Precision Immunotherapy for Sepsis

Abstract

Decades of sepsis research into a specific immune system-targeting adjunctive therapy have not resulted in the discovery of an effective compound. Apart from antibiotics, source control, resuscitation and organ support, not a single adjunctive treatment is used in current clinical practice. The inability to determine the prevailing immunological phenotype of patients and the related large heterogeneity of study populations are regarded by many as the most important factors behind the disappointing results of past clinical trials. While the therapeutic focus has long been on immunosuppressive strategies, increased appreciation of the importance of sepsis-induced immunoparalysis in causing morbidity and mortality in sepsis patients has resulted in a paradigm shift in the sepsis research field towards strategies aimed at enhancing the immune response. However, similar to immunosuppressive therapies, precision medicine is imperative for future trials with immunostimulatory compounds to succeed. As such, identifying those patients with a severely suppressed or hyperactive immune system who will most likely benefit from either immunostimulatory or immunosuppressive therapy, and accurate monitoring of both the immune and treatment response is crucial. This review provides an overview of the challenges lying ahead on the path towards precision immunotherapy for patients suffering from sepsis.

Epigenetic stabilization of DC and DC precursor classical activation by TNFα contributes to protective T cell polarization

“…These therapies could be particularly important in situations when these myeloid cells need to tolerate immunomodulatory or suppressive environments (chronic infections or tumors) to trigger and sustain protective immunity. For example, immunostimulatory treatments like IFN are emerging as possible adjunctive treatments for immunoparalysis induced by sepsis (60,61).…”

Circadian Rhythms in Septic Shock Patients

“…Estimates suggest that sepsis affects more than 19 million people worldwide every year and might cause up to 5 million deaths [1]. In adult intensive care units (ICUs), sepsis and septic shock are the leading causes of death [2]. Even though a multitude of studies provided a substantial improvement in understanding the complex pathophysiology of sepsis, several treatments have failed in clinical trials [2].…”

Activation of α7 Nicotinic Acetylcholine Receptor Upregulates HLA-DR and Macrophage Receptors: Potential Role in Adaptive Immunity and in Preventing Immunosuppression

“…Stimulation of α7 nAChR can be achieved with agonists or positive allosteric modulators, both types of ligands being potential therapeutics [73,74]. Usually, therapeutic strategies for the treatment of sepsis are aimed at suppressing the early phase of the hyperinflammatory response [75]. However, the immunosuppression state exists simultaneously with the persistent inflammation and contributes to the development of persistent, recurrent, secondary and nosocomial infections, which lead to poorer outcomes and increased mortality [59].…”