Systemic lupus erythematosus (SLE) is an autoimmune disorder of unknown etiology characterized by diverse T cell effector dysfunction. Interleukin-2 (IL-2) production is decreased in patients with SLE and lupus-prone mice and this contributes to the immunopathogenesis of the disease. This proposal is based on published and preliminary data which demonstrate that anti-CD3/TCR antibodies present in the sera of patients with SLE cause translocation of Calcium/calmodulin kinase 4 (CaMK4) from the cytoplasm to the nucleus where it suppresses IL-2 production. In the lupus prone MRL.lpr lupus-prone mouse, pharmacologic inhibition or genetic deletion of CaMK4 with a small drug inhibitor suppresses autoimmunity, mesangial cell proliferation and lupus nephritis. In additional data, CaMK4 appears to be involved in the generation of regulatory T cells. Based on these data we hypothesize that the ser/thr kinase CaMK4 contributes to the expression of autoimmunity by suppressing IL-2 production and Treg function and to the development of lupus nephritis by promoting mesangial cell proliferation. First, we will establish that CaMK4 translocates to the nucleus of SLE T cells, determine how it becomes activated and how it affects immunoregulation. Second, we will establish whether CaMK4 expressed in mesangial cells is independently responsible for excessive proliferation and the development of lupus nephritis. And, third, we plan to use nanolipogels loaded with an inhibitor of CaMK4 and tagged with antibodies to deliver the drug to T and mesangial cells. To carry out the studies we will use cells from patients with SLE and a newly constructed MRL.lpr mouse which lacks CaMK4 and nanolipogel technology to delver the CaMK4 inhibitor. The proposal identifies a new Ser/Thr kinase, CaMK4, in the regulation/dysregulation of the immune response and proliferation of mesangial cells and proposes the use of a novel nanolipogel delivery system to target a small drug inhibitor of CaMK4 to T and mesangial cells. The significance of the proposed work lies with the fact that it presents a novel target for the treatment of SLE and that it develops a targeted delivery of a small drug.

Public Health Relevance

Lupus afflicts more than one million Americans who are mostly women and young. Because of a number of limitations a clinically useful drug is still missing. Through this project we plan to develop a small drug inhibitor of a kinase deliverable in an organ targeted fashion for the treatment of the disease.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Mancini, Marie
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Beth Israel Deaconess Medical Center
Independent Hospitals
United States
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Li, Hao; Tsokos, Maria G; Bickerton, Sean et al. (2018) Precision DNA demethylation ameliorates disease in lupus-prone mice. JCI Insight 3:
Maeda, Kayaho; Otomo, Kotaro; Yoshida, Nobuya et al. (2018) CaMK4 compromises podocyte function in autoimmune and nonautoimmune kidney disease. J Clin Invest 128:3445-3459
Moulton, Vaishali R; Suarez-Fueyo, Abel; Meidan, Esra et al. (2017) Pathogenesis of Human Systemic Lupus Erythematosus: A Cellular Perspective. Trends Mol Med 23:615-635
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Ichinose, Kunihiro; Ushigusa, Takeshi; Nishino, Ayako et al. (2016) Lupus Nephritis IgG Induction of Calcium/Calmodulin-Dependent Protein Kinase IV Expression in Podocytes and Alteration of Their Function. Arthritis Rheumatol 68:944-52
Koga, Tomohiro; Otomo, Kotaro; Mizui, Masayuki et al. (2016) Calcium/Calmodulin-Dependent Kinase IV Facilitates the Recruitment of Interleukin-17-Producing Cells to Target Organs Through the CCR6/CCL20 Axis in Th17 Cell-Driven Inflammatory Diseases. Arthritis Rheumatol 68:1981-8
Moulton, Vaishali R; Tsokos, George C (2015) T cell signaling abnormalities contribute to aberrant immune cell function and autoimmunity. J Clin Invest 125:2220-7
Otomo, Kotaro; Koga, Tomohiro; Mizui, Masayuki et al. (2015) Cutting Edge: Nanogel-Based Delivery of an Inhibitor of CaMK4 to CD4+ T Cells Suppresses Experimental Autoimmune Encephalomyelitis and Lupus-like Disease in Mice. J Immunol 195:5533-7
Grammatikos, Alexandros P; Kyttaris, Vasileios C; Kis-Toth, Katalin et al. (2014) A T cell gene expression panel for the diagnosis and monitoring of disease activity in patients with systemic lupus erythematosus. Clin Immunol 150:192-200
Koga, Tomohiro; Hedrich, Christian M; Mizui, Masayuki et al. (2014) CaMK4-dependent activation of AKT/mTOR and CREM-? underlies autoimmunity-associated Th17 imbalance. J Clin Invest 124:2234-45

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