CELLULAR MECHANISMS OF SEPSIS AND ORGAN FAILURE

Washington University, Saint Louis MO

Investigators

Linked publications, trials & patents

Abstract

Abstract 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.