Understanding the effects of Gender Affirming Hormone Therapy (GAHT) on immune function using a systems immunology approach

项目摘要 美国有100万人被认定为跨性别者（占人口的0.39%），其中90%是 无论是在性别肯定激素治疗（GAHT）或考虑开始GAHT。了解如何 女性化GAHT（雌二醇）和男性化GAHT（睾酮）影响免疫功能是必要的， 考虑到（i）变性妇女的人类免疫缺陷病发病率显著增加， 病毒（艾滋病毒）感染的全球范围内和（ii）很少有人知道如何GAHT影响免疫功能，或 易受感染。 为了解决这一知识缺口，我们的团队将联合收割机结合已建立的最先进的系统免疫学 在GAHT之前和期间完成跨性别女性纵向队列的方法。我们之前 我用这个纵向模型来证明GAHT的雌性化和雄性化都能诱导DNA甲基化 在整个外周血中特定基因组位点的变化，其中一些以前与 青春期或怀孕。 在本项目的前三个目标中，我们将使用来自以下患者的可存活储存的外周血单个核细胞： 在基线和GAHT后3个月和6个月，通过应用系统免疫学 方法，我们首先寻求建立GAHT如何改变循环免疫谱和血浆代谢物， 两者都是对感染和疫苗反应的预测因子。接下来是先天性和适应性免疫功能 将通过一系列微生物和病毒微生物，特别是HIV， 随后进行细胞因子测定。最后，在目标3中，我们将绘制特异性免疫应答的潜在表观基因组图谱。 细胞类型，通过分析活性组蛋白修饰和开放染色质在单细胞水平。总之，上述 这种方法将确定响应GAHT的免疫功能改变的关键分子驱动因素，并产生 为进一步研究提出新的假设。最终，了解GAHT如何改变免疫系统的分子生物学， 细胞将为免疫功能受损的情况下的治疗干预开辟新途径 因为GAHT。 在目标4中，我们将使用我们建立的纵向GAHT招募策略来建立一个跨性别者队列。 收集大量生物标本的人。这将使我们能够探索GAHT对阴道的影响， 以及粪便微生物群和应激，它们是已知的免疫调节剂。一旦建立，这种纵向 队列将提供应用一系列最先进的分子和免疫表型分析的机会 了解GAHT是否以及如何影响HIV感染易感性的技术。

PROJECT SUMMARY One million individuals in the United States identify as transgender (0.39% of population), of which 90% are either on gender-affirming hormone therapy (GAHT) or considering starting GAHT. Understanding how feminizing GAHT (estradiol) and masculinizing GAHT (testosterone) influence immune function is imperative, considering that (i) transgender women have a significantly increased prevalence of Human Immunodeficiency Virus (HIV) infection worldwide and (ii) little is known about how GAHT influences immune function or susceptibility to infections. To address this gap in knowledge, our team will combine established state-of-the-art systems immunology approaches to a completed longitudinal cohort of transgender women before and during GAHT. We previously used this longitudinal model to show that both feminizing and masculinizing GAHT induced DNA methylation changes at specific genomic loci in whole peripheral blood, some of which were previously associated with puberty or pregnancy. In the first three aims of this project, we will use viably stored peripheral blood mononuclear cells from transgender women at baseline, and 3 and 6 months following GAHT. By applying a systems immunology approach, we first seek to establish how GAHT changes the circulating immune profile and plasma metabolites, both of which are predictors of response to infection and vaccines. Next, innate, and adaptive immune function will be assessed through in vitro stimulation with a range of microbial and viral microbes, specifically HIV, followed by cytokine assays. Finally, in Aim 3 we will map the underlying epigenomic profile of specific immune cell types, by profiling active histone modifications and open chromatin at single cell level. Together, the above approach will identify the key molecular drivers of altered immune function in response to GAHT and generate new hypotheses for further study. Ultimately, understanding how GAHT alters the molecular biology of immune cells will open new avenues to therapeutic intervention in cases where immune function is compromised because of GAHT. In aim 4, we will use our established longitudinal GAHT recruitment strategy to establish a cohort of transgender individuals with extensive biospecimen collection. This will allow us to explore the effects of GAHT on the vaginal and fecal microbiota and stress, which are known modulators of immunity. Once established, this longitudinal cohort will provide opportunities to apply a range of state-of-the-art molecular and immunophenotyping techniques to understand if and how GAHT affects susceptibility to HIV infection.