Dataset Information

Preferential inhibition of adaptive immune system dynamics by glucocorticoids in patients after acute surgical trauma.

ABSTRACT: Glucocorticoids (GC) are a controversial yet commonly used intervention in the clinical management of acute inflammatory conditions, including sepsis or traumatic injury. In the context of major trauma such as surgery, concerns have been raised regarding adverse effects from GC, thereby necessitating a better understanding of how GCs modulate the immune response. Here we report the results of a randomized controlled trial (NCT02542592) in which we employ a high-dimensional mass cytometry approach to characterize innate and adaptive cell signaling dynamics after a major surgery (primary outcome) in patients treated with placebo or methylprednisolone (MP). A robust, unsupervised bootstrap clustering of immune cell subsets coupled with random forest analysis shows profound (AUC?=?0.92, p-value?=?3.16E-8) MP-induced alterations of immune cell signaling trajectories, particularly in the adaptive compartments. By contrast, key innate signaling responses previously associated with pain and functional recovery after surgery, including STAT3 and CREB phosphorylation, are not affected by MP. These results imply cell-specific and pathway-specific effects of GCs, and also prompt future studies to examine GCs' effects on clinical outcomes likely dependent on functional adaptive immune responses.

SUBMITTER: Ganio EA

PROVIDER: S-EPMC7385146 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Preferential inhibition of adaptive immune system dynamics by glucocorticoids in patients after acute surgical trauma.

Ganio Edward A EA Stanley Natalie N Lindberg-Larsen Viktoria V Einhaus Jakob J Tsai Amy S AS Verdonk Franck F Culos Anthony A Ghaemi Sajjad S Rumer Kristen K KK Stelzer Ina A IA Gaudilliere Dyani D Tsai Eileen E Fallahzadeh Ramin R Choisy Benjamin B Kehlet Henrik H Aghaeepour Nima N Angst Martin S MS Gaudilliere Brice B

Nature communications 20200727 1

Glucocorticoids (GC) are a controversial yet commonly used intervention in the clinical management of acute inflammatory conditions, including sepsis or traumatic injury. In the context of major trauma such as surgery, concerns have been raised regarding adverse effects from GC, thereby necessitating a better understanding of how GCs modulate the immune response. Here we report the results of a randomized controlled trial (NCT02542592) in which we employ a high-dimensional mass cytometry approac ...[more]

PMID: 32719355

Similar Datasets

Project description:ObjectiveDespite years of research and the development of countless awareness campaigns, the number of deaths related to prescription opioid overdose is steadily rising. Often, naive patients undergoing trauma-related surgery are dispensed opioids while in the hospital, resulting in an escalation to long-term opioid misuses. We explored the impact of an educational intervention to modify perceptions of opioid needs at the bedside of trauma inpatients in post-surgery pain management.Materials and methodsTwenty-eight inpatients with acute post-surgical pain completed this proof-of-concept study adopting an educational intervention related to opioids and non-pharmacological strategies in the context of acute post-surgical pain. An education assessment survey was developed to measure pre- and post-education perceptions of opioid needs to manage pain. The survey statements encompassed the patient's perceived needs for opioids and other pharmacological and non-pharmacological therapeutics to manage acute pain. The primary outcome was the change in the patient's perceived need for opioids. The secondary (explorative) outcome was the change in Morphine Milligram Equivalents (MME) used on the day of the educational intervention while inpatients and prescribed at the time of the hospital discharge.ResultsAfter the educational intervention, patients reported less agreement with the statement, "I think a short course of opioids (less than 5 days) is safe." Moreover, less agreement on using opioids to manage trauma-related pain was positively associated with a significant reduction in opioids prescribed at discharge after the educational intervention. The educational intervention might have effectively helped to cope with acute trauma-related pain while adjusting potential unrealistic expectancies about pain management and, more in general, opioid-related needs.ConclusionThese findings suggest that trauma patients' expectations and understanding of the risks associated with the long-term use of opioids can be modified by a short educational intervention delivered by health providers during the hospitalization. Establishing realistic expectations in managing acute traumatic pain may empower patients with the necessary knowledge to minimize the potential of continuous long-term opioid use, opioid misuse, and the development of post-trauma opioid abuse and/or addiction.

Project description:Oncolytic viruses are of growing interest to cancer researchers and clinicians, due to their selectivity for tumor cells over healthy cells and their immunostimulatory properties. The immune response to an oncolytic virus plays a critical role in treatment efficacy. However, uncertainty remains regarding the circumstances under which the immune system either assists in eliminating tumor cells or inhibits treatment via rapid viral clearance, leading to the cessation of the immune response. In this work, we develop an ordinary differential equation model of treatment for a lethal brain tumor, glioblastoma, using an oncolytic Herpes Simplex Virus. We use a mechanistic approach to model the interactions between distinct populations of immune cells, incorporating both innate and adaptive immune responses to oncolytic viral therapy (OVT), and including a mechanism of adaptive immune suppression via the PD-1/PD-L1 checkpoint pathway. We focus on the tradeoff between viral clearance by innate immune cells and the innate immune cell-mediated recruitment of antiviral and antitumor adaptive immune cells. Our model suggests that when a tumor is treated with OVT alone, the innate immune cells' ability to clear the virus quickly after administration has a much larger impact on the treatment outcome than the adaptive immune cells' antitumor activity. Even in a highly antigenic tumor with a strong innate immune response, the faster recruitment of antitumor adaptive immune cells is not sufficient to offset the rapid viral clearance. This motivates our subsequent incorporation of an immunotherapy that inhibits the PD-1/PD-L1 checkpoint pathway by blocking PD-1, which we combine with OVT within the model. The combination therapy is most effective for a highly antigenic tumor or for intermediate levels of innate immune localization. Extreme levels of innate immune cell activity either clear the virus too quickly or fail to activate a sufficiently strong adaptive response, yielding ineffective combination therapy of GBM. Hence, we show that the innate and adaptive immune interactions significantly influence treatment response and that combining OVT with an immune checkpoint inhibitor expands the range of immune conditions that allow for tumor size reduction or clearance.

Dataset Information

Preferential inhibition of adaptive immune system dynamics by glucocorticoids in patients after acute surgical trauma.

Publications

Preferential inhibition of adaptive immune system dynamics by glucocorticoids in patients after acute surgical trauma.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets