Mechanisms of sex-determined resistance to L. mexicana

性激素已被证明对男性和女性的免疫反应的调节和各种疾病的结果具有深远的影响。 我们发现雌性小鼠比雄性小鼠对内脏和皮肤利什曼病的抵抗力相对更强。 在L.在墨西哥模型中，我们发现雌性DBA/2小鼠产生有效的Th 1样应答，并且比雄性小鼠产生更小的损伤，所述雄性小鼠产生大的、不愈合的损伤。 此外，我们还发现去卵巢雌性DBA/2小鼠经双氢睾酮（DHT）处理后，对L。而用17-β-雌二醇处理的去势雄性小鼠变得有抗性。 这些结果表明，虽然雌激素在诱导抗L。墨西哥人睾丸激素可能有害 尽管有这些发现，但性激素（雌激素和睾酮）如何调节L。墨西哥感染。 我们的长期目标是了解负责小鼠对不同利什曼原虫物种的易感性性别二型性的免疫机制。 在这个项目中，我们打算确定这些性激素（雌激素和睾酮）如何调节体内免疫反应，并影响由L。墨西哥。 第一个特定的目标是确定雌激素如何诱导对L.墨西哥。 在第二个具体目标中提出的研究将确定睾酮如何防止保护性免疫反应的发展和介导对L。墨西哥。 第三个具体的目标将集中在研究使用骨髓嵌合体，以确定是否内源性激素调节功能的发展，T细胞在体内，并影响其分化为Th 1或Th 2亚群的能力，在这个项目中提出的实验旨在研究几个潜在的机制，保护作用的雌激素（17-β-雌二醇）和易感性诱导作用的睾酮。 我们假设，每种激素将通过一个子集的建议机制。 我们希望能找出每一种基因都能特异性调节的免疫机制。

Sex hormones have been shown to have a profound influence on modulation of immune responses and the outcome of various diseases in males and females. We have found that female mice are relatively more resistant visceral and cutaneous leishmaniasis than the male mice. In the L. mexicana model, we found that female DBA/2 mice mount an efficient Th1-like response and develop smaller lesions than the male mice that develop large, non-healing lesions. Moreover, we also found that ovactomized female DBA/2 mice treated with dihydrotestosterone (DHT); a derivative of testosterone that can not be converted to estradiol, become susceptible to L. mexicana whereas castrated male mice treated with 17-beta-estradiol become resistant. These findings suggest that while estrogen plays a critical role in induction of protective immunity against L. mexicana, testosterone may be detrimental. Despite these findings it is not clear how sex hormones (estrogen and testosterone) regulate immune responses during L. mexicana infection. Our long term goal is to understand the immunological mechanisms responsible for gender dimorphism in susceptibility of mice to different Leishmania species. In this project, we propose to determine how these sex hormones (estrogen and testosterone) regulate in vivo immune responses and influence the outcome of cutaneous leishmaniasis caused by L. mexicana. The first specific aim would determine how estrogen induces the development of protective immunity against L. mexicana. The studies proposed in the second specific aim would determine how testosterone prevents development of protective immune response and mediates susceptibility to L. mexicana. The third specific aim will focus on studies using bone marrow chimeras to determine whether endogenous sex hormones regulate functional development of T cells in vivo and affects their ability to differentiate into Th1 or Th2 subsets The experiments proposed in this project are designed to investigate several potential mechanisms of the protective effects of estrogen (17-beta-estradiol) and the susceptibility-inducing effects of testosterone. We hypothesize that each hormone will act through a subset of the proposed mechanisms. We hope to identify immune mechanisms that are specifically modulated by each.