2003/2004 Biomarkers, Kidney
2009 B Cells, Kidney, New Treatments
TNF antagonism in SLE
In this innovative study, Dr. Davidson takes on the challenge of teasing apart the complex mechanisms by which a protein (a cytokine) called “TNF-alpha” apparently protects against systemic lupus at the same time that it increases inflammation and worsens lupus kidney disease.
Drugs that block TNF-alpha already have successfully produced remission in a small group of people with lupus nephritis whose condition hadn’t responded to other treatments. But TNF-alpha also increased the production of damaging auto-antibodies, raising the risk of a disease flare. This dual and conflicting result may occur because TNF-alpha binds two different receptors.
By shedding light on how TNF-alpha both protects and worsens lupus damage in several animal models of lupus, Dr. Davidson aims to set the groundwork for designing smart, selective blockers of TNF-alpha that can help without hurting at the same time.
In her 2003/2004 grant, Dr. Davidson set out to determine if certain early markers (“biomarkers”) of kidney damage and remission in a mouse model of immunotherapy-induced lupus remission might be applicable to humans.
Could inflammatory molecules in the urine of mice similarly indicate nephritis onset or remission in humans?
Dr. Davidson ultimately published her findings that remission phases are associated with loss of activated macrophages from the kidney—which suggests that these are the cells that cause the damage.
She also identified six genes expressed by activated macrophages that are down-regulated during remission. These are all potential biomarkers that may be useful for early detection of lupus nephritis and in assessing responses to new therapies in clinical trials.
“I now have two postdocs working on this project and an active collaboration with nephrologists at Mount Sinai Medical School and at the University of Michigan.” – Dr. Davidson in 2010
Mechanism of action of transmembrane activator and calcium modulator ligand interactor-Ig in murine systemic lupus erythematosus. Ramanujam M, Wang X, Huang W, Schiffer L, Grimaldi C, Akkerman A, Diamond B, Madaio MP, Davidson A. J Immunol. 2004 Sep 1;173(5):3524-34.
The current status of targeting BAFF/BLyS for autoimmune diseases. Ramanujam M, Davidson A. Arthritis Res Ther. 2004;6(5):197-202. Epub 2004 Jul 29.
Targeting of the immune system in systemic lupus erythematosus. Ramanujam M, Davidson A. Expert Rev Mol Med. 2008 Jan 21;10:e2.
Block and tackle: CTLA4Ig takes on lupus. Davidson A, Diamond B, Wofsy D, Daikh D. Lupus. 2005;14(3):197-203.
Activated renal macrophages are markers of disease onset and disease remission in lupus nephritis. Schiffer L, Bethunaickan R, Ramanujam M, Huang W, Schiffer M, Tao H, Madaio MM, Bottinger EP and A Davidson. J. Immunol 2008 180: 1938-1947.
Dr. Davidson won a 2-year, $234,000 grant from the Alliance for Lupus Research in 2007 to further characterize the inflammatory macrophages and dendritic cells that she initially described in her LRI-funded work and in 2010 was awarded a $2.4 million RO1 grant from the NIH’S National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).
“This project took a long time to get off the ground and I am grateful to the LRI for seeding it. Without this funding we would not have been able to go on to compete successfully for NIH funds. – Dr. Davidson in 2010
Rev. July 2010