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 生理性别影响免疫系统，男女在疫苗接种方面的差异证明了这一点。 诱导体液反应。然而，在知识方面存在着相当大的差距， 变性人的免疫反应，艾滋病毒感染风险相当高的人群， 其他性传播疾病。为了解决这一差距，我们建议开发一种雌性化激素治疗的动物模型， 研究雌激素/抗睾酮治疗对HIV疫苗诱导的免疫应答的影响。 交叉性激素治疗（XHT）是过渡期相关护理的最常见方法，但免疫学 对变性人的研究一般限于个案研究。性腺切除术和/或 超正常激素治疗涉及性激素作为免疫系统的有效调节剂， 雌激素通常表现为增强免疫反应，而睾酮抑制免疫反应。然而，在这方面， 模棱两可的（有时是自相矛盾的）观察模糊了对性的总体共识 激素对免疫力的影响近年来，XHT的小鼠模型提供了重要的见解， 长期激素治疗对骨生理学、生殖功能等的影响，但是关于 性激素治疗对免疫反应性的影响很少。 在这个项目中，我们将开发一种XHT小鼠模型，以重现临床激素治疗， 人类从男性到女性的转变我们假设小鼠和人类共享免疫相关的 受女性化激素方案影响的基因，以及接受XHT的小鼠将表现出改变的基因， 与对照组雄性小鼠相比，对HIV疫苗的免疫反应。为了验证这些假设，我们将定义 该小鼠模型通过单细胞转录组学与人类过渡相关护理的相关性 方法来确定差异表达的基因在对照组和XHT小鼠，然后比较这些细胞类型 特定的差异表达基因组与那些从接受基因治疗的人的相同分析中获得的基因组相比， 女性化激素治疗（激素治疗开始前和开始后2年）（具体目标1）。测试 激素治疗对体内疫苗应答的影响，我们将免疫对照雄性小鼠和XHT小鼠 使用对性别依赖因素高度敏感的HIV疫苗方案（具体目标2）。 这项研究是否应该揭示女性化激素治疗对HIV疫苗的免疫调节作用 小鼠的反应性，这将为评估性激素对疫苗的影响提供新的平台 应答此外，该动物模型然后可用于测试各种疫苗接种参数（佐剂， 剂量、间隔等）的艾滋病毒疫苗，最终目标是设计一种 最大限度地提高疗效，但最大限度地减少不良后果。