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Programmed Death 1 Expression as a Marker for Immune and Physiological Dysfunction in the Critically Ill Surgical Patient

Monaghan, Sean F.; Thakkar, Rajan K.; Tran, Mai L.; Huang, Xin; Cioffi, William G.; Ayala, Alfred; Heffernan, Daithi S.

doi: 10.1097/SHK.0b013e31825de6a3
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ABSTRACT Programmed death 1 (PD-1) is an inhibitor protein receptor for the immune system and has been shown to be upregulated in animal models of critical illness as well as after trauma and in burn victims in humans. It is believed that PD-1 may play a role in the immune dysfunction seen in surgical critical illness. However, although prior studies have associated changes in PD-1 expression with altered immune cell function, it is not known if a correlation with clinical status exists. We therefore aimed to describe a potential role for PD-1 in the immune dysfunction seen in critically ill trauma and surgical patients. This is an observational cohort study. Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were calculated on critically ill and injured trauma and surgical intensive care unit patients from a tertiary care/level I trauma center. Blood was drawn within 24 h of establishment of diagnosis and admission to the intensive care unit to measure circulating cytokine levels, as well as PD-1 expression on circulating cells. Main outcome measures included PD-1 expression on leukocytes and the relationship to physiological dysfunction (APACHE II) as well as the correlation of PD-1 expression and interleukin 10 levels among patients with severe physiological dysfunction. Samples were collected from 90 critically ill surgical patients. Among patients with severe physiological dysfunction (APACHE II >20), there were increased numbers of granulocytes (median, 144 vs. 90 cells/μL; P = 0.037) and monocytes (median, 12 vs. 6 cells/μL; P = 0.022) with PD-1 expression. In addition, among patients with an APACHE II score of greater than 20, there was a larger percentage of CD3+ cells (44% vs. 29%; P = 0.015) expressing PD-1. When only patients with an APACHE II score greater than 20 were assessed, PD-1 expression on monocytes correlated positively with interleukin levels in the serum (r = 0.525, P = 0.05). Variability in the expression of PD-1 on leukocytes in critical surgical illness correlates with physiological dysfunction and suggests that PD-1 may be a valuable tool in the assessment of immune dysfunction following trauma or severe surgical insult.

Division of Surgical Research, Department of Surgery, Alpert School of Medicine at Brown, University and Rhode Island Hospital, Providence, Rhode Island

Received 23 Feb 2012; first review completed 27 Feb 2012; accepted in final form 4 May 2012

Address reprint requests to Daithi S. Heffernan, MD, Division of Trauma and Surgical Critical Care, Department of Surgery, 435 APC Bldg, 593 Eddy St, Rhode Island Hospital, Providence, RI 02903. E-mail: dheffernan@brown.edu.

Author Contributions: study design and creation: S.F.M., R.K.T., W.G.C., A.A., D.S.H.; manuscript creation and writing: S.F.M., R.K.T., M.L.T., X.H., W.G.C., A.A., D.S.H.; data acquisition: S.F.M., R.K.T., M.L.T., X.H., D.S.H.; data analysis: S.F.M., A.A., D.S.H. Both S.F.M. and D.S.H. guarantee the paper and take responsibility for the integrity of the work as a whole from inception to published article.

This work was funded in part by the Armand D. Versaci research scholar in surgical sciences award (SFM, RKT).

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INTRODUCTION

Immune dysfunction following severe trauma, burns, and sepsis has been extensively described (1–4). There is also mounting evidence of immune paralysis in patients after undergoing major surgical interventions (5, 6). Numerous immune cofactors, such as interleukin 4 (IL-4), IL-10, or HLA-DR expression, have been investigated previously as possible causative agents of the observed immune derangements (7–9), and some pharmaceutical interventions have shown promise (10), but few have been used by physicians to treat these patients today.

Programmed death 1 (PD-1) is a surface protein on immune cells that has been shown to downregulate T-cell functions when bound to its ligands (PD-L1, PD-L2) (11). Our previous work has established a significant mechanistic role for PD-1 in sepsis (12). We have shown that PD-1−/− mice are profoundly resistant to CLP-induced lethality. Furthermore, PD-1−/− mice were resistant to the development of sepsis-induced cellular dysfunction, particularly as it relates to macrophage bacterial clearance (12). Recently, the lack of PD-1 (in knockout mice) or inhibition by antibodies has been shown to improve survival in animal models of sepsis (12, 13).

The relationship of PD-1 and the immune system has been well studied as it relates to cancer, autoimmunity, and chronic viral infections. In addition, we have shown that PD-1 plays a role in patients with septic shock. Higher levels of PD-1 expression early in the course were seen in patients with septic shock (14). Individuals with septic shock and high levels of PD-1 were more likely to have a secondary nosocomial infection and exhibit higher circulating levels of IL-10 (14). Zhang et al. (15) demonstrated that patients with septic shock exhibited increased levels of PD-1 expression compared with controls. However, ex vivo experiments showed that when patient monocytes were treated with anti–PD-L1 (blocking) antibody, then IL-10 production was decreased (15). However, it is not known whether PD-1 levels correlate with the degree of illness in a broad spectrum of critically ill patients. Establishing the association may help in expanding the clinical application of a PD-1–blocking antibody in clinical trials for malignancy.

However, although the work investigating the role of PD-1 in the immune dysfunction in patients with septic shock is intriguing, several questions remain. First, most of the differences reported were based primarily on comparisons drawn to healthy controls. It is therefore not known how such changes in PD-1 expression compare with other critically ill trauma and surgical patients. Second, does a relationship exist between the extent of injury severity or physiological derangement correlate with the degree the expression of leukocyte PD-1 in trauma and surgical patients? Inasmuch as we have established a mechanistic role for PD-1 in murine sepsis (12) and that PD-1 is known to be altered in sepsis (14), we hypothesized that levels of PD-1 expression will correlate with the degree of physiological derangement. With these questions in mind, we aimed to assess the expression of PD-1 in patients after major trauma or surgical intervention resulting in intensive care unit (ICU) admission.

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METHODS

Patient selection

Patients were enrolled from either the surgical or trauma ICU of a tertiary care/level I trauma center. Patients were included in this study if they have systemic inflammatory response syndrome (SIRS) or sepsis, and blood could be collected within 24 h of arrival in the ICU following their diagnosis. This blood draw occurred early in the hospital course and very proximate to ultimate disposition. Samples were obtained from patients who were already undergoing routine analysis and at the time of their routine standard-of-care blood draws. The institutional review board of Rhode Island Hospital (study no. 211087) approved this study.

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Assessment of clinical information

The Acute Physiology and Chronic Health Evaluation II (APACHE II) (16) score was calculated for the date the sample was drawn. In addition, the presence of SIRS, sepsis, and septic shock was assessed. Systemic inflammatory response syndrome was defined as described by the presence of two or more of the following findings: heart rate greater than 90 beats/min, temperature greater than 38°C or less than 36°C, respiratory rate greater than 20 breaths/min or the need for mechanical ventilation, and a white blood cell count greater than 12,000/μL or less than 4,000/μL (17). Sepsis was the presence of SIRS with an identifiable infection, and septic shock was any patient with sepsis who also required vasoactive medications (17). Survival to discharge was also documented at this time.

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Sample preparation, flow cytometry, and cytokine analysis

Whole blood from patients was collected and centrifuged at 10,000g at 4°C for 10 min. The plasma layer was then isolated, and red blood cells were lysed using 1 L double-distilled water with 0.037 g EDTA (Invitrogen, Carlsbad, Calif), 8.26 g NH4Cl (Sigma, St Louis, Mo), and 1 g KHCO3 (Sigma). Leukocytes were phenotyped for expression of PD-1 with PE-labeled anti–PD-1 (Ms IgG1; Biolegend, San Diego, Calif) using the BD FACSArray and grouped using distinctive forward- and side-scatter patterns for monocytes and granulocytes. Lymphocytes were phenotyped using APC anti-CD3 (UCHT1; Beckman Coulter, Indianapolis, Ind). When samples remained, the serum was then assessed for the presence of cytokines using BD Cytometric Bead Array Human TH1/TH2/TH17 kit per the manufacturer’s recommendations (BD Biosciences, Franklin Lakes, NJ).

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Data analysis and statistics

Results are presented as medians and interquartile ranges or means with SEs. When data were normally distributed, a t test was used; however, if data were not normally distributed, a rank sum test was applied. A Spearman test was used to assess for correlations. Statistical analysis was done using SigmaPlot version 10 (Systat Software, Inc, Chicago, Ill); α was set to 0.05.

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RESULTS

Demographics

Ninety samples from critically ill surgical patients were collected and analyzed. Demographic information based on physiological derangements (APACHE II >20 or <20) is shown in Table 1. Patients with an APACHE II score greater than 20 were older (median, 67 vs. 54; P = 0.003) and were more likely to die (64.5% vs. 16.9%; P < 0.001). Overall, 37 patients had sepsis, 14 of whom (37.8%) had an abdominal source of sepsis. There was no difference in relation to abdominal versus nonabdominal sources of sepsis between the two APACHE II groups. There were no differences in sex or the rates of sepsis or septic shock between the two groups (Table 1). Importantly, the number of white blood cells in the blood was not significantly different between the two groups (Table 1).

Table 1

Table 1

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PD-1 expression on leukocytes

Both the percentage of cells and the absolute number of cells expressing PD-1 were assessed for all white blood cells (Fig. 1), monocytes (Fig. 2), granulocytes (Fig. 3), and lymphocytes (Fig. 4). The percentage and number of leukocytes expressing PD-1 were not different between patients with APACHE II score greater than 20 compared with those with APACHE II score less than 20 (Fig. 1). In patients with severe physiological dysfunction (APACHE II >20), there was a significant increase in the number of monocytes expressing PD-1 (median, 12 vs. 6 cells/μL; P = 0.022) but not in the percentage (Fig. 2). Similar results were seen when assessing the expression on granulocytes. In patients with APACHE II score greater than 20, the number of cells was significantly increased (median, 144 vs. 90 cells/μL; P = 0.037), but not the percentage (Fig. 3). When the CD3+ lymphocyte population was studied, the percentage was also significantly increased (44% vs. 29%; P = 0.015) in patients with worse physiological dysfunction, but the absolute number of lymphocytes expressing PD-1 remained similar (Fig. 4).

Fig. 1

Fig. 1

Fig. 2

Fig. 2

Fig. 3

Fig. 3

Fig. 4

Fig. 4

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Correlation between cytokine and PD-1 expression

To assess the impact of increased PD-1 expression in critically ill patients, serum cytokine levels were also measured and compared with PD-1 expression in 48 samples. The total number of leukocytes expressing PD-1 correlated positively with the rise in levels of interferon γ (IFN-γ) (r = 0.423, P = 0.002), IL-4 (r = 0.342, P = 0.017), and IL-2 (r = 0.350, P = 0.015). Similar results were seen when comparing the number of monocytes and lymphocytes expressing PD-1. For the monocyte population, PD-1 expression correlated with IFN-γ (r = 0.347, P = 0.015), IL-4 (r = 0.312, P = 0.031), and IL-2 (r = 0.304, P = 0.036). Programmed death 1 expression on CD3+ lymphocytes correlated with levels of IFN-γ (r = 0.409, P = 0.008), IL-4 (r = 0.326, P = 0.038), and IL-2 (r = 0.425, P = 0.005). Although not significant, there was a trend in the correlation between the rise in TNF-α and PD-1 expression on CD3+ lymphocytes (r = 0.301, P = 0.055) and all leukocytes (r = 0.277, P - 0.056). Surprisingly, there was no correlation between IL-10 and IL-6 levels when looking at the PD-1 expression on all leukocytes, monocytes, and CD3+ lymphocytes. Also, when comparing PD-1 expression on granulocytes, no correlations were seen with IFN-γ, TNF-α, IL-10, IL-6, IL-4, or IL-2. However, when looking at only samples from patients with severe physiological dysfunction (APACHE II >20, n = 14), IL-10 levels in the serum correlated positively with PD-1 expression on monocytes (r = 0.525, P = 0.05) (Figs. 5–7).

Fig. 5

Fig. 5

Fig. 6

Fig. 6

Fig. 7

Fig. 7

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DISCUSSION

In this report, we have explored the expression of PD-1 on various immune cell populations and how they relate to physiological dysfunction (APACHE II score) in severely ill surgical and trauma patients. In addition, the level of PD-1 expression, as it correlated with circulating levels of cytokines in the blood of these patients, was also assessed. This current work expands on the foundations already laid by our laboratory on the role and mechanisms of PD-1 actions in sepsis and critical illnesses (12, 14, 18, 19). We have demonstrated that modulation of the cell surface receptor PD-1 significantly regulates the functioning of the innate immune systems. Programmed death 1−/− mice had greater bactericidal activity and were noted to produce a less severe inflammatory cytokine storm during the initial stages of severe sepsis. This is not only important knowledge as it is thought that patient survival is often adversely affected in the setting of excessive inflammation, but this information was also the basis for asking if the change in the frequency of PD-1 expression correlates with the degree of physiological derangement. Our work was then expanded into the clinical setting wherein we demonstrated that survival following acute lung injury was seen in patients with lower expression of PD-1 on T cells. This supports the clinical notion that blockade of PD-1 may offer a therapeutic strategy in critical illnesses (18).

Here we report that PD-1 expression is increased on monocytes, granulocytes, and lymphocytes in patients with severe physiological changes as a result of their illness (APACHE II >20) compared with other surgical ICU patients with less severe physiological alterations (APACHE II <20). This increase in PD-1 expression in patients with APACHE II score greater than 20 is similar to increases in PD-1 expression on monocytes and lymphocytes reported in patients with septic shock seen in previous work (12, 14, 15). Previous authors have also shown that the increased expression of PD-1 is associated with markers of immune dysfunction (decreased HLA-DR, decreased CD4+ cells, increased regulatory T cells) in septic patients (14, 20). In addition, in other disease processes such as viral infection due to hepatitis or HIV, increased levels of PD-1 on lymphocytes have been shown to cause dysfunction, and function is restored with the blockade of the PD-1/PD-L1 system (21, 22). As such, although we did not measure any markers of immune dysfunction in this patient population, increased levels of PD-1 on leukocytes in our study can be related as a marker of immune dysfunction in these critically ill surgical patients.

We have also shown correlations between PD-1 expression and cytokine levels in the serum of our population. The expression of PD-1 on these cells correlated positively with IFN-γ, IL-4, and IL-2 blood levels. Although these cytokines represent aspects of both a TH1 and TH2 response from the immune system, the correlation with PD-1 expression suggests that the PD-1 plays a role in the expression of these cytokines. This finding is enhanced by the fact that the correlation was not just seen in total blood leukocyte populations, but rather the correlation between cytokines and PD-1 expression held true across the specific subpopulations of monocytes and lymphocytes. Early studies assessing the role of PD-1 in the immune system focused on lymphocytes (13, 23, 24); however, more recent work has demonstrated that monocytes may also play a possible role as a vehicle for mediating PD-1’s effect on such cytokine release (12, 25).

In addition, when assessing only patients with APACHE II score greater than 20, we found that IL-10 levels in the serum correlated with increased monocyte PD-1 expression. This is in keeping with recent reports linking PD-1 expression by monocytes and IL-10 levels in patients with HIV (25) and in medical ICU patients with septic shock, where PD-1 expression on monocytes correlated with blood IL-10 levels (14). This link between IL-10 and PD-1 expression also strengthens the argument for PD-1 expression as a marker of immune suppression. Interleukin 10 is frequently detected early in critically ill patients. It is a potent TH2 cytokine, which is an important component of the systemic inflammatory response. Interleukin 10 plays a distinct role in dampening the inflammatory response, and elevated IL-10 levels have been associated with worse outcomes in septic patients (26). We have also observed that in septic mice lacking the gene product for PD-1, not only were there decreased IL-10 levels in the blood, but also that ex vivo stimulated monocytes/macrophages from these septic animals produced less IL-10 (12). We speculate that as monocytes/macrophages are important sources of local as well as systemic blood levels of IL-10, such inhibition of IL-10 production/release likely contributed to the improved survival seen in these mice.

In establishing this link to IL-10, it validates the translation of a well-described pathway from animal model to humans. We believe that PD-1 alterations are more upstream in the cascade, and hence, inhibiting PD-1 signaling is potentially more likely to achieve clinical effect rather than aim therapies at a single, more downstream cytokine such as IL-10. Furthermore, knowing a patient’s PD-1 level may have the potential to not only know if he/she is immune suppressed (and possible more susceptible to secondary infection), but also could allow titration of drug dosing (PD-1–blocking antibody and/or other immune pharmacologicals) to individual patients.

In past attempts to “modulate” the immune response to infection, injury, or burn, and so on, single proteins (i.e., TNF- α, IL-1β) have been the primary target of the anti-inflammatory intervention, and for the most part, these clinical trials have subsequently failed (27). However, unlike many of these proinflammatory mediator targets, PD-1 is primarily expressed as a cell surface protein, i.e., CD279, on immune cells and has been observed to alter many cytokines’ release/production both directly and indirectly through its downstream signaling via the phosphatases SHP-1/SHP-2 (23). As seen here, because PD-1 expression is correlated with IFN-γ, IL-4, and IL-2 levels in the serum of our critically ill patients, we believe PD-1 signaling may impact many factors. Thus, PD-1–blocking antibodies, currently in clinical trials in cancer (28), may prove to be an effective therapy that blocks a variety of proinflammatory/anti-inflammatory mediators that play key roles in modulating the morbid state in critically ill surgical patients. In support of this suggestion is the recent report by Brahmamdam et al. (13) that antibody directed against PD-1 has proven beneficial against mortality seen in a murine model of sepsis.

Importantly, by using APACHE II correlating with the expression of PD-1 on a blood leukocyte population (monocytes or lymphocytes), it may be possible to better select patients who would best benefit either from a targeted inhibition of the PD-1 system and/or potential other novel immune modulatory therapies. Although we have not stratified by covariates, we feel that many therapies, such as antibiotics administered for infection, are presently delivered unstratified by age, sex, origin of critical illness, and so on. Using APACHE II better reflects what one is trying to correct in the critical care setting, namely, the effects any covariates have upon the physiological disruptions seen in sepsis.

The exciting aspect of having a PD-1–blocking antibody already in clinical trials is that many of the hurdles associated with phase II/III drug development stages have already been undertaken. Thus, the potential for off-label clinical trialing/application in critically ill patients potentially exists, allowing for a more rapid transition from bench to bedside. Establishing the relationship of PD-1 expression with an easily measured and well-accepted marker of illness in critically ill patients further advances the possible clinical consideration of a PD-1–blocking antibody therapeutically. Thus, it is important that correlation between PD-1 expressions be made with a clinical tool that is already established and widely accepted across multiple ICU settings. Acute Physiology and Chronic Health Evaluation II, and changes therein over time, has been used in medical ICUs to gauge therapy effectiveness and guide prognosis (29). Whereas the Injury Severity Score has been shown to predict mortality across all trauma patients, the APACHE II has been shown to better correlate with survival for trauma patients admitted to the ICU (30). The ability of any therapy to dampen the physiological derangement of the ICU patient is therefore an important marker of the effectiveness of the therapy.

From a clinical perspective, one does not typically measure a bacterial burden or microbial function to establish antibiotic effectiveness. Rather, clinical features such as fever curve, white cell count, and tachycardia (all of which are components of the APACHE II) are the cornerstones of assessing an infected patient’s response (29, 31). Similar analogies can be made for fluids and supportive care for pancreatitis or β-blockers in treating head injury (32). Also, although there was no correlation between levels of PD-1 expression and mortality seen in this sample population (data not shown), this does not necessarily mitigate the potential that changes seen in PD-1 expression could be used as a marker of immune responsiveness in this population of critically ill surgical patients.

A limitation of this work is that these are, first, single-time-point blood collections and, thus, do not provide any potential insight to the significance of changes in PD-1 over time with patient responses, or lack thereof, to any standard ICU care. Future work will be aimed at collecting and following PD-1 levels in the same patient over time, so as to allow correlation with changes in physiological parameters over time. Second, a more complete understanding of PD-1 fluctuations with illness is limited by the lack of healthy controls. Future work is aimed at assessing PD-1 level expression in “healthy” sex-/age-matched individuals. However, this in itself raises several questions—who is the correct healthy control: a young person with no comorbidities or an older patient with stable well-managed medical comorbidities? From publications from other authors assessing PD-1 expression in a variety of illnesses (15, 33, 34), it can be inferred that healthy controls would have lower PD-1 levels compared with our critically ill patients. Overall, we believe that our comparison groups are applicable to health care providers because the primary goal is often to reduce the impact of the critical illness rather than return individuals to perfect normality.

In summary, we have shown that PD-1 levels are increased in patients with severe physiological dysfunction as denoted by an APACHE II score greater than 20. Programmed death 1 expression on blood monocytes could be correlated with IL-10 expression in the most ill patients. Although a single measurement of PD-1 expression cannot predict immune dysfunction, a level of PD-1 in combination with an APACHE II score may allow for a tailored treatment, e.g., PD-1 antibody or another novel molecular-immune modulatory therapy, in these severely ill surgical patients.

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Keywords:

PD-1; APACHE II; surgical; critically ill

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