Defining the roles of TNF, lymphotoxin alpha and LIGHT in experimental visceral leishmaniasis

内脏利什曼病（VL）是由多诺瓦利什曼原虫和婴儿利什曼原虫（chagasi）引起的一种重要的人类疾病。对小鼠多诺瓦氏杆菌感染引起的实验性VL的研究，对VL的病因和VL患者严重免疫功能低下的原因有了重要的认识。我们实验室的工作表明，TNF家族细胞因子的成员在VL期间产生有效的免疫应答中发挥关键作用，但也介导了多诺瓦氏乳杆菌感染后的显著组织病理，特别是脾脏。在这项资助中，我们将确定TNF家族的几个关键成员在实验VL期间产生免疫和病理中的作用。我们还将测试这些分子的活性是否可以通过调节来控制疾病而不会产生有害的副作用。本研究结果对设计控制VL的新疫苗和治疗方法具有指导意义。此外，考虑到TNF家族成员在癌症和自身免疫性疾病中的重要作用，这项资助的工作将促进我们对许多重要人类疾病共同的致病过程的理解。

Visceral leishmaniasis (VL) is an important human disease caused by the protozoan parasites Leishmania donovani and L. infantum (chagasi). Studies in experimental VL caused by L. donovani infection of mice have resulted in major insights into the causes of VL and the reasons why VL patients become severely immunocompromised. Work from our laboratory has shown that members of the TNF family of cytokines play key roles in the generation of effective immune responses during VL, but also mediate significant tissue pathology, particularly in the spleen, following L. donovani infection. In this grant, we will define the roles of several key members of the TNF family in the generation of immunity and pathology during experimental VL. We will also test if the activity of these molecules can be modulated to control disease without detrimental side effects. Results from this research have implication for the design of new vaccines and therapeutics to control VL. In addition, given the important role of TNF family members in cancers and autoimmune diseases, the work in this grant will have advance our understanding of pathogenic processes that are common to many important human diseases.