Targeting Complement C5a Receptor 1 for the Treatment of Immunosuppression in Sepsis

Sommerfeld, Oliver; Medyukhina, Anna; Neugebauer, Sophie; Ghait, Mohamed; Ulferts, Svenja; Lupp, Amelie; König, Rainer; Wetzker, Reinhard; Schulz, Stefan; Figge, Marc Thilo; Bauer, Michael; Press, Adrian T.

doi:10.1016/j.ymthe.2020.09.008

Cited by 38 publications

(24 citation statements)

References 44 publications

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“…In this model, human feces are administered intraperitoneally to induce life‐threatening polymicrobial infection. This model is well characterized with signs of excretory liver failure detectable as early as 6 h after initiation of infection (Gonnert et al , 2011; Recknagel et al , 2012; Schaarschmidt et al , 2018; Sommerfeld et al , 2020). To explore the targeting approach, animals were treated with free AS605240 or T‐LipoAS at 6 h after infection with functional assessment at 24 and 48 h. All animals received supportive antibiotic (meropenem) and analgesic (metamizole) therapy (Fig 3A).…”

Section: Resultsmentioning

confidence: 99%

“…All animals were either subjected to peritoneal contamination and sepsis by injecting a characterized human stool suspension (PCI group) (Gonnert et al , 2011; Sommerfeld et al , 2020) or saline (sham group) intraperitoneally. Our studies were designed to fulfill the minimum quality threshold in pre‐clinical sepsis studies, including antibiotic and analgesic treatment as well as fluid resuscitation (Osuchowski et al , 2018).…”

Section: Methodsmentioning

confidence: 99%

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Targeted delivery of a phosphoinositide 3‐kinase γ inhibitor to restore organ function in sepsis

et al. 2021

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Jaundice, the clinical hallmark of infection‐associated liver dysfunction, reflects altered membrane organization of the canalicular pole of hepatocytes and portends poor outcomes. Mice lacking phosphoinositide 3‐kinase‐γ (PI3Kγ) are protected against membrane disintegration and hepatic excretory dysfunction. However, they exhibit a severe immune defect that hinders neutrophil recruitment to sites of infection. To exploit the therapeutic potential of PI3Kγ inhibition in sepsis, a targeted approach to deliver drugs to hepatic parenchymal cells without compromising other cells, in particular immune cells, seems warranted. Here, we demonstrate that nanocarriers functionalized through DY‐635, a fluorescent polymethine dye, and a ligand of organic anion transporters can selectively deliver therapeutics to hepatic parenchymal cells. Applying this strategy to a murine model of sepsis, we observed the PI3Kγ‐dependent restoration of biliary canalicular architecture, maintained excretory liver function, and improved survival without impairing host defense mechanisms. This strategy carries the potential to expand targeted nanomedicines to disease entities with systemic inflammation and concomitantly impaired barrier functionality.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Targeted delivery of a phosphoinositide 3‐kinase γ inhibitor to restore organ function in sepsis

et al. 2021

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“…Interestingly, Sommerfeld et al observed recently that mouse mutants lacking the receptor of complement factor C5a showed increased survival in mild septic mouse models, and, IFNγ/IL10 was increased compared to wildtype mice under the same conditions (34). The mutants also showed a similar survival benefit when mutant and wildtype mice were treated with antibiotics.…”

Section: Discussionmentioning

confidence: 97%

Use of IFNγ/IL10 Ratio for Stratification of Hydrocortisone Therapy in Patients With Septic Shock

et al. 2021

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Large clinical trials testing hydrocortisone therapy in septic shock have produced conflicting results. Subgroups may benefit of hydrocortisone treatment depending on their individual immune response. We performed an exploratory analysis of the database from the international randomized controlled clinical trial Corticosteroid Therapy of Septic Shock (CORTICUS) employing machine learning to a panel of 137 variables collected from the Berlin subcohort comprising 83 patients including demographic and clinical measures, organ failure scores, leukocyte counts and levels of circulating cytokines. The identified theranostic marker was validated against data from a cohort of the Hellenic Sepsis Study Group (HSSG) (n = 246), patients enrolled in the clinical trial of Sodium Selenite and Procalcitonin Guided Antimicrobial Therapy in Severe Sepsis (SISPCT, n = 118), and another, smaller clinical trial (Crossover study, n = 20). In addition, in vitro blood culture experiments and in vivo experiments in mouse models were performed to assess biological plausibility. A low serum IFNγ/IL10 ratio predicted increased survival in the hydrocortisone group whereas a high ratio predicted better survival in the placebo group. Using this marker for a decision rule, we applied it to three validation sets and observed the same trend. Experimental studies in vitro revealed that IFNγ/IL10 was negatively associated with the load of (heat inactivated) pathogens in spiked human blood and in septic mouse models. Accordingly, an in silico analysis of published IFNγ and IL10 values in bacteremic and non-bacteremic patients with the Systemic Inflammatory Response Syndrome supported this association between the ratio and pathogen burden. We propose IFNγ/IL10 as a molecular marker supporting the decision to administer hydrocortisone to patients in septic shock. Prospective clinical studies are necessary and standard operating procedures need to be implemented, particularly to define a generic threshold. If confirmed, IFNγ/IL10 may become a suitable theranostic marker for an urging clinical need.

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“…In a mouse model, the blockade of C5a or C5aR inhibits the development of sepsis. Significantly increased survival has been shown in models of mild to moderate sepsis of C5aR-deficient mice, accompanied by improved pathogen clearance and largely preserved liver function (33). In patients with sepsis, however, downregulated levels of C5aR correlate with a poor prognosis when C5a levels are simultaneously elevated (34).…”

Section: The Complement System In Sepsismentioning

confidence: 99%

Sepsis—Pathophysiology and Therapeutic Concepts

2021

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Sepsis is a life-threatening condition and a global disease burden. Today, the heterogeneous syndrome is defined as severe organ dysfunction caused by a dysregulated host response to infection, with renewed emphasis on immune pathophysiology. Despite all efforts of experimental and clinical research during the last three decades, the ability to positively influence course and outcome of the syndrome remains limited. Evidence-based therapy still consists of basic causal and supportive measures, while adjuvant interventions such as blood purification or targeted immunotherapy largely remain without proof of effectiveness so far. With this review, we aim to provide an overview of sepsis immune pathophysiology, to update the choice of therapeutic approaches targeting different immunological mechanisms in the course of sepsis and septic shock, and to call for a paradigm shift from the pathogen to the host response as a potentially more promising angle.

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Targeting Complement C5a Receptor 1 for the Treatment of Immunosuppression in Sepsis

Cited by 38 publications

References 44 publications

Targeted delivery of a phosphoinositide 3‐kinase γ inhibitor to restore organ function in sepsis

Targeted delivery of a phosphoinositide 3‐kinase γ inhibitor to restore organ function in sepsis

Use of IFNγ/IL10 Ratio for Stratification of Hydrocortisone Therapy in Patients With Septic Shock

Sepsis—Pathophysiology and Therapeutic Concepts

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