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The new normal: immunomodulatory agents against sepsis immune suppression

2014; Elsevier BV; Volume: 20; Issue: 4 Linguagem: Inglês

10.1016/j.molmed.2014.01.002

1471-499X

Noelle A. Hutchins, Jacqueline Unsinger, Richard S. Hotchkiss, Alfred Ayala,

Thermal Regulation in Medicine

•Sepsis is the leading cause of death in critically ill patients and novel therapies are necessary. •Immune suppression is frequently associated with sepsis-related deaths. •Therapies or immunomodulatory agents that enhance the immune response should be considered. •Cytokines and co-inhibitory receptors represent potential immunomodulatory agents. Sepsis is the leading cause of death among critically ill patients in intensive care units, and treatment options are limited. Therapies developed against the proinflammatory stage have failed clinically; therefore, new approaches that target the host immune response in sepsis are necessary. Increasing evidence suggests that a major pathophysiological event in sepsis is immune suppression, often resulting in secondary fungal, bacterial, or viral infections. Recent studies from animal sepsis models and patient samples suggest that cytokines such as interleukin-7 (IL-7), IL-15, granulocyte macrophage colony-stimulating factor (GM-CSF), as well as co-inhibitory molecule blockade, such as anti-programmed cell death receptor-1 (anti-PD-1) and anti-B and T lymphocyte attenuator (anti-BTLA), may have utility in alleviating the clinical morbidity associated with sustained sepsis. This review discusses some of these novel immunomodulatory agents and evaluates their potential use as therapeutics. Sepsis is the leading cause of death among critically ill patients in intensive care units, and treatment options are limited. Therapies developed against the proinflammatory stage have failed clinically; therefore, new approaches that target the host immune response in sepsis are necessary. Increasing evidence suggests that a major pathophysiological event in sepsis is immune suppression, often resulting in secondary fungal, bacterial, or viral infections. Recent studies from animal sepsis models and patient samples suggest that cytokines such as interleukin-7 (IL-7), IL-15, granulocyte macrophage colony-stimulating factor (GM-CSF), as well as co-inhibitory molecule blockade, such as anti-programmed cell death receptor-1 (anti-PD-1) and anti-B and T lymphocyte attenuator (anti-BTLA), may have utility in alleviating the clinical morbidity associated with sustained sepsis. This review discusses some of these novel immunomodulatory agents and evaluates their potential use as therapeutics. is expressed by T and B lymphocytes; it is an immunoglobin (Ig) domain superfamily member that contains a cytoplasmic tyrosine-based inhibitory motif. The ligand for BTLA is herpesvirus entry mediator (HVEM). The interactions between BTLA and HVEM involve bidirectional signaling and potentiate negative immune responses. Generally, T cell activation is negatively regulated upon HVEM engagement to BTLA. the CLP method is a clinical comparable rodent model of polymicrobial peritonitis used to investigate the pathological changes associated with sepsis/septic shock seen in patients. are cell surface molecules, such as PD-1, BTLA, and CTLA-4, that belong to the CD28/B7 gene family and have been shown to be upregulated on monocytes, macrophages, and lymphocyte populations in patient samples and animals exposed to experimental septic challenge. Traditionally, these molecules are thought to negatively regulate T cell receptor (TCR)-mediated activation as well as cytokine release from immune cells of the adaptive immune system and have been extensively investigated in the processes of viral infection and cancer. is usually succeeded by the proinflammatory phase during sepsis and is hallmarked by increased anti-inflammatory cytokines, such as IL-10, increased lymphocyte apoptosis, diminished human leukocyte antigen (HLA) receptors on monocytes, and decreased cytokine responses by monocytes as well as lymphocytes. IL-7 and IL-15 are closely related and have been shown to improve immune cell function (particularly CD8+ T, NK, and dendritic cells) and decrease lymphocyte apoptosis in sepsis animal models. GM-CSF, however, is a cytokine that improves neutrophil and macrophage functions, and increases HLA-DR expression on monocytes. These cytokines, if directed to the appropriate patient, may address the immune-suppressed state in critically ill patients. the excessive or uncontrolled release of proinflammatory cytokines in the context of acute tissue damage and/or infection, such as traumatic injury/shock/ischemia–reperfusion and/or sepsis. also known as CD152, is expressed on the surface of T lymphocytes, and a member of the Ig superfamily that competes with CD28 for binding to co-stimulatory molecules, CD80 and CD86, on antigen presenting cells. CTLA-4 binding prevents T cell proliferation, expansion, and activation. the inability of the host to mount an appropriate immune response to a defined antigenic stimuli and/or infectious challenge. ideal immunomodulatory therapy directed against sepsis would boost overall patient immunity, drive lymphocyte effector functions, decrease lymphoid apoptosis, and ultimately mitigate the development of immune suppression, which has been often associated with onset of secondary infections and death among critically ill patients. the co-inhibitory receptor molecule, PD-1, is expressed on T and B cells (lymphocytes), myeloid cells, NK cells, and NKT cells. Upon ligation by its ligand, programmed cell death ligand-1 (PD-L1) transduces an inhibitory signal to the leukocyte during the course of activation. the American College of Chest Physicians and the Society for Critical Care Medicine established criteria for SIRS. There are four categories, including body temperature, respiratory rate, white blood cell count, and heart rate. These criteria are not necessarily related to infection. T lymphocytes become functionally inactive or ‘anergic’ following an antigen encounter, typically in the absence of adequate co-stimulatory signaling, yet still remain viable in circulation and can regain responsiveness to select T cell stimuli under the appropriate conditions. this is a state of T cell dysfunction, which is typically defined by decreased lymphocyte effector functions and sustained expression of inhibitory receptors, the results of which the lymphocyte is nonresponsive to exogenous stimuli. T cell exhaustion prevents the clearance of bacterial and chronic viral infections.