What is it about?

TLDR: Sepsis is a dangerous dysregulation of the immune system with signs of both, a too strong and too weak immune reaction, but their relation to each other and their time course are not clear. We demonstrated features of too strong and too weak inflammation to both be present already on the first day of sepsis at the same time and in the same blood samples. Despite these features of a weakened immune response, the samples did not react to Immune Checkpoint Inhibitors, a type of cancer drugs that unleashes the immune system, which is discussed as future sepsis therapy. Sepsis is a very common and deadly disease, especially on intensive care units. In Sepsis, the immune system overreacts against invading germs damaging the host's own body in the process. Together with that overreaction, however, the immune system shuts down core functions, as if 'burning out', which leaves the body vulnerable to secondary infections or an insufficient control of the primary infection. In our study we have drawn blood from 61 Sepsis patients on an intensive care unit within 24 hours of diagnosis. When incubating these samples, we observed that both signs of too much inflammation and to little inflammation are present. Specifically, we observed 1) fragments of dead cells and of germs (Danger and Pathogen-associated molecular patterns) present in the blood activate Toll-like receptors, a very important family of immune receptors, which drives an ongoing immune reaction 2) the blood of sepsis patients reacts far less to added bacteria, than the blood of healthy volunteers. Within these assays, we then tested a potential future class of sepsis therapeutics named "Immune Checkpoint Inhibitors". These drugs were developed to unleash the immune system against cancer cells, but could also support immune recovery in sepsis. Despite the suppressed immune reaction to bacteria in our system, however, the samples did not react to three different classes of Immune Checkpoint Inhibitors, questioning their clinical use for sepsis.

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Why is it important?

1. The data on early sepsis immunity is scarce, because it is difficult to timely recognize and sample these severely ill patients. This hinders development of new diagnostic and therapeutic applications. 2. Considering the range of side-effects of Immune Checkpoint inhibitors and their potential for immune over-activation, thorough testing is warranted before considering clinical use.


Especially during the last decade, people have more and more recognized, what a complex, multilayered, and sometimes weird disease sepsis is, with all its different presentations and features that at times seem to contradict each other or pull in opposite directions. It's been great to be a part of the effort to better understand these intricacies, and maybe eventually develop targeted sepsis therapies.

Willem Buys
Johns Hopkins University

Read the Original

This page is a summary of: Immune hyporeactivity to bacteria and multiple TLR-ligands, yet no response to checkpoint inhibition in patients just after meeting Sepsis-3 criteria, PLoS ONE, August 2022, PLOS, DOI: 10.1371/journal.pone.0273247.
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