A hallmark of sepsis is the extensive apoptosis-induced depletion of lymphocytes and other immune cells. Apoptosis is central to the pathophysiology of sepsis because it results in a massive loss of immune effector cells thereby rendering the host incapable of mounting an effective anti-microbial response. The assertion that apoptosis is critical to the mortality in sepsis is supported by work showing that prevention of apoptosis improves survival. IL-7 is a potent Bcl-2-inducing, anti-apoptotic, cytokine that is essential for lymphocyte survival and expansion. IL-7 also enhances the cytolytic function of mature T cells, augments T cell - antigen- presenting-cell interactions, and restores impaired delayed type hypersensitivity. The likely efficacy of IL-7 in sepsis is underscored by studies showing that IL-7 improves survival in specific models of infection. The enormous potential utility of IL-7's immune boosting properties is best illustrated by the fact that IL-7 is currently in 3 multi-national, FDA-approved, clinical trials including patients with HIV, cancer, and hepatitis C. In a recent NCI study of 16 patients with refractory cancer, patients who received IL-7 had a greater than 3-fold increase in circulating CD4 T and CD8 T cells, a greater than 60% increase in spleen size, and a doubling of lymphocyte intracellular Bcl-2. Because of IL-7's multiple effects to enhance immune function, the NCI has listed IL-7 in the top 5 immunotherapy drugs most likely to improve survival in cancer. Intriguingly, both patients with cancer and patients with sepsis share many features of immunosuppression and IL-7's ability to enhance immune function may be applicable to both conditions. Studies show that IL-7 is well-tolerated in patients and unlike IL-2 or IL-12, IL-7 does not induce fever, capillary leak syndrome, or other clinical abnormalities related to release of pro-inflammatory cytokines. A particular therapeutic challenge in sepsis is determining whether the patient is in the hyper- versus the hypo-inflammatory phase. Therapies that are beneficial in the hyper-inflammatory phase of sepsis may be detrimental if the patient has entered the hypo- inflammatory phase. Given IL-7's moderated effect on cytokine induction, it may be possible to administer IL-7 to septic patients regardless of their particular phase of sepsis, i.e., the hyper- or hypo- immune phase. This proposal seeks to test the hypothesis that IL-7 will improve survival in multiple murine models of sepsis by increasing Bcl-2, preventing sepsis-induced lymphocyte apoptosis, inducing lymphocyte proliferation, and enhancing immune function. We further hypothesize that translational studies of IL-7 conducted in critically-ill patients with sepsis will show similar benefits on circulating lymphocytes and immune function.
The purpose of this grant application is to determine the potential efficacy of a new therapy of sepsis. Sepsis is the host response to severe infection and includes shock and organ failure. Our laboratory is testing the ability of a cell signaling protein to prevent cell death in sepsis and improve survival. This cell signaling protein is made by the body's own cells and is called interleukin 7. We will test its effects in both animal models of sepsis and in patients with sepsis.
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