Systemic lupus erythematosus (SLE) is an autoimmune disorder of largely unknown etiology characterized by profound effector T cell dysfunction. Infection-related morbidity and mortality rates are high among patients with SLE and although multifactorial it has been attributed to disease activity, the use of immunosuppressive drugs and deficient cell-mediated cytotoxic responses that are associated with decreased expression of interleukin (IL)-2. IL-17 production on the other hand is increased in SLE patients and mice and IL17-producing cells invade the kidney in patients with lupus nephritis. cAMP response element modulator (CREM)? has been claimed to suppress the production of IL-2 through transcriptional and epigenetic mechanisms and to promote the production of IL-17 through epigenetic modulation. It is postulated herein that CREM? effects transcriptional and epigenetic modifications which account for the antithetic expression of IL2 and IL-17 and the subsequent disease expression in patients with SLE and lupus- prone mice and that silencing it should have a clinical benefit. Accordingly, experiments are proposed to understand the CREM? -mediated transcriptional and epigenetic mechanisms that are involved in the control of expression of IL-2 and IL-17 in SLE and the distribution of IL-17-producing cells in tissues, to establish the role of CREM? in the regulation of autoimmunity and lupus-related pathology in mice and to treat lupus-prone mice with an inducible IL-2 gene expression system and by silencing CREM?. The proposed work using novel concepts (epigenetic control of cytokine production) and novel, genetically modified, mice intends to clarify central mechanisms in the pathogenesis of SLE and to introduce infusion of IL-2 or silencing of CREM as new treatments for SLE.

Public Health Relevance

Systemic lupus erythematosus (SLE) is an autoimmune disorder of largely unknown etiology in which infection and lupus nephritis -related morbidity and mortality rates are high. Deregulated interleukin-2 and -17 production accounts for disease expression. The proposal will produce information which will explain why cytokine production is aberrant in SLE and through preclinical studies will recommend novel treatment approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI049954-13
Application #
8600229
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Johnson, David R
Project Start
2001-04-01
Project End
2017-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
13
Fiscal Year
2014
Total Cost
$391,500
Indirect Cost
$166,500
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Lieberman, Linda A; Tsokos, George C (2014) Lupus-prone mice fail to raise antigen-specific T cell responses to intracellular infection. PLoS One 9:e111382
Hedrich, Christian M; Crispin, Jose C; Rauen, Thomas et al. (2014) cAMP responsive element modulator (CREM) * mediates chromatin remodeling of CD8 during the generation of CD3+ CD4- CD8- T cells. J Biol Chem 289:2361-70
Mizui, Masayuki; Koga, Tomohiro; Lieberman, Linda A et al. (2014) IL-2 protects lupus-prone mice from multiple end-organ damage by limiting CD4-CD8- IL-17-producing T cells. J Immunol 193:2168-77
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
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
Rauen, Thomas; Hedrich, Christian M; Tenbrock, Klaus et al. (2013) cAMP responsive element modulator: a critical regulator of cytokine production. Trends Mol Med 19:262-9