Background: Depot medroxyprogesterone acetate (DMPA, Depo-Provera) is a progesterone-based drug used for contraception by up to 50 million women world-wide. DMPA has been shown in animals to be a potent down-regulator of the immune system. Autoimmune diseases, such as systemic lupus erythematosus (SLE) are related to high levels of immune activation, as measured by analytes such IFN-a, a potent stimulator of T helper type 1 (Th1)-related immunity and autoimmunity. Women, especially those of reproductive age, are disproportionately impacted by SLE autoimmunity and could receive dual benefit from a contraceptive method that could also decrease IFN- and Th1-related immune activation. In mice, DMPA treatment blocks IFN-a induction and Th1-related autoimmunity. However, little is known about the effects of DMPA on the human immune system. Hypothesis: We propose to test the hypothesis that DMPA treatment in women also inhibits IFN- and Th1-related pathways. Verifying this would support trials of DMPA in SLE patients and offer unique insight into the mechanisms linking progesterone, female reproduction and the immune system. Methods: To test our hypothesis, we will analyze peripheral blood leukocytes from women before and after starting DMPA for birth control or treatment of endometriosis. SLE-related IFN-a induction and IFN-a sensitivity will be assessed using well-established in vitro culture systems with which we have extensive experience. To confirm DMPA’s in vivo effects on IFN- and Th1-pathways in vivo, and to identify additional pathways by which DMPA controls SLE autoimmunity, we will perform whole-genome transcriptional analysis on freshly isolated whole-blood samples. Conclusion: This proposal capitalizes on a unique multidisciplinary collaboration between gynecologists and rheumatologists to identify potentially beneficial immunomodulatory properties of DMPA in women with SLE. Our results also will significantly advance our mechanistic understanding of how DMPA, and progestins in general, link female reproduction to modulation of the immune system.