过用抗LFA-1 a和抗整联蛋白α 4亚基处理）是否阻止OVX诱导的骨损失，和c）OVX是否在缺乏次级淋巴器官的小鼠中引起骨损失。 我们的数据表明，雌激素（E）缺乏导致胸腺T细胞输出的反弹，这有助于T细胞池的扩增和OVX诱导的年轻成年小鼠骨丢失。在老年小鼠中，E缺乏诱导的胸腺活性的复苏减弱，我们假设胸腺T细胞输出的这种减少的反弹减轻了OVX诱导老年小鼠骨丢失的能力。因此，在目标2中，我们将利用胸腺切除/ovx小鼠来确定胸腺T细胞输出对衰老小鼠中ovx诱导的骨丢失的贡献。 衰老和去势都会降低免疫耐受性。因此，我们的数据表明，ovx增加MHC表达和抗原呈递，表明ovx诱导更高的MHC介导的自我肽呈递。我们假设这种增强的T细胞对自身肽/MHC的应答对于OVX诱导的骨丢失是必不可少的。我们将通过以下方式检验这一假设：a）确定MHC表达对OVX诱导的骨丢失的贡献，B）测试OVX后T细胞对自身肽/MHC的应答是否改变，c）确定OVX后T细胞库是否由于自身反应性T细胞的寡克隆扩增而改变，以及d）研究OVX是否破坏对确定抗原的耐受性。 该项目实现了RFA的目标，即征集旨在确定衰老诱导的炎症介质变化的原因（包括对细胞因子产生改变的来源的研究）或衰老特征性疾病和疾病的变化的后果的应用。 该项目也与公共卫生有关，因为可能导致更好地表征不同年龄段骨骼中E的作用机制，证明免疫系统与骨骼之间的联系，并确定骨质疏松症的新治疗靶点。