Myeloid-lineage cells and immunopathology in Leishmania braziliensis

巴西利什曼原虫的骨髓谱系细胞和免疫病理学

• 批准号: 8197000
• 负责人: PHILLIP SCOTT
• 金额: $ 60.16万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197000
• 关键词: Address; Alternative Therapies; Antigen-Presenting Cells; Antimony; Applications Grants; Applied Research; Area; Attention; Automobile Driving; Award; Awareness; Basic Science; Bioinformatics; Biological Markers; Biological Markers; Biology; Biopsy; Blood; Brazil; Budgets; CXCL9 gene; Cell Lineage; Cell physiology; Cells; Clinical; Cohort Studies; Collaborations; Cross-Sectional Studies; Cutaneous Leishmaniasis; Data; Dendritic Cells; Development; Disease; Disease Outcome; Disease Progression; Exhibits; Faculty; Failure; Fellowship; Flow Cytometry; Foundations; Frequencies; Funding; Gene Expression; Genetic Determinism; Genetic Polymorphism; Goals; Grant; Health; Healthcare; Human; Human Biology; Image; Immune response; Immunohistochemistry; Immunology; Immunotherapy; Incidence; Individual; Infection; Infectious Diseases Research; Inflammation; Inflammatory; Inflammatory Response; Institutes; Institution; Instruction; Interferons; International; Intervention; Intramuscular Injections; Knowledge; Laboratories; Learning; Leishmania; Leishmania braziliensis; Leishmaniasis; Lesion; Letters; Link; Lymphangiogenesis; Lymphatic Diseases; Maryland; Mentorship; Microarray Analysis; Minor; Monitor; Myelogenous; Myeloid Cells; Outcome; Paper; Parasites; Parasitic Diseases; Parasitic infection; Parasitology; Participant; Pathogenesis; Pathologic; Pathology; Patients; Pennsylvania; Pentoxifylline; Phagocytes; Pharmaceutical Preparations; Phase; Phosphodiesterase Inhibitors; Play; Population; Postdoctoral Fellow; Principal Investigator; Production; Protozoa; Public Health; Publishing; Recording of previous events; Recruitment Activity; Relative (related person); Research; Research Personnel; Role; Schistosomiasis; Scientist; Series; Services; Site; Staging; Stimulus; T cell response; T-Lymphocyte; TNF gene; Techniques; Teleconferences; Testing; Therapeutic; Time; Tissues; Training; Treatment Efficacy; Tropical Medicine; United States National Institutes of Health; Universities; Visceral Leishmaniasis; Visit; Work; angiogenesis; autocrine; base; cell type; chemokine; chemotherapy; clinical epidemiology; conventional therapy; cytokine; design; disorder control; immunopathology; improved; innovation; interest; intravenous injection; killings; macrophage; medical attention; meetings; monocyte; new technology; novel; novel diagnostics; novel therapeutic intervention; peripheral blood; professor; programs; research study; response; success; treatment strategy

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.

描述(申请人提供)：利什曼病是巴西的一个主要公共卫生问题，我们建议进行实验，以促进我们对这种疾病的了解，以实现更有效的疾病控制。该项目涉及美国宾夕法尼亚大学和马里兰大学以及巴西巴伊亚大学之间的合作。巴西乳杆菌感染与强烈的炎症反应有关，而炎症反应是导致疾病的主要因素。巴西乳杆菌感染患者循环中的致炎单核细胞显著增加，提示这些细胞参与了在这些患者中观察到的严重的病理炎症反应。为了获得有关髓系细胞在这种疾病中的作用的基本信息，我们将在表型和功能水平上评估巴西皮肤利什曼病患者的循环和组织定位的髓系细胞。我们还将确定促炎症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生物标志物。如果我们的研究表明促炎单核细胞在疾病进展中起到致病作用，这将为开发针对巴西乳杆菌患者的促炎效应的新的免疫疗法提供令人信服的理论基础。我们推测，致炎单核细胞的扩张，以及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度产生，从而向病变招募更多的T细胞和单核细胞。为了解决这一假设，我们将对利什曼病患者皮损中的循环单核细胞(目标1)和髓系群体(目标2)进行表型和功能特征分析。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在早期皮肤利什曼病的疾病进展和治疗反应中作为有用的生物标志物。这些研究将增强我们对人类单核细胞生物学的基本了解，并使我们能够应用这些信息来更好地开发控制皮肤利什曼病的策略。