title: Immunotherapy: A promising approach to reverse sepsis-induced immunosuppression.
abstract: Sepsis is defined as life-threatening organ dysfunction caused by dysregulated host responses to infection (Third International Consensus definition for Sepsis and septic shock). Despite decades of research, sepsis remains the leading cause of death in intensive care units. More than 40 clinical trials, most of which have targeted the sepsis-associated pro-inflammatory response, have failed. Thus, antibiotics and fluid resuscitation remain the mainstays of supportive care and there is intense need to discover and develop novel, targeted therapies to treat sepsis. Both pre-clinical and clinical studies over the past decade demonstrate unequivocally that sepsis not only causes hyper-inflammation, but also leads to simultaneous adaptive immune system dysfunction and impaired antimicrobial immunity. Evidences for immunosuppression include immune cell depletion (T cells most affected), compromised T cell effector functions, T cell exhaustion, impaired antigen presentation, increased susceptibility to opportunistic nosocomial infections, dysregulated cytokine secretion, and reactivation of latent viruses. Therefore, targeting immunosuppression provides a logical approach to treat protracted sepsis. Numerous pre-clinical studies using immunomodulatory agents such as interleukin-7, anti-programmed cell death 1 antibody (anti-PD-1), anti-programmed cell death 1 ligand antibody (anti-PD-L1), and others have demonstrated reversal of T cell dysfunction and improved survival. Therefore, identifying immunosuppressed patients with the help of specific biomarkers and administering specific immunomodulators holds significant potential for sepsis therapy in the future. This review focusses on T cell dysfunction during sepsis and discusses the potential immunotherapeutic agents to boost T cell function during sepsis and improve host resistance to infection.
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address: naeem.patil@vanderbilt.edu.
authors.forename: Naeem K
authors.initials: NK
authors.lastname: Patil
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Bohannon
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Sherwood
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D006801:Humans; D016867:Immunocompromised Host; D007155:Immunologic Factors / Q000009:adverse effects / Q000627:therapeutic use*; D007167:Immunotherapy / Q000009:adverse effects / Q000379:methods*; D018579:Patient Selection; D011237:Predictive Value of Tests; D018805:Sepsis / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
chemical_list: D015415:Biomarkers; D007155:Immunologic Factors
keywords: Anti-PD-1; Anti-PD-L1; Biomarkers; Flt3 ligand; IFN-γ; Immunosuppression; Immunotherapy; Interleukin-15; Interleukin-7; Sepsis; T cell