Leptin is a hormone primarily involved in the regulation of basal metabolism and with an important role in immune responses. Leptin promotes inflammation and can accelerate onset and progression of several autoimmune diseases in mice. We have preliminary data that suggest that leptin may also play a role in the pathogenesis of murine and human systemic lupus erythematosus (SLE). Because of that, we will dissect the immune effects of leptin on human SLE and will test new possibilities of leptin-based intervention in SLE. Since we hypothesize that leptin affects the phenotype and function of immune-cell subsets and promotes the release of soluble mediators in order to exert its pro-pathogenic effects in SLE, we will study several cellular aspects (phenotype, function) and molecular events (cell signaling) induced by leptin in human SLE. We will then test different approaches of leptin-based therapeutic intervention in SLE using different leptin antagonists, first in vitro and then in vivo, to ultimately set the stage for translation studies to humans. In parallel, we will do genetic association studies to address whether leptin-related polymorphisms in SLE can contribute to a predisposing background by modulating leptin levels or responsiveness to leptin. By defining some crucial aspects related to the physiopathology of leptin in SLE, these studies will explore new strategies of therapeutic intervention for SLE that may ultimately lead to improved management of the disease. LAY DESCRIPTION OF THE PROJECT: Leptin is a hormone that controls several functions in humans, including immune responses. We have preliminary data that suggest that leptin can play an important role in the development and progression of systemic lupus erhytematosus, an incurable disease that is characterized by systemic effects and by the production of antibodies to self components that cause irreversible kidney damage. This study will detail the effects of leptin on human lupus and compare the potential of different leptin-based approaches with the goal to improve the current therapeutic management of human lupus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR053239-05
Application #
7876917
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Mancini, Marie
Project Start
2006-08-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
5
Fiscal Year
2010
Total Cost
$320,206
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Lourenço, Elaine V; Liu, Aijing; Matarese, Giuseppe et al. (2016) Leptin promotes systemic lupus erythematosus by increasing autoantibody production and inhibiting immune regulation. Proc Natl Acad Sci U S A 113:10637-42
Zhao, Jian; Wu, Hui; Langefeld, Carl D et al. (2015) Genetic associations of leptin-related polymorphisms with systemic lupus erythematosus. Clin Immunol 161:157-62
Yu, Yiyun; Liu, Yaoyang; Shi, Fu-Dong et al. (2013) Cutting edge: Leptin-induced ROR?t expression in CD4+ T cells promotes Th17 responses in systemic lupus erythematosus. J Immunol 190:3054-8
Wong, Maida; La Cava, Antonio; Hahn, Bevra H (2013) Blockade of programmed death-1 in young (New Zealand Black x New Zealand White)F1 mice promotes the suppressive capacity of CD4+ regulatory T cells protecting from lupus-like disease. J Immunol 190:5402-10
Galgani, Mario; Nugnes, Rosa; Bruzzese, Dario et al. (2013) Meta-immunological profiling of children with type 1 diabetes identifies new biomarkers to monitor disease progression. Diabetes 62:2481-91
Matarese, Giuseppe; La Cava, Antonio; Horvath, Tamas L (2012) In vivo veritas, in vitro artificia. Trends Mol Med 18:439-42
La Cava, Antonio (2012) Proinflammatory activities of leptin in non-autoimmune conditions. Inflamm Allergy Drug Targets 11:298-302
Procaccini, Claudio; De Rosa, Veronica; Galgani, Mario et al. (2012) Leptin-induced mTOR activation defines a specific molecular and transcriptional signature controlling CD4+ effector T cell responses. J Immunol 189:2941-53
Liu, Yaoyang; Yu, Yiyun; Matarese, Giuseppe et al. (2012) Cutting edge: fasting-induced hypoleptinemia expands functional regulatory T cells in systemic lupus erythematosus. J Immunol 188:2070-3
Lourenço, Elaine V; La Cava, Antonio (2011) Natural regulatory T cells in autoimmunity. Autoimmunity 44:33-42

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