The treatment of systemic lupus erythematosus (SLE), a systemic autoimmune disease that affects many organs such as the joints, skin and kidneys, is based on non-specific immunosuppressive medications that are often ineffective and have very significant side effects. In order to develop more specific less toxic medications, we need a better understanding of the exact steps that lead and then maintain the abnormal autoimmune response in SLE. Recently, a particular T cell subset that expresses the pro-inflammatory cytokine IL-17 has been shown to be present in the kidneys and peripheral blood of patients with SLE. IL-17 producing cells can induce both local inflammation in the target-organs and also help B cells produce antibodies, two of the hallmarks of SLE pathology. In order to assess the role of IL-17 producing T cells in SLE, we used a mouse model of lupus. Indeed, we showed in this pilot study that IL-17 producing T cells accumulate in the spleen and lymph nodes of these mice and also infiltrate their kidneys. We further evaluated the role of IL-17 by culturing lymphocytes from lupus-prone mice in vitro with IL-23, a cytokine that sustains IL-17 responses, and then injected them in healthy but lymphocyte deficient mice. The recipient mice developed lupus-like disease suggesting a pathogenic role of IL-23 induced IL-17 producing T cells. In a different study we generated IL-23 receptor genetically deficient lupus-prone mice. These mice did not develop lupus. Taken together these results led us to hypothesize that IL-23 represents a key mediator of lupus pathogenesis. In this proposal we will test this hypothesis using lupus prone mice and lymphocytes from patients with SLE. Initially, we will test whether treatment of lupus-prone mice with an anti-IL-23 antibody can ameliorate lupus in mice at various stages of their disease course. We will then a. determine the exact source of IL-23 in lupus-prone mice; b. explore the signaling events that lead to the generation and maintenance of IL-17 producing cells in lupus; and c. unravel the mechanisms that IL-17 producing cells use to cause lupus. In the third aim, we will evaluate the role of IL-23 in the generation of pathogenic immune responses by both T and B cells in patients with SLE. These complementary murine and human studies will allow us to understand the role of IL-23 in the development of the abnormal immune response in lupus. The overall goal of this proposal is to provide the necessary rationale to introduce specific biologic agents that interfere with the IL-23/IL-17 pathway in the treatment of patients with SLE.

Public Health Relevance

Systemic Lupus Erythematosus (SLE) is a disease affecting a million Americans and is currently treated with non-specific, toxic medications. In this proposal, based on our preliminary studies, we will explore the role of IL-23 in the development of lupus in both animals and humans and test whether targeting IL-23 will ameliorate lupus in lupus- prone animals. The goal of these studies is to provide enough evidence for the usefulness of anti-IL-23 treatment in SLE.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
4R01AR060849-05
Application #
9058426
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Mancini, Marie
Project Start
2012-05-14
Project End
2017-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
Suárez-Fueyo, Abel; Bradley, Sean J; Katsuyama, Takayuki et al. (2018) Downregulation of CD3? in NK Cells from Systemic Lupus Erythematosus Patients Confers a Proinflammatory Phenotype. J Immunol 200:3077-3086
Dai, Hong; He, Fan; Tsokos, George C et al. (2017) IL-23 Limits the Production of IL-2 and Promotes Autoimmunity in Lupus. J Immunol 199:903-910
Yoshida, Nobuya; Comte, Denis; Mizui, Masayuki et al. (2016) ICER is requisite for Th17 differentiation. Nat Commun 7:12993
Wang, Jianxun; Mizui, Masayuki; Zeng, Li-Fan et al. (2016) Inhibition of SHP2 ameliorates the pathogenesis of systemic lupus erythematosus. J Clin Invest 126:2077-92
Edwards, Lindsay J; Mizui, Masayuki; Kyttaris, Vasileios (2015) Signal transducer and activator of transcription (STAT) 3 inhibition delays the onset of lupus nephritis in MRL/lpr mice. Clin Immunol 158:221-30
Bradley, Sean J; Suarez-Fueyo, Abel; Moss, David R et al. (2015) T Cell Transcriptomes Describe Patient Subtypes in Systemic Lupus Erythematosus. PLoS One 10:e0141171
Grammatikos, Alexandros P; Ghosh, Debjani; Devlin, Amy et al. (2013) Spleen tyrosine kinase (Syk) regulates systemic lupus erythematosus (SLE) T cell signaling. PLoS One 8:e74550
Kyttaris, Vasileios C; Kampagianni, Ourania; Tsokos, George C (2013) Treatment with anti-interleukin 23 antibody ameliorates disease in lupus-prone mice. Biomed Res Int 2013:861028
Markopoulou, Anastasia; Kyttaris, Vasileios C (2013) Small molecules in the treatment of systemic lupus erythematosus. Clin Immunol 148:359-68
Hedrich, Christian M; Rauen, Thomas; Crispin, Jose C et al. (2013) cAMP-responsive element modulator ? (CREM?) trans-represses the transmembrane glycoprotein CD8 and contributes to the generation of CD3+CD4-CD8- T cells in health and disease. J Biol Chem 288:31880-7

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