JOURNAL OF NEUROTRAUMA Volume 9, Number 1, 1992 Mary Ann Lieben, Inc., Publishers

Impairment of Helper T-Cell Function Following Severe Head Injury KEITH B.

QUATTROCCHI,1 BERNARDO W. ISSEL,1 CLARAMAE H. MILLER,' EDMUND H. FRANK,2 and FRANKLIN C. WAGNER, JR.1

ABSTRACT

Major infections,

such as sepsis and pneumonia, occur in 50-75% of patients following isolated severe head injury. Previous studies have demonstrated that this high incidence of infection following severe head injury may be related to a decrease in helper T-cell activation and function. The present study was designed to investigate the effect of severe head injury on specific subgroups of helper T cells known to enhance or suppress cellular immune function. Specifically, peripheral blood lymphocytes (PBLs) from 10 head-injured patients and 10 matched controls were evaluated following in vitro stimulation with the T-cell mitogen, phytohemagglutinin (PHA). Subsets of helper T cells evaluated included activated helper (CD4+/CD25+) T cells; helper/inducer (CD4+/CDw29+) T cells, which enhance cellular immune activity; and suppressor/inducer (CD4+/CD45R+) T-cells, which induce suppressor (CD8+) T-cells. In addition, the effect of intraventricular fluid (IVF) on PHA-stimulated in vitro CD4 and CD25 expression was investigated to determine whether severe head injury results in the production of mediators within the central nervous system capable of affecting T-cell activation. The results of this study indicate that isolated severe head injury selectively reduces the ability of PHA-stimulated PBLs to express the helper/inducer (CD4+/CDw29+) T-cell (p 0.023) and activated helper (CD4+/CD25 + ) T-cell (P = 0.041) phenotypes. There was no significant change in PHA-stimulated CD4 or CD25 expression following incubation of PBLs with intraventricular fluid (IVF) from head-injured patients. The relationshp between these changes in specific helper T-cell subpopulations and the infectious complications of severe head injury are discussed. =

INTRODUCTION CONTRIBUTES significantly to the morbidity and mortality associated with severe head injury and traumatic injury (Goris and Drammisma, 1982; Baker et al., 1980). Following severe head injury, 50-75% of patients develop secondary infections with 5-25% developing fatal sepsis (Baker et al., 1980;

INFECTI ON multiple

'Departments of Neurosurgery and Pathology, University of California, Davis, California. 2Division of Neurosurgery, Oregon Health Sciences University, Portland, Oregon. 1

QUATTROCCHI ET AL. Goris and Drammisma, 1982). Previous investigations have demonstrated a relationship between central nervous system (CNS) injury in animals and immunosuppression (Besrdovsky etal., 1979; Cross et al., 1984; Fornietal., 1983; Jankovic and Isakovic, 1973; Roszman etal., 1982; Dunn, 1988, 1989). These studies, as well as the high incidence of infection seen following isolated severe head injury, suggest that a better understanding of immune alterations following severe head injury is warranted. We have previously demonstrated that the increased incidence of infection following severe head injury may be related to the suppression of cellular immune activity (Quattrocchi et al., 1990, 1991a,b; Miller et al., 1991). The effects of isolated severe head injury on immune activity include an absence of delayed type hypersensitivity (DTH) skin test responses; decreased expression of mitogen-stimulated helper (CD4+) T-cell expression; decreased expression of the early T-cell activation marker, the interleukin-2 receptor (CD25); decreased blastogenic proliferation in response to mitogen stimulation; reduced production of the helper T-cell cytokines, interleukin-2 (IL-2) and interferon-gamma (INF-G); and suppression of lymphokineactivated killer (LAK) cell cytotoxicity (Quattrocchi et al., 1990, 1991a,b; Miller et al., 1991). Humoral immune activity, based on circulating immunoglobulin and complement levels, appears to be unaffected (Miller etal. 1991). The purposes of the present study were to define better the specific lymphocyte subpopulations affected by severe head injury and determine the effect of I VF upon T-cell activation. The identification of specific lymphocyte subpopulations altered by severe head injury is critical to understanding how cellular immune function is altered. For example, helper (CD4+) T cells have been shown, in humans, to be subdivided into reciprocal subgroups, the helper/inducer (CD4+/CDw29+ ) T cells, which activate cellular immune function, and the suppressor/inducer (CD4+/CD45R + ) T cells, which induce suppressor T-cell activity (Sanders et al., 1988b; Akbaret al., 1991). The CD4+/CDw29+ subset of helper T cells (previously designated the CD4+/4B4+ subset) has been identified as comprising mature or memory helper T cells with helper/inducer activity. This is based on their favorable proliferative response to recall antigens, production of cytokines that enhance immune activity (such as IL-2 and INF-G), and presence of essential adhesion molecules on their surface (De Paoli et al., 1987). The CD4+/CD45R+ subset (previously designated the CD4+/2H4+) appears to have suppressor/inducer function and many represent a less mature, antigenically virgin subset of helper T cells that respond poorly to recall antigens and appear to induce suppressor (CD8 + ) T cells (De Paoli et al., 1987; Takeuchi et al., 1987). The clinical relevance of these subgroups is illustrated by certain autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and recurrent aphthous stomatitis, in which a selective decrease in the suppressor/inducer (CD4+/CD45R+) T cells has been found to occur (Morimoto et al., 1987; RohowskyKochanetal., 1990; Calabrese etal., 1990; Takeuchi etal., 1988; Savage etal., 1988). In addition, a selective decrease in helper/inducer (CD4+/CDw29) T cells has been found to correlate with the extent of disease in patients with acquired immunodeficiency syndrome (AIDS) (van Noesel et al., 1990). In view of the importance of lymphocyte subsets on immune activity, we performed dual labeling studies of mitogen-stimulated PBLs from 10 head-injured patients and 10 matched controls. Primary markers included pan (CD2 + ) T cells, helper (CD4+) T cells, suppressor/cytotoxic (CD8 + ) T cells, and monocytes (CD 14+). The secondary markers included CDw29, the helper/inducer marker for CD4+ PBLs; CD45R, the suppressor/inducer marker for CD4+ PBLs; the interleukin-2 receptor (CD25 + ), an early activation marker of PBLs; and HLA-DR, a late marker for PBL activation. In addition, the effect of IVF on in vitro PHA-stimulated expression of CD4 and CD25 was investigated to determine whether severe head injury results in the production of mediators capable of affecting T-cell activation.

MATERIALS AND METHODS Patient Selection Between January 1, 1991, and April 30, 1991, 6 male and 4 female patients (mean age 24, range of 18-44) with severe head injury were prospectively investigated. Six healthy male and 4 healthy female subjects with a mean age of 26 (range, 20-39) were used as controls. Criterion for admission to the study was an admission Glasgow Coma Scale (GCS) score of less than 9 following severe head injury. Patients with significant 2

IMMUNOSUPPRESSION AND HEAD INJURY

systemic injury, as defined by an injury severity score (ISS) greater than 27 were excluded. Patients with a history consistent with immunosuppression, any history of intravenous drug abuse, aspirin or nonsteroidal anti-inflammatory medication use, previous malignancy, or risk factors for AIDS were excluded. Patients treated with blood transfusions, corticosteroids, and those with documented posttraumatic hypotension, hypoxia, or spinal cord injury were excluded. On admission, all patients were intubated forhyperventilation: six received mannitol (0.5 g/kg intravenous loading dose), and seven received dilantin (15 mg/kg intravenous loading dose). Initial venipuncture was performed preoperatively in four cases and postoperatively in six cases (no operation was performed in three cases). Table 1 illustrates the admission and treatment data. In addition, IVF was obtained from eight consecutive patients who met the criteria noted above and also had a ventriculosomy placed to monitor intracranial pressure. Analysis of variance with multiple comparisons was used to evaluate the data and significance was defined by a probability of greater than 95%. The study was evaluated and approved by the Human Subjects Review Committee at the University of California, Davis Medical Center, Sacramento, CA.

Isolation

of Peripheral Blood Lymphocytes and Mitogen Stimulation

Within 6 hr of head injury, venous blood was drawn and PBLs were isolated essentially as described by Hornicek et al. (1987). Venous blood was collected and mononuclear cells isolated by density gradient. The PBLs were then adjusted to 5 X 106 cells/ml in cell culture medium (CCM), which consisted of RPMI 1640 with L-glutamine and Hepes buffer (Gibco Laboratories, Grand Island, NY), 15% fetal calf serum (Gibco Laboratories), and 100 units/ml of penicillin with 100 |xg/ml of streptomycin (Gibco Laboratories). PBLs were incubated in the presence of 4 (xg/ml of PHA-L (Sigma Chemical Company) for 72 hr at 37°C in 10% C02 Following incubation cell purity was determined by microscopic evaluation of Wright-Giemsa-stained cytocentrifuged preparations and viability was determined by trypan blue exclusion (always greater than

95%).

Monoclonal

Antibody Staining

and Flow

Cytometric Analysis

After 72 hr of culture with PHA, the cells were adjusted to 1 X 107 cells/ml. Fluorochrome-conjugated murine monoclonal antibodies (Coulter Laboratories, Miami Lakes, FL) included CD2 (pan T-cell marker), CD4 (helper T-cell marker), CD8 (suppressor/cytotoxic T-cell marker), CD 14 (monocyte marker), HLA-DR (late activation marker for lymphocytes), CD25 (IL-2R marker, an early lymphocyte activation marker), CDw29 (marker for the helper/inducer subset of helper T-cells), and CD45R (marker for the suppressor/ inducer subset of helper T-cells). Cells were stained with two monoclonal antibodies, one conjugated to fluorescein isothiocyanate (FITC) and the other to phycoerythrin (PE). Appropriate isotypic controls were used to determine nonspecific binding. All studies were performed in duplicate. Table 1.

Age

GCS

18 20 32 19 30 24 36 18 23 19

5 7 4

7 6

4 X

CT

scan

Patient Profile Data Dilantin

Mannitol

Surgeryh

No Yes Yes No Yes Yes Yes Yes No Yes

Yes No Yes

EDH evacuation ICP monitor

EDH Contusion SDH EDH Contusion Contusion GSW SDH Contusion SDH

No No Yes Yes Yes No Yes

Lobectomy

EDH evacuation ICP monitor

Lobectomy Debridement

Lobectomy

None SDH evacuation

GSC, Glasgow Coma Scale score; EDH, epidural hematoma; SDH, subdural hematoma; GSW, gunshot wound brain; ICP, intracranial pressure. 3

to

QUATTROCCHI ET AL. Stained cells

were

counted

on a

Coulter

Epics-Profile II

flow cytometer. To avoid

subjectivity, only the

small, well-differentiated lymphocyte region was gated for analysis. This gated area was determined from the scattergram generated by plotting size (foreward angle scatter) against granularity (90° light scatter).

Phenotype Expression Following Incubation

with Intraveniricular Fluid

PBLs from eight healthy subjects were incubated concomitantly with PHA and IVF from eight head-injured subjects. These subjects met the admission criteria for the study, and had ventriculostomies placed to monitor intracranial pressure. PBLs were prepared as noted above, except that IVF was included during the incubation at a volume concentration of 2%, 8%, or 32%. Phenotyping was performed using single-label analysis following incubation. Cerebrospinal fluid (CSF) obtained from patients being evaluated for lumbar disc disease, by lumbar puncture before computed tomographic (CT) myelogram, was used as a control to assess the effect on CSF from normal subjects on lymphocyte activity. In addition, the effect of equal volumes of culture media alone on lymphocyte activity was determined.

Assessment

of Infections

The hospital day of clinical diagnosis of infections, site of infection, and primary causative agent of infection were recorded. Pneumonia was defined by the presence of fever, leukocytosis, new infiltrates on chest roentgenograms, diagnostic Gram's stains, and cultures following bronchoscopy. Sinusitis was diagnosed by the presence of fever, leukocytosis, purulent nasal drainage with new opacification of the involved sinus on sinus series roentgenograms or CT scans, and diagnostic Gram's stains and cultures. The diagnosis of meningitis required fever, leukocytosis, unstable vital signs with a high cardiac output index and with low systemic vascular resistance, and diagnostic blood cultures.

RESULTS PBL

Phenotype Expression

Phenotype expression of PHA-stimulated PBLs from head injured patients and normal subjects are shown in Table 2. There was a significant decrease in the percentage of CD4+ cells coexpressing the early activation marker CD25; 11% vs. 23% when head-injured patients are compared to controls (p 0.023). There was no =

Table 2.

Lymphocyte Surface Marker Expression Following Incubation

(mean % Normal

Secondary

CD2 CD2 CD4 CD4 CD4 CD4 CD8 CD8 CD14

CD25 HLA-DR CD25 HLA-DR

CDw29 CD45R CD25 HLA-DR HLA-DR

PHA

Percentage of PBLs labeled ± ! standard error)

Dual label markers

Primary

with

(n

=

subjects

Head

10)

41 ± 6 25 ± 4 23 ±4 8 ± 2 28 ± 3 8 ± 3 18 ± 5 7 ± 1 4± 2

"Analysis of variance with multiple comparisons, comparing normal subjects significant at 95%. bAll patients phlebotomized within 24 hr of injury.

indicates

4

injured^

(n =10)

P value''

25 ± 7 16 ±4

0.094 0.201 0.023* 0.979 0.041* 0.901 0.214 0.114 0.685

11 ±2 7 14 8 12 4 5 to

±4 ± 5 ± 2 ±4 ± 1

±

3

head

injured patients. Asterisk

IMMUNOSUPPRESSION AND HEAD INJURY

significant difference in the coexpression of CD25 and CD2 orCD8. There were no significant differences in coexpression of HLA-DR on CD2+, CD4+, CD8+, or CD14+ cells, when PBLs from head-injured patients are compared to normal subjects. When examining the percentages of PHA-stimulated PBLs coexpressing the phenotypes CD4+/CDw29 + (helper/inducer T cells) or CD4+/CD45R+ (suppressor/inducer T cells), a significant decrease was found in the CD4+/CDw29+ (helper/inducer) subset, from 14% to 28%, when head-injured patients are compared to controls (p 0.041). No difference between patients and normals was observed in the CD4+/CD45R + (suppressor/inducer) subset. There were no significant differences in PBL surface antigen expression when those patients who were treated with phenytoin or mannitol were compared, or among those patients not taken the

=

to

surgery

(p > 0.05).

Effect of IVF on Phenotype Expression

and Activation

When normal PBLs were incubated with varying concentrations of IVF from head-injured patients, no significant or dose-response differences occurred in expression of CD4 of CD25 (Table 3). Likewise, neither CSF from normal subjects nor culture media alone, used as controls, affected phenotype expression significantly (p > 0.05).

Infectious Complications The overall incidence of infection was 60%. The most common infections included pneumonia (40%), bronchitis (10%), and sepsis (10%). The most common isolates included Staphylococcus aureus (60%),

Heamophilus influenzae (20%), and Enterobacter species (20%). DISCUSSION

The purpose of this study was to define better the effects of isolated severe head injury on immune function. We were interested in determining whether the expression of specific subsets of PBLs, known to suppress immune function, was affected following head injury; and whether IVF from head-injured patients was capable of altering PBL activation.

Table 3.

Effect of Intraventricular Fluid From Head-Injured Patients on Surface Marker Expression of PHA-Stimulated PBls from Normal Subjects'1 Incubation without PHA CD4

CD25

Volume % IVF (n 8)

CD4

CD25

Percentage of PBLs labeled (mean %

=

0% 2% 8% 32% Statistical 2% 8% 32%

Incubation with PHA

±

1 standard

44 ± 1 44± 5 43 ±6 46 ± 2

analysis

P

0.644 0.647 0.625

0.787 0.220 0.492

error) 51 ±4 31 ± 5 41 ±4 35 ± 3

53 ± 15 43 ± 4 43 ± 4 49 ± 3

0.119 0.473 0.333

0.557

valueb 0.716 0.753

"Normal PBLs incubated in cell culture media with 0%, 2%, 8%, or 32% (by volume) of CSF taken from head-injured patients within 24 hr of head injury. hStatistical analysis by analysis of variance with multiple comparisons. Significance set at 95%. All p values obtained by comparing study conditions to values obtained following incubation with 0% IVF.

5

QUATTROCCHI ET AL. Activation

of T Cells

analysis of PHA-stimulated PBLs demonstrated a decrease in the expression of activated helper (CD4+/CD25 + ) T cells. There was no significant change in the expression of activated suppressor/ cytotoxic (CD8+/CD25 + ) T cells. This indicates a selective inhibition in the in vitro expression of early activation markers by helper (CD4+) T cells following isolated severe head injury. In contrast, we did not find any significant changes in late activation markers, such as HLA-DR expression. This lack of changes in HLA-DR expression is in contrast to data reported by Hoyt et al. (1990), and may be due to differences in the concentration of PHA used in our assay and in the shorter incubation time of our study. The observation that head injury results in a decrease in CD25 expression on the surface of PHA-stimulated PBLs may be due to inherent defects in helper T-cell activation, or may be a secondary effect due to selective sequestration, in vivo, of specific subpopulations of PBLs. Flow cytometric

Depression of Helper/inducer (CD4+/CDw29+)

T-Cell

Expression

Helper (CD4+) T cells, previously believed to act exclusively in the enhancement of cellular immune function, have recently been subdivided into either helper/inducer (CD4+/CDw29) or suppressor/inducer (CD4+/CD45R+) subsets (Bos et al., 1987; Sanders et al., 1988b). The helper/inducer (CD4+/CDw29+) subset appears to enhance cellular immune function and most likely represents a mature and antigenically

expreienced subset of lymphocytes with specific adhesion molecules responsible for their preferential sequestration at peripheral sites of injury (Bos et al., 1987, 1989; Bourgault et al., 1989). In contrast, the suppressor/inducer (CD4+/CD45R+) subset appears to be an antigenically naive subset that enhances suppressor T-cell function. These cells are thought to be preferentially sequestered by peripheral lymph nodes where they become antigenically challenged (Bos et al., 1987, 1989; Bourgault et al., 1989; Sanders et al., 1988a). This decrease in the in vitro expression of helper/inducer (CD4+/CDw29+) T cells may be due to selective sequestration of PBLs capable of expressing these markers or to intrinsic defects in the ability of PBLs, from head-injured patients, to express helper/inducer (CD4+/CDw29+) T-cell subset (Pitzalis et al., 1988, 1991; Bos et al., 1989).

The importance of this finding is underscored by the importance of the helper/inducer (CD4+/CDw29+) T-cell subset in activating monocytes and other cells responsible for the destruction of Staphylococcus aureus and other common pathogens seen following severe head injury (McLean et al., 1975; O'Mahony et al., 1985; Abo et al., 1986; Morgan et al., 1984; Damle et al., 1986; Nencioni et al., 1983; Klimpel et al., 1988). Specifically, the helper/inducer (CD4+/CDw29 + ) T-cell subset is believed to be the human analog of the murine TH, cell, which has been characterized in animal models as the T cell producing IL-2, INF-G, and other cytokines responsible for the upregulation of cellular immunity. In addition, it has also been suggested that helper/inducer (CD4+/CDw29 + ) T cells are responsible for the activation of antigenically naive suppressor/cytotoxic (CD8+) T cells into cytotoxic (CD8 + ) T cells with MHC class I restricted cytotoxic activity (Kalish et al., 1988). Thus, the decrease in the ability to express helper/inducer (CD4+/CDw29+) T cells following severe head injury would be expected to result in an increase in infections that require cellular immunity to assist the humoral response in the irradication of infectious agents, such as Staphylococcus aureus. In contrast, suppressor/inducer (CD4+/CD45R+) T cells may induce antigenically naive CD8+ T cells to mature into suppressor (CD8 + ) T-cells (Kalish et al, 1988). Therefore the changes in the relative proportions of these important subsets may have important implications in the immune status of severely

head-injured patients. Soluble Mediators

of Immune Activity

IVF from patients with severe head injury was not found to affect the PHA-stimulated expression of CD4 orCD25. Measures of lymphocyte function, such as cytokine production orcytotoxicity, were not, however, measured. Previous studies have demonstrated the presence of immunosuppressive serum factors that affect lymphocyte function following multitraumatic injury (McLean et al., 1985). It has also been demonstrated that, in response to PHA or allogenic cells, the helper/inducer (CD4+/CDw29 + ) subset produces fivefold 6

IMMUNOSUPPRESSION AND HEAD INJURY INF-G then the suppressor/inducer (CD4+/CDw29) subset (Sanders et al., 1988a,b; Salmon et al., 1989;Sleasmanetal., 1990; Dohlsten et al., 1988a,b; Sanderset al., 1988, 1989). In view of these findings

more

it is recommended that further studies of lymphocyte function such as cytokine production or cytotoxicity, be determined following incubation of PBLs with IVF or serum from head-injured patients.

Relationship of Infectious Complications

to

Immune

Dysfunction

The finding that Staphylococcus aureus pneumonia is the most frequent form of infection following isolated head injury is consistent with previous studies (Helling et al., 1988; Quattrocchi et al., 1990, 1991a,b; Miller et al., 1991; Hoyt et al., 1990). Although cellular immunity has classically been cited in immune surveilance against intracellular bacterial, viral, and fungal infections, several studies have demonstrated the importance of cellular immunity in defending against pyogenic bacterial and nonintracellular bacterial infections (McLean et al., 1975; O'Mahony et al., 1985; Abo et al., 1986; Morgan et al., 1984; Damleetal., 1986; Nencioni et al., 1983; Klimpel et al., 1988). Recent studies of alveolar macrophages in humans have shown that intact cellular immune function involving T-cell activity is required for clearing of Staphylococcus aureus following ingestion by polymorphonuclear cells and alveolar macrophages (McLean et al., 1975; O'Mahony et al., 1985; Abo et al., 1986). This pathogen accounts for the majority of infections seen in the acute phase following severe head injury, underscoring the clinical relevance of alterations in cellular immunity that occur after head injury (Helling et al., 1988; Quattrocchi et al., 1990, 1991a,b; Milleret al., severe

1991; Hoyt et al., 1990).

In summary, the results of this study indicate that isolated severe head injury results in the suppression of in vitro mitogen-induced expression of activated helper (CD4 +/CD25 +) T cells and helper/inducer (CD4 +/ CDw29) T cells, both of which are necessary for normal cellular immune function. These findings are consistent with the high incidence of infection seen following isolated severe head injury. Further studies designed to further characterize the specific PBL subpopulations responsible for this suppression in T-cell activation and to determine the affect of serum from head injured patients on lymphocyte function are recommended.

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Address Keith B.

reprint requests

to:

Quattrocchi, M.D., Ph.D. Department of Neurosurgery

2516 Stockton Boulevard, Room 254 Sacramento, CA 95817

9

Impairment of helper T-cell function following severe head injury.

Major infections, such as sepsis and pneumonia, occur in 50-75% of patients following isolated severe head injury. Previous studies have demonstrated ...
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