Highlights • 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.
Patients with protracted sepsis develop impaired immunity, which predisposes them to acquiring secondary infections. One of the most common and lethal secondary infections is Pseudomonas aeruginosa ...pneumonia. Immunoadjuvant therapy is a promising approach to reverse sepsis‐induced immunosuppression and improve morbidity and mortality from secondary infections. Interleukin‐7 is an immunoadjuvant that improves survival in clinically relevant animal models of polymicrobial peritonitis and in fungal sepsis. This study investigated the effect of recombinant human interleukin‐7 (rhIL‐7) on survival in a 2‐hit model of sublethal cecal ligation and puncture followed by P. aeruginosa pneumonia. Potential immunologic mechanisms responsible for the rhIL‐7 putative beneficial effect were also examined, focusing on IL‐17, IL‐22, IFN‐γ, and TNF‐α, cytokines that are critical in the control of sepsis and pulmonary Pseudomonas infections. Results showed that rhIL‐7 was highly effective in preventing P. aeruginosa–induced death, i.e., 92% survival in rhIL‐7–treated mice versus 56% survival in control mice. rhIL‐7 increased absolute numbers of immune effector cells in lung and spleen and ameliorated the sepsis‐induced loss of lung innate lymphoid cells (ILCs). rhIL‐7 also significantly increased IL‐17–, IFN‐γ–, and TNF‐α–producing lung ILCs and CD8 T cells as well as IFN‐γ– and TNF‐α–producing splenic T cell subsets and ILCs. Furthermore, rhIL‐7 enhanced NF‐κB and STAT3 signaling in lungs during sepsis and pneumonia. Given the high mortality associated with secondary P. aeruginosa pneumonia, the ability of rhIL‐7 to improve immunity and increase survival in multiple animal models of sepsis, and the remarkable safety profile of rhIL‐7, clinical trials with rhIL‐7 should be considered.
Blocking the negative co‐stimulatory molecule PD‐1 prevents immune suppression, blocks apoptosis, and improves survival in sepsis.
There is increasing recognition that a major pathophysiologic event ...in sepsis is the progression to an immunosuppressive state in which the host is unable to eradicate invading pathogens. Although there are likely numerous causes for the immunosuppression, expression of negative costimulatory molecules on immune effector cells is a likely contributing factor. PD‐1 is a recently described, negative costimulatory molecule that has potent effects to inhibit T cell activation, cytokine production, and cytotoxic functions. PD‐1 plays a critical role in the host response to specific pathogens, but relatively little work has been done on the possible effects of PD‐1 in sepsis. We hypothesized that the anti‐PD‐1 antibody would improve survival in sepsis. Mice underwent CLP, and PD‐1 expression was quantitated. Additionally, the effects of anti‐PD‐1 antibody on lymphocyte apoptosis, cytokine production, host immunity, and survival were determined. PD‐1 expression increased beginning 48 h after sepsis, and >20% of CD4 and CD8 T cells were positive by 7 days. Anti‐PD‐1 antibody administered 24 h after sepsis prevented sepsis‐induced depletion of lymphocytes and DCs, increased Bcl‐xL, blocked apoptosis, and improved survival. Anti‐PD‐1 also prevented the loss in DTH, a key indicator of immunocompetence in sepsis. Thus, delayed administration of anti‐PD‐1 antibody, an important therapeutic advantage, was effective in sepsis. Furthermore, these results add to the growing body of evidence that modulation of the positive and negative costimulatory pathways on immune cells represents a viable therapeutic approach in reversing immunosuppression and improving sepsis survival.
Sepsis remains a major cause of morbidity and mortality in most intensive care units. Protracted sepsis can evolve into a state of profound immunosuppression characterized by secondary infections, ...frequently with opportunistic-type pathogens. Immunoadjuvant therapy is currently being evaluated as a novel treatment for patients with sepsis. Two of the most promising immunoadjuvants are interleukin-7 (IL-7) and anti-programmed cell death 1 antibody (anti-PD-1). Both IL-7 and anti-PD-1 have been reported to boost host immunity and improve outcomes in patients with viral infections and cancer. The purpose of this study was to define the immunological mechanisms of action of IL-7 and anti-PD-1 in the two-hit sepsis model of cecal ligation and puncture followed by Candida albicans. In addition, we examined whether combined treatment with IL-7 and anti-PD-1 provided any additive beneficial effects in reversing immune dysfunction. The present findings demonstrated that IL-7 and anti-PD-1 had differing effects on innate and adaptive immune functions. Compared with anti-PD-1, IL-7 increased lymphocyte proliferation; expression of lymphocyte adhesion molecules, lymphocyte function-associated antigen 1, and very late antigen-4; interferon-γ production; and CD28 expression on splenic CD8 T cells. In contrast, anti-PD-1 seemed to have a greater effect on major histocompatibility complex class II expression on splenic macrophages and dendritic cells than IL-7. Combined treatment with IL-7 and anti-PD-1 produced additive effects on CD28 expression, lymphocyte proliferation, and splenic secretion of interferon-γ. In conclusion, the present study shows differences in immunomodulatory actions between IL-7 and anti-PD-1 and provides a potential rationale for combining IL-7 and anti-PD-1 in the therapy of sepsis.
Introduction Fungal sepsis is an increasingly common problem in intensive care unit patients.Mortality from fungal sepsis remains high despite antimicrobial therapy that is highly active against most ...fungal pathogens, a finding consistent with defective host immunity that is present in many patients with disseminated fungemia.One recently recognized immunologic defect that occurs in patients with sepsis is T cell "exhaustion" due to increased expression of programmed cell death -1 (PD-1).This study tested the ability of anti-PD-1 and anti-programmed cell death ligand -1 (anti-PD-L1) antagonistic antibodies to improve survival and reverse sepsis-induced immunosuppression in two mouse models of fungal sepsis. Methods Fungal sepsis was induced in mice using two different models of infection, that is, primary fungal sepsis and secondary fungal sepsis occurring after sub-lethal cecal ligation and puncture (CLP).Anti-PD-1 and anti-PD-L1 were administered 24 to 48 h after fungal infection and effects on survival, interferon gamma production, and MHC II expression were examined. Results Anti-PD-1 and anti-PD-L1 antibodies were highly effective at improving survival in primary and secondary fungal sepsis.Both antibodies reversed sepsis-induced suppression of interferon gamma and increased expression of MHC II on antigen presenting cells.Blockade of cytotoxic T-lymphocyte antigen-4 (CTLA-4), a second negative co-stimulatory molecule that is up-regulated in sepsis and acts like PD-1 to suppress T cell function, also improved survival in fungal sepsis. Conclusions Immuno-adjuvant therapy with anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibodies reverse sepsis-induced immunosuppression and improve survival in fungal sepsis.The present results are consistent with previous studies showing that blockade of PD-1 and CTLA-4 improves survival in bacterial sepsis.Thus, immuno-adjuvant therapy represents a novel approach to sepsis and may have broad applicability in the disorder.Given the relative safety of anti-PD-1 antibody in cancer clinical trials to date, therapy with anti-PD-1 in patients with life-threatening sepsis who have demonstrable immunosuppression should be strongly considered.
Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is one of the critical inhibitory regulators of early stages of T-cell activation and proliferation, which opposes the actions of CD28-mediated ...costimulation. Anti-CTLA-4 therapy has been effective clinically in enhancing immunity and improving survival in patients with metastatic cancer. Sepsis is a lethal condition that shares many of the same mechanisms of immune suppression with cancer. Given the similarities in immune defects in cancer and sepsis, we examined the ability of anti-CTLA-4 antibody to block apoptosis, reverse the immunosuppression of sepsis, and improve survival in the cecal ligation and puncture model. Mice underwent sham or cecal ligation and puncture, and spleens harvested at various time points after surgery. Expression of CTLA-4 on CD4, CD8, and regulatory T cells was quantitated. Anti-CTLA-4 was administrated 6 and 24 h after surgery. Spleens were harvested at 48 h after surgery, and apoptosis and cytokine production determined. Seven-day survival studies were also conducted. Expression of CTLA-4 on CD4, CD8, and regulatory T cells increased during sepsis. Anti-CTLA-4 therapy decreased sepsis-induced apoptosis but had little effect on proinflammatory or anti-inflammatory cytokines. There was a dose-dependent effect of anti-CTLA-4 on survival. At high dose, anti-CTLA-4 worsened survival, but at lower doses, survival was significantly improved. Survival in sepsis depends on the proper balance between the proinflammatory and anti-inflammatory/immunologic systems. Anti-CTLA-4-based immunotherapy offers promise in the treatment of sepsis, but care must be used in the timing and dose of administration of the drug to prevent adverse effects.
IL-15 is a pluripotent antiapoptotic cytokine that signals to cells of both the innate and adaptive immune system and is regarded as a highly promising immunomodulatory agent in cancer therapy. ...Sepsis is a lethal condition in which apoptosis-induced depletion of immune cells and subsequent immunosuppression are thought to contribute to morbidity and mortality. This study tested the ability of IL-15 to block apoptosis, prevent immunosuppression, and improve survival in sepsis. Mice were made septic using cecal ligation and puncture or Pseudomonas aeruginosa pneumonia. The experiments comprised a 2 x 2 full factorial design with surgical sepsis versus sham and IL-15 versus vehicle. In addition to survival studies, splenic cellularity, canonical markers of activation and proliferation, intracellular pro- and antiapoptotic Bcl-2 family protein expression, and markers of immune cell apoptosis were evaluated by flow cytometry. Cytokine production was examined both in plasma of treated mice and splenocytes that were stimulated ex vivo. IL-15 blocked sepsis-induced apoptosis of NK cells, dendritic cells, and CD8 T cells. IL-15 also decreased sepsis-induced gut epithelial apoptosis. IL-15 therapy increased the abundance of antiapoptotic Bcl-2 while decreasing proapoptotic Bim and PUMA. IL-15 increased both circulating IFN-gamma, as well as the percentage of NK cells that produced IFN-gamma. Finally, IL-15 increased survival in both cecal ligation and puncture and P. aeruginosa pneumonia. In conclusion, IL-15 prevents two immunopathologic hallmarks of sepsis, namely, apoptosis and immunosuppression, and improves survival in two different models of sepsis. IL-15 represents a potentially novel therapy of this highly lethal disorder.
Background
Profound lymphopenia is an independent predictor of adverse clinical outcomes in sepsis. Interleukin-7 (IL-7) is essential for lymphocyte proliferation and survival. A previous phase II ...study showed that CYT107, a glycosylated recombinant human IL-7, administered intramuscularly reversed sepsis-induced lymphopenia and improved lymphocyte function. Thepresent study evaluated intravenous administration of CYT107. This prospective, double-blinded, placebo-controlled trial was designed to enroll 40 sepsis patients, randomized 3:1 to CYT107 (10 µg/kg) or placebo, for up to 90 days.
Results
Twenty-one patients were enrolled (fifteen CYT107 group, six placebo group) at eight French and two US sites. The study was halted early because three of fifteen patients receiving intravenous CYT107 developed fever and respiratory distress approximately 5–8 h after drug administration. Intravenous administration of CYT107 resulted in a two–threefold increase in absolute lymphocyte counts (including in both CD4
+
and CD8
+
T cells (all
p
< 0.05)) compared to placebo. This increase was similar to that seen with intramuscular administration of CYT107, was maintained throughout follow-up, reversed severe lymphopenia and was associated with increase in organ support free days (OSFD). However, intravenous CYT107 produced an approximately 100-fold increase in CYT107 blood concentration compared with intramuscular CYT107. No cytokine storm and no formation of antibodies to CYT107 were observed.
Conclusion
Intravenous CYT107 reversed sepsis-induced lymphopenia. However, compared to intramuscular CYT107 administration, it was associated with transient respiratory distress without long-term sequelae. Because of equivalent positive laboratory and clinical responses, more favorable pharmacokinetics, and better patient tolerability, intramuscular administration of CYT107 is preferable.
Trial registration
: Clinicaltrials.gov, NCT03821038. Registered 29 January 2019,
https://clinicaltrials.gov/ct2/show/NCT03821038?term=NCT03821038&draw=2&rank=1
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Graphical Abstract
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