IL-7 Restores Lymphocyte Functions in Septic Patients

Abstract

Septic syndrome is the leading cause of mortality for critically ill patients worldwide. Patients develop lymphocyte dysfunctions associated with increased risk of death and nosocomial infections. In this study, we performed preclinical experiments testing the potential of recombinant human IL-7 (rhIL-7) as a lymphostimulating therapy in sepsis. Circulating IL-7 and soluble IL-7 receptor α-chain (soluble CD127) concentrations were measured in plasma, whereas cellular CD127 expression was evaluated on circulating CD4+ and CD8+ lymphocytes from septic shock patients and healthy volunteers. Lymphocyte proliferation, IFN-γ production, STAT5 phosphorylation, and B cell lymphoma 2 induction were measured ex vivo in response to T cell stimulation in the presence or not of rhIL-7. We show that IL-7 pathway (plasmatic IL-7 concentration and cellular and soluble CD127 expressions) is not overtly altered and remains activable in septic patients. Most importantly ex vivo treatment of patients’ cells with rhIL-7 significantly improves lymphocyte functionality (CD4+ and CD8+ lymphocyte proliferations, IFN-γ production, STAT5 phosphorylation, and B cell lymphoma 2 induction after stimulation). To our knowledge, this constitutes the first report of rhIL-7 ability to restore normal lymphocyte functions in septic patients. These results support the rational for initiating a clinical trial testing rhIL-7 in septic shock.

Is this critically ill patient immunocompromised?

“…A lower expression and especially failure of restoration of HLA-DR expression appear indicative of immunoparalysis, as it is related to the susceptibility to opportunistic infections and outcome in sepsis patients [15]. Several promising immuno-adjuvant agents are slated for testing in the near future, including GM-CSF (ClinicalTrials.gov identifier: NCT02361528), IL-7, anti-PD-L1 (ClinicalTrials.gov identifier: NCT02576457), and thymosin-alpha-1 [2,8,12,13,16,17]. Given the remarkable success of immunotherapy in cancer and the similarities in the immune defects in cancer and sepsis patients [18], it appears plausible that immunotherapy may represent a major advance in the treatment of this highly lethal disease.…”

Mechanisms of sepsis‐induced immunosuppression and immunological modification therapies for sepsis

“…IL‐7 is a multifunctional cytokine of the immune system that affects both T cells and B cells and induces the proliferation of naïve and memory T cells 44. Venet et al45 showed that IL‐7 treatment of isolated lymphocytes from septic patients restored T‐cell proliferation and IFN‐γ secretion.…”

Critical Illness–Induced Immune Suppression: Current State of the Science

“…[65][66][67][68][69][70] Ex vivo treatment of lymphocytes from patients with sepsis with IL-7 signifi cantly improved T-cell proliferation, up-regulation of anti-apoptotic proteins, and IFN-γ production capacity. 63 Whereas rhIL-7 is currently being evaluated in patients with chronic viral infection and cancer, to date it remains unstudied in vivo in the setting of critical illness.…”