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Suppression of activation and costimulatory signaling in splenic CD4+ T cells after trauma-hemorrhage reduces T-cell function: a mechanism of post-traumatic immune suppression.

ABSTRACT: Reduced immune function is frequently a consequence of serious injury such as trauma-hemorrhage (T-H). Injury may lead to reduced T-cell activation, resulting in decreased engagement of costimulatory molecules after antigen recognition and in subsequent immunological compromise and anergy. We hypothesized that inhibition of CD28 expression is one possible mechanism by which immune functions are suppressed after T-H. Male C3H/HeN mice (with or without ovalbumin immunization) were subjected to sham operation or T-H and sacrificed after 24 hours. Splenic T cells were then stimulated with concanavalin A or ovalbumin in vivo or in vitro, and CD28, cytotoxic T-lymphocyte antigen 4 (CTLA-4), CD69, and phospho-Akt expression was determined. T-cell proliferation/cytokine production was measured in vitro. Stimulation-induced CD69, CD28, and phospho-Akt up-regulation were significantly impaired after T-H compared with sham-operated animals; however, CTLA-4 expression was significantly higher in the T-H group. Over a 3-day span, stimulated T cells from sham-operated animals showed significantly higher proliferation compared with the T-H group. IL-2 and IFN-gamma were elevated in sham-operated animals, whereas IL-4 and IL-5 rose in the T-H group, revealing a shift from T(H)1 to T(H)2 type cytokine production after T-H. Dysregulation of the T-cell costimulatory pathway is therefore likely to be a significant contributor to post-traumatic immune suppression.

SUBMITTER: Hsieh CH

PROVIDER: S-EPMC2751547 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Suppression of activation and costimulatory signaling in splenic CD4+ T cells after trauma-hemorrhage reduces T-cell function: a mechanism of post-traumatic immune suppression.

Hsieh Chi-Hsun CH Hsu Jun-Te JT Hsieh Ya-Ching YC Frink Michael M Raju Raghavan R Hubbard William J WJ Bland Kirby I KI Chaudry Irshad H IH

The American journal of pathology 20090903 4

Reduced immune function is frequently a consequence of serious injury such as trauma-hemorrhage (T-H). Injury may lead to reduced T-cell activation, resulting in decreased engagement of costimulatory molecules after antigen recognition and in subsequent immunological compromise and anergy. We hypothesized that inhibition of CD28 expression is one possible mechanism by which immune functions are suppressed after T-H. Male C3H/HeN mice (with or without ovalbumin immunization) were subjected to sha ...[more]

PMID: 19729482

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Project description:Background/Objective: Traumatic intracranial hemorrhage (tICH) accounts for significant trauma morbidity and mortality. Several studies have developed prognostic models for tICH outcomes, but previous models face limitations, including poor generalizability and limited accuracy. The objective was to develop a prognostic model and determine predictors of mortality using the largest trauma database in the U.S., applying rigorous analytical methodology with true hold-out-set model validation. Methods: We identified 248,536 patients in the National Trauma Data Bank (NTDB) from 2012 to 2016 with a diagnosis code associated with tICH. For each admission, we collected demographic information, systolic blood pressure, blood alcohol level (BAL), Glasgow Coma Score (GCS), Injury Severity Score (ISS), presence of epidural/subdural/subarachnoid/intraparenchymal hemorrhage, comorbidities, complications, trauma center level, and trauma center region. Our final study population was 212,666 patients following exclusion of records with missing data. The dependent variable was patient death. Linear support vector machine (SVM) classification was carried out with recursive feature selection. Model performance was assessed using holdout 10-fold cross-validation. Results: Cross-validation demonstrated a mean accuracy of 0.792 (95% CI 0.783-0.799). Accuracy, precision, recall, and AUC were 0.827, 0.309, 0.750, and 0.791, respectively. In the final model, high ISS, advanced age, subdural hemorrhage, and subarachnoid hemorrhage were associated with increased mortality, while high GCS verbal and motor subscores, current smoker, BAL beyond the legal limit, and level 1 trauma center were associated with decreased mortality. Conclusions: A linear SVM model was developed for tICH, with nine features selected as predictors of mortality. These findings are applicable to multiple hemorrhage subtypes and may benefit the triage of high risk patients upon admission. While many studies have attempted to create models to predict mortality in TBI, we sought to confirm those predictors using modern modeling approaches, machine learning, and true hold-out test sets, using the largest available TBI database in the U.S. We find that while the predictors we identify are consistent with prior reports, overall prediction accuracy is somewhat lower than prior reports when assessed more rigorously.

Project description:BackgroundIntracranial hemorrhage occurs in over 60% of severe head injuries in one of three types: extradural (EDH); subdural (SDH); and intraparenchymal (TICH). Prompt surgical removal of significant SDH and EDH is established and widely accepted. However, TICH is more common and is found in more than 40% of severe head injuries. It is associated with a worse outcome but the role for surgical removal remains undefined. Surgical practice in the treatment of TICHs differs widely around the world. The aim of early surgery in TICH removal is to prevent secondary brain injury. There have been trials of surgery for spontaneous ICH (including the STICH II trial), but none so far of surgery for TICH.Methods/designThe UK National Institutes of Health Research has funded STITCH(Trauma) to determine whether a policy of early surgery in patients with TICH improves outcome compared to a policy of initial conservative treatment. It will include a health economics component and carry out a subgroup analysis of patients undergoing invasive monitoring. This is an international multicenter pragmatic randomized controlled trial.Patients are eligible if: they are within 48 h of injury; they have evidence of TICH on CT scan with a confluent volume of attenuation significantly raised above that of the background white and grey matter that has a total volume >10 mL; and their treating neurosurgeon is in equipoise.Patients will be ineligible if they have: a significant surface hematoma (EDH or SDH) requiring surgery; a hemorrhage/contusion located in the cerebellum; three or more separate hematomas fulfilling inclusion criteria; or severe pre-existing physical or mental disability or severe co-morbidity which would lead to poor outcome even if the patient made a full recovery from the head injury.Patients will be randomized via an independent service. Patients randomized to surgery receive surgery within 12 h. Both groups will be monitored according to standard neurosurgical practice. All patients have a CT scan at 5 days (+/-2 days) to assess changes in hematoma size. Follow-up is by postal questionnaire at 6 and 12 months. The recruitment target is 840 patients.Trial registrationCurrent Controlled Trials ISRCTN19321911.

Dataset Information

Suppression of activation and costimulatory signaling in splenic CD4+ T cells after trauma-hemorrhage reduces T-cell function: a mechanism of post-traumatic immune suppression.

Publications

Suppression of activation and costimulatory signaling in splenic CD4+ T cells after trauma-hemorrhage reduces T-cell function: a mechanism of post-traumatic immune suppression.

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