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.
