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

Abstract

Surgical injury can be a life‐threatening complication, not only due to the injury itself, but also due to immune responses to the injury and subsequent development of infections, which readily result in sepsis. Sepsis remains the leading cause of death in most intensive care units. Unfavorable outcomes of several high‐profile trials in the treatment of sepsis have led researchers to state that sepsis studies need a new direction. The immune response that occurs during sepsis is characterized by a cytokine‐mediated hyper‐inflammatory phase, which most patients survive, and a subsequent immunosuppressive phase. Therefore, therapies that improve host immunity might increase the survival of patients with sepsis. Many mechanisms are responsible for sepsis‐induced immunosuppression, including apoptosis of immune cells, increased regulatory T cells and expression of programmed cell death 1 on CD4+ T cells, and cellular exhaustion. Immunomodulatory molecules that were recently identified include interleukin‐7, interleukin‐15, and anti‐programmed cell death 1. Recent studies suggest that immunoadjuvant therapy is the next major advance in sepsis treatment.

Immunosuppression, rather than inflammation, is a salient feature of sepsis in an Indian cohort

“…Our result is supportive of Ono et al [19] who argued in favour of immunostimulation over targeting inflammation as a possible therapeutic startegy to treat patients suffering from sepsis. As the immunosuppression involves chiefly the adaptive immune system, there have been attempts to boost adaptive immunity through IFNγ, granulocyte-macrophage colony-stimulating factor (GMCSF), or granulocyte colony-stimulating factor GCSF [27] .…”

“…Our finding raises questions for management of patients in this region. If validated on a larger set of patients, it appears that immune-enhancement e.g., immune adjuvant therapy [19]) shall be a better strategy than inhibition of inflammation.…”

“…IL7 treatment to sepsis patients restored IFN-gamma secretion and T-cell proliferation [29] in them. PD-1 is another interesting target molecule for immunostimulatory therapy, as it causes immunosuppression through IL-10 expression [19]. Anti PD-1 [31] and PDL-1 [32] therapy in bacterial and fungal murine sepsis showed increased survival.…”

LDK378 inhibits the recruitment of myeloid‐derived suppressor cells to spleen via the p38–GRK2–CCR2 pathway in mice with sepsis

“…Immunosuppression in the late phase of sepsis has been considered a major cause of sepsis‐related adverse outcomes . Shift from a Th1 to a Th2 cell phenotype, reduced Th17 cell response, T‐cell exhaustion and increase in the number of Treg cells are the abnormal immunological reactions in sepsis .…”

“…Immunosuppression in the late phase of sepsis has been considered a major cause of sepsis-related adverse outcomes. 18 Shift from a Th1 to a Th2 cell phenotype, reduced Th17 cell response, T-cell exhaustion and increase in the number of Treg cells are the abnormal immunological reactions in sepsis. 19 To investigate whether LDK378 affects T cells and its subsets in the late immunosuppressive state of sepsis, we investigated the percentages of CD3 + CD4 + and CD3 + CD8 + T cells, and their apoptosis in the spleen of sham and sepsis mice.…”