The changing immune system in sepsis: is individualized immuno-modulatory therapy the answer?

Abstract

Sepsis remains the leading cause of death in most intensive care units. Advances in understanding the immune response to sepsis provide the opportunity to develop more effective therapies. The immune response in sepsis can be characterized by a cytokine-mediated hyper-inflammatory phase, which most patients survive, and a subsequent immune-suppressive phase. Patients fail to eradicate invading pathogens and are susceptible to opportunistic organisms in the hypo-inflammatory phase. Many mechanisms are responsible for sepsis-induced immuno-suppression, including apoptotic depletion of immune cells, increased T regulatory and myeloid-derived suppressor cells, and cellular exhaustion. Currently in clinical trial for sepsis are granulocyte macrophage colony stimulating factor and interferon gamma, immune-therapeutic agents that boost patient immunity. Immuno-adjuvants with promise in clinically relevant animal models of sepsis include anti-programmed cell death-1 and interleukin-7. The future of immune therapy in sepsis will necessitate identification of the immunologic phase using clinical and laboratory parameters as well as biomarkers of innate and adaptive immunity.

Keywords: adaptive immunity; cell exhaustion; immune suppression; immune therapy; sepsis.

Figure 1. Immune response in sepsis. The immune response in sepsis is determined by many factors including co-morbidities (i.e., diabetes, heart disease, malignancy) as well as the pathogen virulence and size of the microbial inoculums. Although both pro- and anti-inflammatory processes are activated simultaneously during the onset of sepsis, during the first few days, a hyper-inflammatory response often dominates the clinical picture. The hyper-inflammatory phase has been termed a “cytokine storm” that is indicated by increased levels of TNF-α, IL-1β, and IL-6. A robust depletion of both innate and adaptive immune cells through apoptosis occurs to dampen the response. (A) At this stage, patients may undergo a controlled anti-inflammatory response enabling them to return to immune homeostasis. Alternatively, patients may undergo an uncontrolled anti-inflammatory response and enter a hypo-inflammatory phase yet survive (B) or succumb. Protracted time spent in this hypo-inflammatory phase may lead to cellular exhaustion; a cellular phenotype indicated by impaired function as well as increased PD-1 and decreased IL-7R expression on T lymphocytes. In this phase, patients fail to mount proper immune responses leading to viral re-activation and secondary infections, frequently caused by avirulent and opportunistic organisms and of ventilator-associated pneumonia.

Figure 2. Pathways of immune dysfunction and targets for immune enhancing therapy in sepsis. In the initial pro-inflammatory response of sepsis, both the adaptive and innate immune systems are rapidly activated. This activation of monocytes, dendritic cells (DC), and macrophages (MAC), as well as CD4 helper and CD8 cytotoxic T cells results in the release of pro-inflammatory cytokines (TNF, IL-6, IL-1β) and chemokines. This pro-inflammatory response normally results in cellular activation and clearance of the primary pathogen (~~, pathogen). In the instance of a healthy individual, the immune system maintains homeostasis by employing counter inflammatory mechanisms such as regulatory T cells (Tregs), apoptosis, production of cytokines, expression of inhibitory receptors and myeloid-derived suppressor cells (MDSC) concurrently during inflammation. However, in some septic patients these normal homeostatic counter inflammatory mechanisms remain elevated such as expression of inhibitory receptors including: programmed death receptor -1 (PD-1), programmed death ligand (PD-L), B and T lymphocyte attenuator (BTLA), and herpesvirus entry mediator (HVEM) as well as the production of the immune modulating cytokine IL-10. Immune dysfunction occurs as activated innate and adaptive immune cells undergo rapid apoptosis while in the presence of increased suppressor cell populations like Tregs or MDSC. The primary infection fails to be cleared and may progress into immune suppression. Prolonged immune suppression and persistent antigen may result in T-cell exhaustion indicated by a T cell’s increased expression of PD-1 and decreased expression of the IL-7R as well as a functional impairment that includes failure to proliferate, secrete cytokines, and kill target cells. Potential targets for immune-therapy are indicted in the dotted GREEN line. Potential therapeutic targets include using blocking antibodies such as anti-IL-10 to decrease Treg function; anti-PD-1 and anti-PD-L to reverse the induction of T-cell exhaustion; and anti-HVEM or anti-BTLA to block tissue suppression of immune cells. IL-7 or IL-15 may be effective in blocking apoptosis and reversing cell exhaustion; GM-CSF to stimulate APC function by increasing recruitment and HLA-DR expression; and IFN-γ to increase PMN recruitment and function.