Both percentage of gammadelta T lymphocytes and CD3 expression are reduced during septic shock

OBJECTIVE: The mechanisms involved during sepsis-induced immunosuppression are far from being extensively established. The objective of the present study was to investigate whether two characteristics of T cells were altered in this situation: the percentage of circulating gammadelta T lymphocytes and the level of CD3 expression on T lymphocytes. DESIGN: Observational study. SETTING: Adult intensive care units in a university hospital. PATIENTS: Patients with septic shock (n = 21) and healthy individuals (n = 21). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In patients, we first observed the decreased percentage of gammadelta T lymphocytes in peripheral blood (1% [0.7-3.1], median [interquartile range]) in comparison with healthy individuals (3.5% [2.1-4.8]). Regarding CD3, we measured a highly significant decrease of its expression on both alphabeta and gammadelta T lymphocytes from patients (p < .005), whereas the CD3 mean fluorescence intensities ratio (gammadelta/alphabeta) was not affected: 2.2 [2.1-2.4] and 2.1 [1.9-2.3] in healthy individuals and septic patients, respectively. The magnitude in the decrease of CD3 expression was thus similar in alphabeta and gammadelta cells, suggesting a common down-regulation mechanism for both T-cell lineages. CONCLUSIONS: Combined with a reduced percentage of monocytes expressing human leukocyte antigen-DR, a reduced CD3 expression may be involved in the failure of antigen presentation depicted after septic shock, whereas the diminished percentage of circulating gammadelta T cells could be partly responsible for the elevated incidence of secondary infections. These two observations constitute additional pieces of the complex puzzle of sepsis-induced immunosuppression.     

Activation-induced modification in the CD3 complex of the gammadelta T cell receptor

The T cell antigen receptor complexes expressed on alphabeta and gammadelta T cells differ not only in their respective clonotypic heterodimers but also in the subunit composition of their CD3 complexes. The gammadelta T cell receptors (TCRs) expressed on ex vivo gammadelta T cells lack CD3delta, whereas alphabeta TCRs contain CD3delta. While this result correlates with the phenotype of CD3delta(-/-) mice, in which gammadelta T cell development is unaffected, it is inconsistent with the results of previous studies reporting that CD3delta is a component of the gammadelta TCR. Since earlier studies examined the subunit composition of gammadelta TCRs expressed on activated and expanded peripheral gammadelta T cells or gammadelta TCR(+) intestinal intraepithelial lymphocytes, we hypothesized that activation and expansion may lead to changes in the CD3 subunit composition of the gammadelta TCR. Here, we report that activation and expansion do in fact result in the inclusion of a protein, comparable in mass and mobility to CD3delta, in the gammadelta TCR. Further analyses revealed that this protein is not CD3delta, but instead is a differentially glycosylated form of CD3gamma. These results provide further evidence for a major difference in the subunit composition of alphabeta- and gammadelta TCR complexes and raise the possibility that modification of CD3gamma may have important functional consequences in activated gammadelta T cells.     

CD3 bright lymphocyte population reveal gammadelta T cells

BACKGROUND: In routine CD3/CD4/CD8 T-cell analysis, a CD3 bright population of lymphocytes is frequently observed. The aim of the present study was to identify the immunological significance of such CD3 bright lymphocytes. METHODS: We analyzed samples from 31 healthy adult volunteers, 78 human immunodeficiency virus (HIV)-positive, and 78 renal transplanted patients. RESULTS: A clearly distinct CD3 bright (frequently CD4-/CD8-) T-cell fraction was observed in 84% of donors and was directly correlated with the fraction of gammadelta T cells (r2 = 0.64). CD3 overexpression on gammadelta T cells was confirmed by a combination of monoclonal antibody staining (CD3-ECD, gammadeltaTCR-FITC, and alphabetaTCR-PE-Cy5) or immunomagnetic purification of gammadelta T cells (i.e., MdFI 20 vs 8.86). The gammadelta T cells expressed CD8 polypeptide chains (alpha and beta) in all possible combinations. The largest proportion, surprisingly, were cells expressing CD8betabeta homodimers (43.8 +/- 16.5%). CD8alphaalpha homodimers were expressed on 14.2% (+/- 12.3) of total gammadelta T cells, whereas CD8alphabeta heterodimers were expressed on 12.2% (+/- 7.5). We also observed a bimodal distribution of the intensity of CD3 fluorescence of gammadelta T cells in immunocompromised patients with a threshold at 105 cell/microl. CD3 bright gammadelta T cells were more frequently observed in HIV patients (29%) compared with renal transplant patients (11%) and healthy donors (3%; chi2 test: P = 0.0007). CONCLUSIONS: The simple observation of a CD3 bright T-cell subset on CD3/CD4/CD8 routine analysis suggests a high gammadelta T-cell fraction and, in our opinion, should be followed by a complementary analysis to determine precisely the number of gammadelta T cells and to identify their CD8alpha/beta phenotype. When CD3 bright T cells/microl were more than 40%, high gammadelta T cells were detected in more than 87% of cases, with a specificity of 76%. Occasionally, the CD3 bright subset appeared to be strongly homogeneous, suggesting an oligoclonal proliferation that could possibly reveal a chronic localized stimulation or an early lymphoproliferative disorder. Because the gammadelta T cells have interesting immunological peculiarities, the clinical significance of their quantitative abnormality should be clarified in diseases such as HIV, organ transplantation, autoimmunity and lymphoma.     

再生障碍性贫血患者T淋巴细胞早期激活及可溶性肿瘤坏死因子受体的研究

目的研究再生障碍性贫血 (再障 )患者外周血CD4 、CD8 T淋巴细胞早期激活标志CD6 9的表达及血清、骨髓中可溶性肿瘤坏死因子受体 1和 2 (sTNF R1和sTNF R2 )的水平及其意义。方法将外周血在 2 0 μg ml植物血凝素 (PHA)条件下进行全血细胞培养 ,于 0h和 4h分别用双色免疫荧光标记流式细胞术对CD4 、CD8 T淋巴细胞CD6 9的表达进行分析。用ELISA法检测血清和骨髓中sTNF R1和sTNF R2的水平。结果PHA刺激前重型再障 (SAA)患者CD4 、CD8 细胞CD6 9的表达率增高 [分别为 (8.96± 7.2 3) %和 (10 .6 7± 7.5 8) % ],慢性再障 (CAA)患者CD8 细胞CD6 9的表达率增高[(7.36± 5 .4 9) % ];PHA刺激后再障患者CD4 、CD8 细胞表达CD6 9明显增强 [SAA为 (71.73±11 91) %和 (6 1.74± 13.4 4 ) % ;CAA为 (5 9.35± 10 .15 ) %和 (4 8.78± 8.2 5 ) % ],CD4 细胞CD6 9的表达率高于CD8 细胞。SAA患者两种sTNF R水平均明显升高 [sTNF R1血清为 (12 5 8.5 8± 385 .6 9)ng L ,骨髓为 (16 5 0 .6 0± 6 6 5 .0 1)ng L ;sTNF R2血清为 (12 5 7.10± 2 95 .4 9)ng L ,骨髓为 (2 0 73.5 7± 5 6 1.17)ng L]。CAA患者骨髓两种sTNF R水平升高 [sTNF R1为 (10 94 .2 1± 2 91.93)ng L ,sTNF R2为 (15 0 2 .4 8±385 .5     

Epidemiology of sepsis in patients with traumatic injury

OBJECTIVE: To characterize the epidemiology of sepsis in trauma. DESIGN: Analysis of a prospectively collected administrative database (Pennsylvania trauma registry). SETTING: All trauma centers in the state of Pennsylvania (n = 28) PATIENTS: All patients (n = 30,303) with blunt or penetrating injury admitted to Pennsylvania trauma centers over a 2-yr period (January 1996-December 1997). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Incidence of sepsis in trauma, independent predictors of sepsis, and associated mortality were evaluated. Analyses controlled for age, gender, preexisting disease, injury type, Revised Trauma Score, Injury Severity Score, and admission vital signs. Sepsis occurred in 2% of all patients and was associated with a significant increase in mortality (23.1% vs. 7.6%, p < .001) compared with nonseptic patients. Respiratory tract infections were the most common cause of sepsis. Septic trauma patients had increased ICU length of stay (21.8 vs. 4.7 days, p < .001) and hospital length of stay (34.1 vs. 7.0 days, p < .001). Logistic regression identified Injury Severity Score, Revised Trauma Score, lower admission Glasgow Coma Scale score, and preexisting diseases as significant independent predictors of sepsis, whereas female gender was associated with a decreased risk of sepsis. Increasing injury severity measured by Injury Severity Score was associated with increased incidence of sepsis. Moderate (Injury Severity Score 15-29) and severe injury (Injury Severity Score >/=30) had a six-fold and 16-fold, respectively, increased incidence of sepsis compared with mild injury. Multivariate analysis confirmed that the effect of sepsis on mortality was greater in trauma patients with mild injury than those with moderate or severe injury. CONCLUSIONS: This study reports the incidence of sepsis and its associated mortality and critical care resource utilization in a large, state-wide population-based trauma registry. Increasing injury severity, measured by Injury Severity Score, was a significant independent predictor of sepsis in trauma and was associated with increased intensive care unit resource utilization and mortality. These results suggest that future studies should attempt to delineate interventional strategies to prevent sepsis in trauma patients with moderate and severe injury, given their significantly increased risk.     

Pulmonary artery catheter use is associated with reduced mortality in severely injured patients: a National Trauma Data Bank analysis of 53,312 patients

OBJECTIVE: To evaluate the association between pulmonary artery catheter (PAC) use and mortality in a large cohort of injured patients. We hypothesized that PAC use is associated with improved survival in critically injured trauma patients. DESIGN: Retrospective database analysis. SETTING: A total of 268 level 1 trauma centers from across the United States. PATIENTS: A total of 53,312 patients admitted to the intensive care units of the trauma centers participating in the National Trauma Data Bank maintained by the American College of Surgeons. MEASUREMENTS AND MAIN RESULTS: The National Trauma Data Bank was queried to identify patients aged 16-90 yrs with complete data on base deficit, and Injury Severity Score (n=53,312). Patients were initially divided into two groups: those managed with a PAC (n=1,933) and those managed without a PAC (n=51,379). Chi-square and Student's t-test analysis were utilized to explore group differences in mortality. In a second analysis, groups were stratified by base deficit, Injury Severity Score, and age to further explore the influence of injury severity on PAC use and mortality. In addition, a logistic regression model was developed to assess the relationship between PAC use and mortality after adjusting for differences in age, mechanism, injury severity, injury pattern, and co-morbidities. Overall, patients managed with a PAC were older (45.8+/-21.3 yrs), had higher Injury Severity Score (28.4+/-13.5), worse base deficit (-5.2+/-6.5), and increased mortality (PAC, 29.7%; no PAC, 9.8%; p<.001). However, after stratification for injury severity, PAC use was associated with a survival benefit in four subgroups of patients. Each of these groups had advanced age or increased injury severity. Specifically, patients aged 61-90 yrs, with arrival base deficit worse than -11 and Injury Severity Score of 25-75, had a decrease in the risk of death with PAC use (odds ratio, 0.33; 95% confidence interval, 0.17-0.62). Three additional groups had a similar decrease in the risk of death with PAC use: odds ratio, 0.60 (95% confidence interval, 0.43-0.83), 0.82 (95% confidence interval, 0.44-1.52), and 0.63 (95% confidence interval, 0.40-0.98). Logistic regression analysis demonstrated a decreased mortality when a PAC was used in the management of patients with the following severe injury characteristics: Injury Severity Score of 25-75, base deficit of less than -11, or age of 61-90 yrs (odds ratio, 0.593; 95% confidence interval, 0.437-0.805). CONCLUSIONS: Trauma patients managed with a PAC are more severely injured and have a higher mortality. However, severely injured patients (Injury Severity Score, 25-75) who arrive in severe shock, and older patients, have an associated survival benefit when managed with a PAC. This is the first study to demonstrate a benefit of PAC use in trauma patients.     

CCL25 mediates the localization of recently activated CD8alphabeta(+) lymphocytes to the small-intestinal mucosa

The recruitment of antigen-specific T lymphocytes to the intestinal mucosa is central to the development of an effective mucosal immune response, yet the mechanism by which this process occurs remains to be fully defined. Here we show that the CC chemokine receptor 9 (CCR9) is selectively and functionally expressed on murine alpha(E)beta(7)(+) naive CD8alphabeta(+) lymphocytes and a subset of recently activated CD69(+) CD8alphabeta(+) lymphocytes. Using a T cell receptor transgenic transfer model, we demonstrate that CCR9 expression is functionally maintained on CD8alphabeta(+) lymphocytes following activation in mesenteric lymph nodes but rapidly downregulated on CD8alphabeta(+) lymphocytes activated in peripheral lymph nodes. These recently activated CCR9(+) CD8alphabeta(+) lymphocytes selectively localized to the small-intestinal mucosa, and in vivo neutralization of the CCR9 ligand, CCL25, reduced the ability of these cells to populate the small-intestinal epithelium. Together these results demonstrate an important role for chemokines in the localization of T lymphocytes to the small-intestinal mucosa and suggest that targeting CCL25 and/or CCR9 may provide a means to selectively modulate small-intestinal immune responses.     

Correlation between the numbers of gammadelta T cells and CD4+ HLA-DR+ T cells in broncho-alveolar lavage fluid from patients with diffuse lung disease

CD4+ HLA-DR+ T cells are known to be increasing in broncho-alveolar lavage fluid (BALF) from patients with sarcoidosis, and related to disease activity. Although there are several reports that the number of gammadelta T cells in peripheral blood from patients with sarcoidosis are increasing, contradictory assertions can be seen about the number of gammadelta T cells in BALF, and the clinical significance on the presence of gammadelta T cells in disease site of patients with diffuse lung disease including sarcoidosis. The absolute number of gammadelta T cells and CD4+ HLA-DR+ T cells in BALF were determined by flow cytometry in 107 patients with diffuse lung diseases; 56 with sarcoidosis, 36 with collagen vascular diseases with lung involvement and 15 with idiopathic pulmonary fibrosis. We also measured the number of the transferrin receptor-positive macrophages in BALF. The correlation between gammadelta T cells and activated (maybe antigen-specific) T cells and macrophages were evaluated. Sarcoidosis patients were also evaluated from the data of the number of gammadelta T cells in peripheral blood by flow cytometry and clinical backgrounds. A significant correlation between the numbers of these two cell types was detected in each of the three patient groups. The percentage of peripheral gammadelta T cells was markedly increased in 7 sarcoidosis patients, each of whom also showed affected organs other than lung, however, 5 individuals did not show an increased number of gammadelta T cells in BALF. The number of gammadelta T cells in BALF did not correlate with the number of transferrin receptor-positive macrophages in all three patient groups. These results suggest that the increased number of gammadelta T cells in diffuse lung diseases likely plays a role in immunosurveillance and contributes to the activation of antigen-specific alphabeta T cell.     

Relationship between procalcitonin plasma levels and severity of injury, sepsis, organ failure, and mortality in injured patients

OBJECTIVE: To compare procalcitonin (PCT) plasma levels of injured patients with the incidence and severity of systemic inflammatory response syndrome (SIRS), infection, and multiple organ dysfunction syndrome (MODS) and to assess the predictive value of PCT for these posttraumatic complications. DESIGN: Retrospective study comparing patients with mechanical trauma in terms of severity of injury, development of infectious complications, and organ dysfunctions. SETTING: Level I trauma center with emergency room, intensive care unit, and research laboratory. PATIENTS: Four hundred five injured patients with an Injury Severity Score of > or =9 points were enrolled in this study from January 1994 to February 1996. INTERVENTIONS: Blood samples were collected on the day of admission and on days 1, 3, 5, 7, 10, 14, and 21 thereafter. MEASUREMENTS AND MAIN RESULTS: We determined PCT serum levels using a specific immunoluminometric assay. We retrospectively evaluated the occurrence of SIRS, sepsis, and MODS using patients' charts. Mechanical trauma led to increased PCT plasma levels dependent on the severity of injury, with peak values on days 1 and 3 (p < .05) and a continuous decrease within 21 days after trauma. Patients who developed SIRS demonstrated a significant (p < .05) increase of peak PCT plasma levels compared with patients without SIRS. The highest PCT plasma concentrations early after injury were observed in patients with sepsis (6.9+/-2.5 ng/mL; day 1) or severe MODS (5.7+/-2.2 ng/mL; day 1) with a sustained increase (p < .05) for 14 days compared with patients with an uneventful posttraumatic course (1.1+/-0.2 ng/mL). Moreover, these increased PCT plasma levels during the first 3 days after trauma predicted (p < .0001; logistic regression analysis) severe SIRS, sepsis, and MODS. CONCLUSIONS: These data indicate that PCT represents a sensitive and predictive indicator of sepsis and severe MODS in injured patients. Routine analysis of PCT levels seems to aid early recognition of these posttraumatic complications. Thus, PCT may represent a useful marker to monitor the inflammatory status of injured patients at risk.     

High concentrations of circulating macrophage migration inhibitory factor in patients with severe blunt trauma: Is serum macrophage migration inhibitory factor concentration a valuable prognostic factor?

OBJECTIVE: To determine serum concentrations of macrophage migration inhibitory factor and other cytokines in severe blunt trauma patients in critical settings and to evaluate their association with patient outcome. DESIGN: Prospective, observational study. SETTING: Emergency department and surgical intensive care unit of a university hospital. PATIENTS: Fifty-four severe blunt trauma patients with systemic inflammatory response syndrome requiring intensive care, emergency surgical intervention, or both were enrolled in the study. Forty-four patients with minor injuries were the controls. INTERVENTIONS: Serum macrophage migration inhibitory factor concentrations were measured in the emergency department <4 hrs postinjury (day 1) and the surgical intensive care unit 24 hrs later (day 2). Blood samples for determination of tumor necrosis factor-alpha, interleukin-6, interleukin-8, and interleukin-10 were measured both in patients with severe blunt trauma and in controls. The Acute Physiology and Chronic Health Evaluation II, Injury Severity Score, Revised Trauma Score, and Trauma Revised Injury Severity Score were used for clinical evaluation of trauma severity. MEASUREMENTS AND MAIN RESULTS: Serum macrophage migration inhibitory factor concentrations were higher in severe blunt trauma patients than in controls; were significantly correlated with Acute Physiology and Chronic Health Evaluation II, Revised Trauma Score, and Trauma Revised Injury Severity Score scores in severe blunt trauma patients but not in controls; and were higher in nonsurvivors than in survivors. CONCLUSIONS: Our data suggest that the serum macrophage migration inhibitory factor concentration is higher in severe blunt trauma and that it reflects the severity of trauma. The serum macrophage migration inhibitory factor concentration might be a valuable predictor for the outcome of severe blunt trauma.     

Intestinal platelet trapping after traumatic and septic shock. An early sign of sepsis and multiorgan failure in critically ill patients?

OBJECTIVES: Patients resuscitated after severe traumatic or septic shock were studied with reference to the behavior of radiolabeled platelets in vital organs, the occurrence of sepsis, and multiorgan failure. These findings were compared with findings of patients who had sustained severe head trauma, but had reportedly not been in shock. DESIGN: Prospective, clinical trial of consecutive patients. SETTING: Multidisciplinary ICU. PATIENTS: Thirteen critically ill patients who were considered at high risk for developing multiorgan failure. These patients had all been resuscitated after major trauma (Injury Severity Score 50.2 +/- 7.2) or severe septic shock (group A, Acute Physiology and Chronic Health Evaluation [APACHE II] score 21.7 +/- 4.4). For comparison, six patients with head trauma, who were considered at low risk for multiorgan failure were studied (group B, Injury Severity Score 26.0 +/- 5.1 and APACHE II score 12.3 +/- 2.4). MEASUREMENTS: Platelet trapping was studied in multiple organs by external detection of platelets labeled with 111indium-oxine. Measurements were started on the third day and continued for seven consecutive days or until death. RESULTS: Eight of 13 patients in group A developed sepsis and multiorgan failure and six of these eight patients died 8 to 29 days after the initial insult. No patient in group B developed multiorgan failure, and all survived. The patients in group A had significant increases in platelet trapping in the liver and the lungs, but the increase was significantly (p less than .01) greater in the nonsurvivors than in the survivors. All the nonsurvivors had markedly increased platelets sequestration in the intestine (less than 10 times the activity in blood), but none of the survivors had increased platelet sequestration in the intestine (p less than .01). This increase was recorded 1 to 4 days before the first clinical signs of sepsis and 3 to 7 days before the development of multiorgan failure. No patient in group B had increased activity in the liver or in the intestine, and only one patient had a slight increase in the lung. CONCLUSIONS: The results indicate that, in patients resuscitated after severe traumatic or septic shock, increased sequestration of platelets in the intestine, as measured by external detection of radioisotope-labeled autologous platelets, may precede clinical signs of sepsis and multiorgan failure and may possibly predict the outcome.     

Premature expression of T cell receptor (TCR)alphabeta suppresses TCRgammadelta gene rearrangement but permits development of gammadelta lineage T cells

The T cell receptor (TCR)gammadelta and the pre-TCR promote survival and maturation of early thymocyte precursors. Whether these receptors also influence gammadelta versus alphabeta lineage determination is less clear. We show here that TCRgammadelta gene rearrangements are suppressed in TCRalphabeta transgenic mice when the TCRalphabeta is expressed early in T cell development. This situation offers the opportunity to examine the outcome of gammadelta versus alphabeta T lineage commitment when only the TCRalphabeta is expressed. We find that precursor thymocytes expressing TCRalphabeta not only mature in the alphabeta pathway as expected, but also as CD4(-)CD8(-) T cells with properties of gammadelta lineage cells. In TCRalphabeta transgenic mice, in which the transgenic receptor is expressed relatively late, TCRgammadelta rearrangements occur normally such that TCRalphabeta(+)CD4(-)CD8(-) cells co-express TCRgammadelta. The results support the notion that TCRalphabeta can substitute for TCRgammadelta to permit a gammadelta lineage choice and maturation in the gammadelta lineage. The findings could fit a model in which lineage commitment is determined before or independent of TCR gene rearrangement. However, these results could be compatible with a model in which distinct signals bias lineage choice and these signaling differences are not absolute or intrinsic to the specific TCR structure.     

Evidence that gammadelta versus alphabeta T cell fate determination is initiated independently of T cell receptor signaling

Two types of T cells, alphabeta and gammadelta, develop in vertebrates. How these two T cell lineages arise from a common thymic T progenitor is poorly understood. Differentiation of alphabeta lineage T cells requires the surrogate alpha chain (pTalpha), which associates with the T cell receptor (TCR) beta chain to form the pre-TCR. gammadelta lineage development does not appear to involve an obligatory surrogate chain, but instead requires productive rearrangement and expression of both TCR gamma and delta genes. It has been proposed that the quality of signals transmitted by the pre-TCR and gammadelta TCR are distinct and that these "instructive" signals determine the lineage fate of an uncommitted progenitor cell. Here we show that the thymic T progenitor cells (CD25(+)CD44(+)c-kit(+)CD3(-)CD4(-)CD8(-) thymocytes, termed pro-T cells) from young adult mice that have yet to express TCRs can be subdivided based on interleukin 7 receptor (IL-7R) expression. These subsets exhibit differential potential to develop into gammadelta versus alphabeta lineage (CD4+CD8+ cells) in the thymus. Upon intrathymic injection, IL-7R(neg-lo) pro-T cells generated a 13-fold higher ratio of alphabeta lineage to gammadelta lineage cells than did IL-7R(+) pro-T cells. Much of this difference was due to a fivefold greater potential of IL-7R(+) pro-T cells to develop into TCR-gammadelta T cells. Evidence indicates that this biased developmental potential is not a result of enhanced TCR-gamma gene rearrangement/expression in IL-7R(+) pro-T cells. These results indicate that the pro-T cells are heterogeneous in developmental potential before TCR gene rearrangement and suggest that in some precursor cells the initial lineage commitment is independent of TCR-mediated signals.     

Hydrocortisone increases the sensitivity to alpha1-adrenoceptor stimulation in humans following hemorrhagic shock

OBJECTIVE: To assess the pressor response to phenylephrine infusion before and after hydrocortisone in severe trauma patients and to correlate this response with their adrenal reserve. DESIGN: Prospective clinical study. SETTING: Surgical intensive care unit in a university teaching hospital. PATIENTS: Twenty-three young trauma patients (Injury Severity Score, 38 +/- 14) were studied at the end of the resuscitative period (27 +/- 15 hrs after trauma). INTERVENTIONS: Total cortisol response to intravenous corticotropin bolus (250 microg) was obtained. Total cortisol response <9 microg/dL defined an impaired adrenal function and the patient was called a nonresponder. Twelve to 24 hrs following this stimulation, phenylephrine was infused in a stepwise manner to establish the phenylephrine-mean arterial pressure dose-response curve before and after intravenous hydrocortisone administration (50 mg). An Emax model was used to describe the curve; the influence of the group (responder/nonresponder), the sequence (before/after hydrocortisone), and three covariates (Injury Severity Score, shock, and interleukin-6) were thereafter tested. MEASUREMENTS AND MAIN RESULTS: Forty-three percent of patients were nonresponders. Total cortisol response was not correlated with serum albumin concentration and was negatively correlated with the interleukin-6 concentration. A trend for a higher incidence of nonresponders (53% vs. 36%) and a lesser total cortisol response (7.9 +/- 5.1 vs. 12.5 +/- 5.1 microg/dL) was observed in the shock patients. A phenylephrine dose-response structure (E0, ED50, and Emax) was described without influence of the group and the sequence. However, hydrocortisone induced a 37% decrease in ED50 without change in Emax in the shock patients. CONCLUSION: An acute administration of hydrocortisone increases the sensitivity to alpha1-adrenoceptor stimulation in fully resuscitated severe trauma patients following hemorrhagic shock. This effect is independent of the adrenal reserve of the patients and different from that previously reported in septic patients.     

Genetic predisposition for a compromised immune system after multiple trauma

Severe trauma induces sustained changes of the immune response, which are thought to be related to secondary organ dysfunction. Despite a similar injury severity, the extent of the inflammatory response may vary between polytraumatized patients. It is unclear whether inflammatory variability is associated with genetic variations. In this prospective cohort study, patients were included when the following criteria were fulfilled: Injury Severity Score >16, age 18 to 60 years, and a survival >48 h after injury. Four different polymorphisms (TNF-Nco1, IL-1-Taq1, IL-6-174G/C, and IL-8-251A/T) were determined. Patients were separated according to the severity of the systemic inflammatory response syndrome (SIRS; ACCP/SCCM criteria: >2 criteria at 2 consecutive days or at 3 days of the observation period: group +SIRS; 相似文献   

Flow cytometric assessment of autologous gammadelta T cells in patients with acute myeloid leukemia: potential effector cells for immunotherapy?

BACKGROUND: Gammadelta T cells are a rare component of the circulating innate immune system capable of exerting anti-neoplastic activity. This population may be suitable for the adoptive immunotherapy of acute myeloid leukemia (AML). Little is known however, about the frequency and function of circulating gammadelta T cells in AML. The aim of the study was to enumerate peripheral blood gammadelta T cells in patients with AML and explore the feasibility of their use clinically. METHODS: We compared the absolute circulating gammadelta T cell levels in 33 AML patients before and after treatment versus 20 healthy volunteers using flow cytometry. The function of gammadelta T cells was assessed by detection of intracelluar interferon-gamma (IFN-gamma) and cytotoxicity against leukemic blasts. RESULTS: AML patients with high blast counts prior to induction chemotherapy had marginally decreased gammadelta T cell levels compared with healthy controls: median 38/microL versus 83/microL; P = 0.051. Sequential gammadelta T cell enumeration after induction showed significantly decreased counts in patients with a persistently high blast burden compared to patients with reduced but detectable residual disease (molecular maker or borderline bone marrow infiltration): median 7/microL versus 105/microL; P = 0.008. Patients with residual disease had significantly higher gammadelta T cell counts compared to those retested after they had achieved complete remission (CR); P = 0.0025. In CR, gammadelta T cell counts remained lower than those of healthy individuals: median 33/microL versus 83/microL, P = 0.030. We detected a sharp increase (on average, four-fold higher than values in CR) of gammadelta T cells in patients in very early morphologic or molecular relapse. We also tested the functional properties of gammadelta T cells from patients with AML in CR. Flow cytometric assessment of IFN-gamma revealed similar numbers of gammadelta T cells expressing the T1 cytokine compared with healthy controls. We also showed that gammadelta T cells were able to kill leukemic target cells in vitro. CONCLUSION: Flow cytometric assessment of gammadelta T cells in patients with AML revealed quantitative shifts with respect to disease status. Our data suggest that gammadelta T cells warrant further investigation as potential therapeutic agents.     

Role of systemic inflammatory response syndrome and infection in the occurrence of early multiple organ dysfunction syndrome following severe trauma

Objective To evaluate the role of infection and systemic inflammatory response syndrome (SIRS) on the occurrence of early posttraumatic MODS.Design Retrospective study.Setting University Teaching Hospital ICU.Patients 163 consecutive patients hospitalized for more than 48 hours following severe trauma.Measurements and main results The patients were classified into two groups in respect to the existence of MODS at day 2. There was 27 patients in the MODS group and 136 patients in the no MODS group. The two groups were similar with respect to age, sex ratio and Simplified Acute Physiology Score. The MODS group had a higher mortality (52 versus 7%), Injury Severity Score (45±14 versus 31±13), hypovolemic shock rate (74 versus 30%), massive volume replacement rate (59 versus 6%) and SIRS rate (81 versus 54%) than the no MODS group (p<0.05). The rate of infection was similarly low in the MODS and no MODS group (4 versus 6% respectively).Conclusion Early MODS is often associated with hypotension and massive volume administration but very rarely with infection, despite the high rate of SIRS.     

Sepsis is characterized by the increases in percentages of circulating CD4+CD25+ regulatory T cells and plasma levels of soluble CD25

The function of immune system is to protect hosts from invading microorganisms by destroying infected cells while minimizing damage to tissues. Among immune cells, CD4(+)CD25(+) regulatory T cells (Treg cells) control immune responses by limiting infectious processes. However, it remains unclear whether Treg cells are induced in systemic inflammatory response syndrome (SIRS) or infectious SIRS (i.e. sepsis). SIRS and sepsis are associated with stressful inflammatory conditions. We therefore measured CD25(+) T cells and circulating CD4(+) T cells, along with plasma levels of CD25, interleukin (IL)-6, and IL-10, in 20 septic patients (64 +/- 11 years), 16 SIRS patients (59 +/- 16 years), and control subjects: 13 elderly (60 +/- 16 years) and 14 young volunteers (28 +/- 3 years). Septic patients (23.3 +/- 11.8%, p < 0.01) showed significantly higher percentages of CD25(+) cells among CD4(+) T cells (i.e. Treg cells) than did either young (10.6 +/- 3.7%) or elderly volunteers (11.1 +/- 3.8%). The percentages of Treg cells in septic patients were higher than those in SIRS patients (12.4 +/- 6.9%, p < 0.01). Moreover, plasma levels of soluble CD25 were significantly higher in septic patients, compared to the levels in SIRS patients or volunteers (p < 0.01). No significant difference in plasma levels of IL-6 or IL-10 was found between septic patients and SIRS patients. Thus, sepsis is associated with the increased percentages of Treg cells and elevated plasma level of soluble CD25. The elevation of these parameters might be a useful marker of infections in SIRS.     

Increased incidence of sepsis and altered monocyte functions in severely injured type A- glucose-6-phosphate dehydrogenase-deficient African American trauma patients

OBJECTIVE: To determine whether trauma patients with the common, type A- glucose-6-phosphate dehydrogenase (G6PD) deficiency have an aggravated inflammatory response, increased incidence of septic complications, and/or more profound alterations in leukocyte functions compared with nondeficient trauma patients. SETTINGS: Intensive and surgical care units of a trauma center and flow cytometry and experimental laboratories at a teaching university hospital. DESIGN: Prospective cohort clinical study with measurements on days 2 and 5 postinjury. Monocyte and neutrophil oxidant content, apoptosis, and CD11b expression and plasma cytokine levels were compared between G6PD-deficient and nondeficient patients. PATIENTS: A total of 467 male African American trauma patients were screened for the deficiency. Forty-four type A-202/376 G6PD-deficient patients were identified and enrolled in the study; 43 nondeficient patients were also enrolled and were matched by age, clinical criteria of injury severity, and type of trauma. MAIN RESULTS: After severe injury (Injury Severity Score, > or =16), 50% of the deficient and 6.2% of nondeficient patients developed sepsis with positive bacterial blood cultures. In deficient patients, the frequency of bronchial (75%) and wound infections (25%) was also increased compared with nondeficient patients (32% and 0%). The durations of systemic inflammatory response syndrome, Sepsis Syndrome, and days on antibiotics were three times longer in deficient than in nondeficient individuals. However, adult respiratory distress syndrome occurred in 37% of both groups. Anemia was more severe in the deficient than nondeficient patients from day 10 posttrauma. On day 5, the peroxide content was doubled, apoptosis was decreased, and CD11b expression was increased in monocytes from deficient patients compared with cells from nondeficient patients. On day 5, the plasma interleukin (IL)-10 concentration was significantly lower in deficient than nondeficient patients, whereas tumor necrosis factor-alpha, IL-6, and IL-8 levels were similar. After moderate injuries (Injury Severity Score, 9-16), the deficiency was not associated with adverse clinical effects, and the trauma-induced changes in leukocyte function were similar in deficient and nondeficient patients. CONCLUSIONS: The common type A- G6PD deficiency predisposes septic complications and anemia in trauma patients after severe injuries as defined by an Injury Severity Score of > or =16. This adverse clinical course is accompanied by altered monocyte functions manifested as augmented oxidative stress, a decreased apoptotic response, increased cell adhesion properties, and a diminished IL-10 response.