Myeloid-lineage cells and immunopathology in Leishmania braziliensis

描述（由申请人提供）：利什曼病是巴西的一个主要公共卫生问题，我们提出的实验将促进我们对这种疾病的理解，目的是更有效地控制疾病。该项目涉及美国宾夕法尼亚大学和马里兰州大学以及巴西巴伊亚大学之间的合作。L.巴西人感染与强烈的炎症反应有关，这是引起疾病的主要因素。L.巴西红细胞瘤表现出循环促炎单核细胞的显著增加，表明这些细胞促成了在这些患者中观察到的严重病理性炎症反应。为了获得有关骨髓系细胞在这种疾病中的作用的基本信息，我们将在巴西皮肤利什曼病患者的表型和功能水平上评估循环和组织定位的骨髓细胞。我们还将确定促炎单核细胞的相对频率和/或其分泌产物的水平是否可作为治疗成功的预测性生物标志物。如果我们的研究表明促炎性单核细胞在疾病进展中起着致病作用，那么这将为开发特异性靶向促炎性效应物的新免疫疗法提供令人信服的理论基础。巴西患者。我们假设促炎单核细胞的扩增及其随后在病变内分化为树突状细胞，导致炎症细胞因子和趋化因子的过量产生，从而向病变募集额外的T细胞和单核细胞。为了解决这一假设，我们将表型和功能特点的循环单核细胞（目标1）和骨髓谱系人群的病变（目标2）的利什曼病患者。在目标3中，我们将直接测试促炎单核细胞或其分泌产物是否可作为早期皮肤利什曼病疾病进展和治疗反应的有用生物标志物。这些研究将增强我们对人类单核细胞生物学的基本理解，并使我们能够应用这些信息更好地制定控制皮肤利什曼病的策略。

DESCRIPTION (provided by applicant): Leishmaniasis is a major public health problem in Brazil, and we propose experiments that will advance our understanding of this disease with the goal of more effective disease control. This project involves collaborations between the Universities of Pennsylvania and Maryland in the USA, and the University of Bahia in Brazil. L. braziliensis infection is associated with a strong inflammatory response that is the major factor in causing disease. Patients with L. braziliensis exhibit a pronounced increase in circulating proinflammatory monocytes, suggesting that these cells contribute to the severe pathologic inflammatory response observed in these patients. To obtain fundamental information about the role of myeloid-lineage cells in this disease, we will evaluate circulating and tissue-localized myeloid cells at a phenotypic and functional level in cutaneous leishmaniasis patients in Brazil. We will also determine if the relative frequency of proinflammatory monocytes and/or levels of their secreted products serve as predictive biomarkers of treatment success. If our studies indicate that proinflammatory monocytes play a causative role in the disease progression, it would provide a convincing rationale for the development of new immunotherapies specifically targeting proinflammatory effectors for L. braziliensis patients. We hypothesize that the expansion of proinflammatory monocytes, and their subsequent differentiation into dendritic cells within lesions, results in the excess production of inflammatory cytokines and chemokines that recruit additional T cells and monocytes to the lesion. To address this hypothesis, we will phenotypically and functionally characterize both circulating monocytes (Aim 1) and the myeloid-lineage populations in the lesion (Aim 2) of leishmaniasis patients. In Aim 3 we will directly test if either proinflammatory monocytes or their secreted products serve as useful biomarkers in disease progression and response to therapy in early cutaneous leishmaniasis. These studies will enhance our basic understanding of the biology of human monocytes, and allow us to apply that information to better develop strategies to control cutaneous leishmaniasis.