Initiation Of Immune Responses in Chronic Leishmaniasis

利什曼病是一个主要的人类健康问题，需要新的免疫疗法， 缓解通常与这种感染相关的慢性疾病。C57 BL/6小鼠的感染 与墨西哥利什曼原虫未能解决，因此提供了一个很好的模式，调查 导致人类慢性利什曼病的免疫反应在本提案中， 导致由L.墨西哥群岛 研究，特别是对这些寄生虫无法诱导持续的 淋巴结的扩张引流感染部位。淋巴结肿大或肥大 是对感染的生理反应，确保最大数量的T细胞接触 与抗原呈递树突状细胞结合。与L. mexicana、L.少校， 诱导C57 BL/6小鼠的愈合感染，并刺激细胞大小的快速扩张。 淋巴结引流病变部位。树突状细胞已被证明是启动 淋巴结肥大，并研究确定什么可能缺乏树突状细胞反应 去洛墨西哥正在进行中。发现的一个缺陷是L.墨西哥感染的 树突状细胞对免疫刺激DNA或CpG应答。CpG激活树突状细胞， 连接TLR 9，与L.墨西哥感染的树突状细胞 发现L. major不能诱导TLR 9缺陷小鼠的淋巴结肥大。这 结果表明，TLR 9在早期免疫应答中起着以前未被认识到的作用， 利什曼原虫在目的1中，提出研究解剖介导淋巴结的事件 肥大，以了解为什么L。墨西哥没有引起这种反应。在目标2中， 与L.墨西哥感染的树突状细胞对CpG的反应 将被调查。最后，在目标3中，研究促进增加淋巴结扩张，使用 树突状细胞和TLR配体。综合起来，这些实验应该提供 为慢性利什曼病的新免疫疗法的发展奠定了基础。

Leishmaniasis is a major human health problem, and new immunotherapies are required to alleviate the chronic disease that is often associated with this infection. Infections of C57BL/6 mice with Leishmania mexicana fail to resolve, and therefore provide an excellent model to investigate the immune responses that lead to chronic human leishmaniasis. In this proposal, the mechanisms responsible for the meager immune response elicited by L. mexicana are investigated, focusing specifically on the inability of these parasites to induce a sustained expansion of the lymph node draining the site of infection. Lymph node expansion or hypertrophy is a physiologic response to infection, ensuring that the largest number of T cells come in contact with antigen-presenting dendritic cells. In contrast to L. mexicana, a related parasite, L. major, induces a healing infection in C57BL/6 mice and stimulates a rapid expansion in the size of the lymph node draining the lesion site. Dendritic cells have been shown to be critical for initiating lymph node hypertrophy, and studies to define what may be lacking in the dendritic cell response to L. mexicana are ongoing. One deficit uncovered was the inability of L. mexicana-infected dendritic cells to respond to immunostimulatory DNA or CpG. CpG activates dendritic cells by ligating TLR9, and corresponding with the deficit observed in L. mexicana-infected dendritic cells was the finding that L. major cannot induce lymph node hypertrophy in TLR9 deficient mice. This result indicates that TLR9 plays a previously unappreciated role in the early immune response to Leishmania. In Aim 1, studies are proposed to dissect the events mediating lymph node hypertrophy to understand why L. mexicana fails to induce this response. In Aim 2, the mechanisms associated with the inability of L. mexicana-infected dendritic cells to respond to CpG will be investigated. Finally, in Aim 3, studies to promote increased lymph node expansion, using dendritic cells and TLR ligands, are proposed. Taken together, these experiments should provide the foundation for the development of new immunotherapies for chronic leishmaniasis.