Mechanisms of sex-determined resistance to L. mexicana

性激素已被证明对免疫反应的调节和男性和女性各种疾病的结果有深远的影响。我们发现雌性小鼠对内脏和皮肤利什曼病的抵抗力相对强于雄性小鼠。在L. mexicana模型中，我们发现雌性DBA/2小鼠产生有效的th1样反应，并且比雄性小鼠产生较大的，不可愈合的病变产生更小的病变。此外，我们还发现，经双氢睾酮（DHT）治疗的雌性DBA/2小鼠；一种不能转化为雌二醇的睾酮衍生物，变得对墨西哥乳杆菌敏感，而被阉割的雄性小鼠用17- β -雌二醇治疗后变得耐药。这些发现表明，虽然雌激素在诱导对墨西哥杆菌的保护性免疫中起着关键作用，但睾酮可能是有害的。尽管有这些发现，性激素（雌激素和睾酮）如何调节墨西哥乳杆菌感染期间的免疫反应尚不清楚。我们的长期目标是了解小鼠对不同利什曼原虫易感性的性别二态性的免疫学机制。在这个项目中，我们建议确定这些性激素（雌激素和睾酮）如何调节体内免疫反应并影响墨西哥L.引起的皮肤利什曼病的预后。第一个具体目标是确定雌激素如何诱导对墨西哥杆菌的保护性免疫的发展。在第二个特定目标中提出的研究将确定睾酮如何阻止保护性免疫反应的发展并介导对墨西哥杆菌的易感性。第三个具体目标将集中在骨髓嵌合体的研究上，以确定内源性性激素是否调节体内T细胞的功能发育并影响其向Th1或Th2亚群分化的能力。本项目提出的实验旨在研究雌激素（17- β -雌二醇）保护作用和睾酮诱导易感性作用的几种潜在机制。我们假设每种激素都将通过所提出的机制的一个子集起作用。我们希望能确定由每一种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.