Systemic Lupus Erythematosus (SLE) is an autoimmune disease of unknown etiliology, characterized by aberrant T cell function which contributes to disease pathology. T cells once activated, have elevated levels of CD40L and decreased levels of interleukin-2 (IL-2). Elevated CD40L expression provides help to B cells while decreased IL-2 prevents proper regulation of the immune response. The underlying reasons for this abnormality remain elusive. Finding key molecules that regulate T cell function in SLE will lead to the design of appropriate biomarkers and more specific treatment modalities. This proposal aims at the career development of Dr. Kyttaris as an independent translational investigator in SLE. During the years of award, Dr. Kyttaris will investigate the expression and cooperation between nuclear factor of activated T cells (NFAT) and activator protein-1 (AP-1) in T cell function in SLE. Beth Israel Deaconess Medical Center will provide an ideal clinical, educational and research environment for Dr. Kyttaris to conduct under the guidance of two accomplished mentors his research and develop into an independent investigator. Dr. Kyttaris will attend courses and interact with experts in the fields of basic immunology, systemic autoimmunity, clinical rheumatology, biostatistics and epidemiology. The study proposed herein is a cross- sectional case-control study of patients with SLE. The preliminary results that form the basis for this proposal showed that SLE T cells once activated, have increased NFAT and decreased AP-1 activity;in turn this leads to increased CD40L and decreased interleukin (IL)-2 expression. In the three aims analyzed Dr. Kyttaris will compare the expression of NFAT and AP-1 in T cells from patients with SLE and controls confirming the preliminary data and ascertaining the effect of disease activity in the expression of these molecules. Thereafter, Dr. Kyttaris will elucidate the underlying mechanisms for the differential expression of these two transcription factors in SLE. Finally he will apply novel techniques to correct the aberrant expression of NFAT/AP-1 on gene transcription. In conclusion, the results of these studies will help us better understand how the SLE T cells respond to stimulation, identify potential targets for therapy and molecules that can be used as biomarkers.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Mentored Patient-Oriented Research Career Development Award (K23)
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Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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Mancini, Marie
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Beth Israel Deaconess Medical Center
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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
Rosetti, Florencia; Tsuboi, Naotake; Chen, Kan et al. (2012) Human lupus serum induces neutrophil-mediated organ damage in mice that is enabled by Mac-1 deficiency. J Immunol 189:3714-23
del Rio, Roxana; McAllister, Ryan D; Meeker, Nathan D et al. (2012) Identification of Orch3, a locus controlling dominant resistance to autoimmune orchitis, as kinesin family member 1C. PLoS Genet 8:e1003140
Kyttaris, Vasileios C (2012) Kinase inhibitors: a new class of antirheumatic drugs. Drug Des Devel Ther 6:245-50
Kyttaris, Vasileios C (2012) Targeting B cells in severe thrombotic thrombocytopenic purpura--a road to cure? Crit Care Med 40:317-8
Hedrich, Christian M; Rauen, Thomas; Kis-Toth, Katalin et al. (2012) cAMP-responsive element modulator ? (CREM?) suppresses IL-17F protein expression in T lymphocytes from patients with systemic lupus erythematosus (SLE). J Biol Chem 287:4715-25
Chatterjee, Madhumouli; Rauen, Thomas; Kis-Toth, Katalin et al. (2012) Increased expression of SLAM receptors SLAMF3 and SLAMF6 in systemic lupus erythematosus T lymphocytes promotes Th17 differentiation. J Immunol 188:1206-12
Kyttaris, Vasileios C (2012) The role of Syk in osteoarthritis. Clin Immunol 144:283-4
Ghosh, Debjani; Tsokos, George C; Kyttaris, Vasileios C (2012) c-Jun and Ets2 proteins regulate expression of spleen tyrosine kinase in T cells. J Biol Chem 287:11833-41

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