The new normal: immunomodulatory agents against sepsis immune suppression

Abstract

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.

Keywords: co-inhibitory molecules; cytokines; immunomodulatory agents; immunosuppression; sepsis.

Figure 1. The potential immune-stimulatory effects of IL-7 in sepsis

Interleukin 7 (IL-7) is mainly produced by stromal and parenchymal cells and is absolutely required for T cell maintenance. IL-7 has multiple beneficial effects that act to enhance immune function. These include: (1) increased expression of integrins, resulting in enhanced cell trafficking to the infection site and (2) increased T cell activation and CD4⁺ and CD8⁺ T cell proliferation (3). IL-7’s affects on T cell expansion leads to a significant increase in TCR repertoire diversity (4), thereby improving T cell activation to subdominant antigens. IL-7 can also aid in reversing the exhausted phenotype (5), decreasing apoptosis of immune effector cells (6) and aiding in efficient macrophage activation (7). IL-7’s immune stimulatory effects can also improve crosstalk between the innate and adaptive branch of the immune system, and therefore restore immune function under septic conditions. Abbreviations: TCR, T cell receptor; LFA-1, lymphocyte function associated antigen 1; VLA-4, very late antigen 4; PD-1, programmed cell death 1; IFN-y; interferon-gamma.

Figure 2. The potential immune-stimulatory effects of IL-15 in sepsis

Interleukin 15 (IL-15) is a potential candidate to improve immune function under septic conditions. IL-15 binds to the high-affinity IL-15Rα chain and trans-presented to an opposing IL-2Rβ/yc receptor complex on NK cell, NKT cell or CD8 T cell through cell-cell contact. IL-15 signaling improves activation, proliferation, as well as cytotoxicity of stimulated cells leading to increased expression of interferon gamma (IFN-γ) and IFN-α. Furthermore, IL-15 prevents apoptosis of immune effector cells by up-regulating expression of anti-apoptotic proteins. Abbreviations: IL-15Rα, Interleukin-15 receptor alpha chain; IL-2Rβ, Interleukin-2 receptor beta chain; γc, common gamma chain; NK, natural killer cell; IFNγ, interferon gamma; IFNα, interferon alpha.

Figure 3. GM-CSF improves immune function in sepsis

Granulocyte-macrophage colony stimulating factor (GM-CSF), released from activated lymphoid cells (T cells, B cells or NK cells) as well as macrophages/monocytes or mast cells, acts in two major ways to increase immune function. First, GM-CSF leads to mobilization of myeloid cells such as dendritic cells, monocytes and granulocytes from the bone marrow, thereby significantly increasing myeloid cell counts. Second, GM-CSF also directly acts on these cells by increasing survival, maturation, activation and migration to the site of infection. Furthermore, GM-CSF treatment reverses critically low human leukocyte antigen D-related (HLA-DR) expression on antigen presenting cells (APCs) in septic patients, leading to improved immune function. Abbreviations: GM-CSF, granulocyte-macrophage colony stimulating factor; HLA-DR, human leukocyte antigen D-related; NK cell, natural killer cell.

Figure 4. Anti-PD-1 immunotherapy proposed for septic patients

The co-inhibitory molecule, programmed death receptor-1 (PD-1), and its ligand (PD-L1) are up-regulated on monocytes, macrophages, and T lymphocytes during sepsis. PD-L1 has also been shown to be increased on epithelial and endothelial cell populations in septic animal models, and may play a role in barrier function. Future potential anti-PD-1 therapy, indirectly impacting the effects of PD-L1, would improve immune cell function, particularly monocyte/macrophage function, phagocytosis, and their ability to secrete anti-inflammatory cytokine, interleukin-10 (IL-10), directly addressing the immune suppressed state in the critically ill patient.