A Mouse Model to Test the Effects of Gender-affirming Hormone Therapy on HIV Vaccine-induced Immune Responses

测试性别肯定激素疗法对 HIV 疫苗诱导的免疫反应影响的小鼠模型

• 批准号: 10748892
• 负责人: Derek Wilson Cain
• 金额: $ 25.52万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-26 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10748892
• 关键词: Address; Adjuvant; Adverse effects; Animal Model; Antiandrogen Therapy; Antibody Response; Antigens; Autoimmune Diseases; B-Lymphocytes; C57BL/6 Mouse; Caring; Case Study; Cells; Clinical; Consensus; Data Set; Development; Dose; Estrogens; Exhibits; Female; Feminization; Gene Expression; Genes; Genetic Transcription; Goals; Gonadal Steroid Hormones; Grant; HIV; HIV vaccine; HIV-1; Homeostasis; Hormones; Human; Immune; Immune response; Immune system; Immunity; Immunize; Immunologic Tests; Immunologics; Immunomodulators; Immunophenotyping; Incidence; Individual; Knock-in Mouse; Knowledge; Lymphoid Tissue; Measurement; Medicine; Mus; Natural Immunity; Peripheral Blood Mononuclear Cell; Persons; Physiology; Population; Reaction; Regimen; Serology test; Structure of germinal center of lymph node; Testing; Testosterone; Vaccination; Vaccine Adjuvant; Vaccines; Woman; adaptive immunity; adverse outcome; aluminum sulfate; biological sex; bone; cell type; cis-female; cis-male; comparison control; design; differential expression; experimental study; gender affirming hormone therapy; gender transition; high risk; hormone therapy; human model; human subject; immunoregulation; in vivo; innate immune pathways; innovation; insight; male; men; mouse model; neutralizing antibody; reproductive function; response; sex; single-cell RNA sequencing; transcriptome; transcriptomics; transgender; vaccine development; vaccine response; vaccine-induced antibodies

Project Summary Biological sex impacts the immune system, as evidenced by differences between men and women in vaccine- induced humoral responses. There is a considerable gap in knowledge, however, surrounding the immunological responsiveness of transgender people, a population at considerably higher risk for HIV and other STIs. To address this gap, we propose to develop an animal model of feminizing hormone therapy to study the effects of estrogen/anti-testosterone therapy on HIV vaccine-induced immune responses. Cross-sex hormone therapy (XHT) is the most common approach for transition-related care, but immunological studies of transgender individuals are generally limited to case studies. Animal models of gonadectomy and/or supranormal hormone treatment have implicated sex hormones as potent modulators of the immune system, with estrogens generally appearing to enhance immune responses and testosterone inhibiting them. However, ambiguous (and sometimes paradoxical) observations have obscured an overarching consensus for sex hormone effects on immunity. In recent years, mouse models of XHT have provided important insights into effects of prolonged hormone therapy on bone physiology, reproductive function etc., but information on the effects of sex hormone therapy on immune responsiveness is scarce. For this project, we will develop a mouse model of XHT that recapitulates clinical hormone therapy for male-to-female transition in humans. We hypothesize that mice and humans share sets of immune-related genes that are impacted by a feminizing hormone regimen, and that mice undergoing XHT will exhibit altered immune responses to a HIV vaccine compared to control male mice. To test these hypotheses, we will define the relevance of this mouse model to human transition-related care through a single-cell transcriptomics approach to define differentially expressed genes in control and XHT mice, and then compare these cell-type specific sets of differentially expressed genes to those obtained from the same analyses of people undergoing feminizing hormone therapy (pre and two years post-initiation of hormone therapy) (Specific Aim 1). To test the effects of hormone therapy on in vivo vaccine responses, we will immunize control male mice and XHT mice with a HIV vaccine regimen that is highly sensitive to sex-dependent factors (Specific Aim 2). Should this study reveal an immunoregulatory effect of feminizing hormone therapy on HIV vaccine responsiveness in mice, it will provide a new platform for assessing the effects of sex hormones on vaccine responses. Moreover, this animal model could then be used to test various vaccination parameters (adjuvant, dose, interval, etc.) for sex hormone-dependent effects, with the ultimate goal of designing an HIV vaccine that maximizes efficacy but minimizes adverse outcomes.

项目摘要 生物学性别会影响免疫系统，这是由疫苗中男女之间的差异所证明的 诱导体液反应。但是，知识的差距很大 跨性别者的免疫反应能力，艾滋病毒风险高得多的人群 其他性传播感染。为了解决这一差距，我们建议开发一种女性激素治疗的动物模型 研究雌激素/抗托酮治疗对HIV疫苗诱导的免疫反应的影响。 跨性激素治疗（XHT）是过渡相关护理的最常见方法，但免疫学 跨性别者的研究通常仅限于案例研究。腺切除术和/或的动物模型 超型激素治疗已将性激素视为免疫系统的有效调节剂， 由于雌激素通常似乎增强了免疫反应，睾丸激素抑制了它们。然而， 模棱两可（有时甚至是矛盾的）观察结果掩盖了性别的总体共识 激素对免疫的影响。近年来，XHT的鼠标模型为 长时间激素治疗对骨生理，生殖功能等的影响，但有关 性激素疗法对免疫反应性的影响很少。 对于这个项目，我们将开发XHT的小鼠模型，该模型概括了临床激素治疗的 男性到女性的过渡。我们假设小鼠和人类共享一组免疫相关的 受女性激素方案影响的基因，并且经历了XHT的小鼠会显示出改变 与对照雄性小鼠相比，对HIV疫苗的免疫反应。为了检验这些假设，我们将定义 通过单细胞转录组学 定义对照和XHT小鼠中差异表达基因的方法，然后比较这些细胞类型 从相同分析的人中获得的特定差异表达基因 女性激素治疗（激素治疗后两年）（特定目标1）。测试 激素治疗对体内疫苗反应的影响，我们将免疫对照雄性小鼠和XHT小鼠 具有对性依赖性因素高度敏感的HIV疫苗方案（特定目标2）。 这项研究是否应揭示女性激素治疗对HIV疫苗的免疫调节作用 在小鼠中的反应性，它将提供一个新的平台来评估性激素对疫苗的影响 回答。此外，该动物模型然后可用于测试各种疫苗接种参数（辅助，， 剂量，间隔等）用于性激素依赖性作用，其最终目标是设计一种HIV疫苗 最大化功效，但最大程度地减少不良结果。