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.
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.
1. Munford R, Pugin J: Normal responses to injury prevent systemic inflammation and can be immunosuppressive. Am J Respir Crit Care Med 163: 316–321, 2001.
2. Ward N, Casserly B, Ayala A: The compensatory anti-inflammatory response syndrome (CARS) in critically ill
patients. Clin Chest Med 29 (4): 617–625, 2008.
3. Kasten K, Tschop J, Goetzman HS, England LG, Dattilo JR, Cave CM, Seitz AP, Hildeman DA, Caldwell CC: T-cell activation differentially mediates the host response to sepsis. Shock 34 (4): 377–383, 2012.
4. Alves-Filho J, Spiller F, Cunha F: Neutrophil paralysis in sepsis. Shock 34 (Suppl 1): 15–21, 2010.
5. Flohe S, Lendemans S, Schade FU, Kreuzfelder E, Waydhas C: Influence of surgical
intervention in the immune response of severely injured patients. Intensive Care Med 30 (1): 96–102, 2004.
6. Angele M, Chaudry I: Surgical
trauma and immunosuppression: patholophysiology and immunomodulatory approaches. Langenbecks Arch Surg 390: 333–341, 2005.
7. Ditschkowski M, Kreuzfelder E, Rebmann V, Ferencik S, Majetschak M, Schmid EN, Obertacke U, Hirche H, Schade UF, Grosse-Wilde H: HLA-DR expression and soluble HLA-DR levels in septic patients after trauma. Ann Surg 229 (2): 246–254, 1999.
8. Klava A, Windsor AC, Farmery SM, Woodhouse LF, Reynolds JV, Ramsden CW, Boylston AW, Guillou PJ: Interleukin-10. A role in the development of post-operative immunosuppression. Arch Surg 132 (4): 425–429, 1997.
9. Majetschak M, Borgemann J, Waydhas C, Obertacke U, Nast-Kolb D, Schade FU: Whole blood tumor necrosis factor-alpha production and its relation to systemic concentrations of interleukin-4, interleukin-10, and transforming growth factor-beta 1 in multiply injured blunt trauma victims. Crit Care Med 28 (6): 1847–1853, 2000.
10. Spruijt N, Visser T, Leenen L: A systematic review of randomized controlled trials exploring the effect of immunomodulative interventions on infection, organ failure, and mortality in trauma patients. Crit Care 14 (4): R150, 2010.
11. Sharpe A, Wherry EJ, Ahmed R, Freeman GJ: The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol 8 (3): 239–245, 2007.
12. Huang X, Venet Fabienne, Wang YL, Lepape A, Yuan Z, Chen Y, Swan R, Kherouf H, Monneret G, Chung CS, et al.: PD-1
expression by macrophages play a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis. Proc Natl Acad Sci U S A 106 (15): 6303–6308, 2009.
13. Brahmamdam P, Inoue S, Unsinger J, Chang KC, McDunn JE, Hotchkiss RS: Delayed administrationi of anti–PD-1
antibody reverses immune dysfunction and improves survival during sepsis. J Leukoc Biol 88 (2): 233–240, 2010.
14. Guignant C, Lepape A, Huang X, Kherouf H, Denis L, Poitevin F, Malcus C, Chéron A, Allaouchiche B, Gueyffier F, et al.: Programmed death-1 levels correlate with increased mortality, nosocomial infection and immune dysfunction in septic shock patients. Crit Care 15 (2): R99, 2011.
15. Zhang Y, Li J, Lou J, Zhou Y, Bo L, Zhu J, Zhu K, Wan X, Cai Z, Deng X: Upregulation of programmed death-1 on T cells and programmed death ligand-1 on monocytes in septic shock patients. Crit Care 15 (1): R70, 2011.
16. Knaus W, Draper EA, Wagner DP, Zimmerman JE: APACHE II
: a severity of disease classification system. Crit Care Med 13 (10): 818–829, 1985.
17. The ACCP/SCCM Consensus Conference Committee. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 20 (6): 864–874, 1992.
18. Monaghan S, Thakkar RK, Heffernan DS, Huang X, Chung CS, Lomas-Neira J, Cioffi WG, Ayala A: Mechanisms of indirect acute lung injury: A novel role for the co-inhibitory receptor Programmed-Death-1 (PD-1
). Ann Surg 255 (1): 158–164, 2012.
19. Perl M, Chung CS, Swan R, Ayala A: Role of Programmed Cell Death in the immunopathogenesis of sepsis. Drug Discov Today 4 (4): 223–230, 2007.
20. Monneret G, Venet F, Pachot, Lepape A: Monitoring immune dysfunction in the septic patient: a new skin for the old ceremony. Mol Med 14 (1–2): 64–78, 2008.
21. Zhang J, Zhang Z, Wang X, Fu JL, Yao J, Jiao Y, Chen L, Zhang H, Wei J, Jin L, et al.: PD-1
upregulation is correlated with HIV-specific memory CD8+
T-cell exhaustion in typical progressors but not in long-term non-progressors. Blood 109 (11): 4671–4678, 2007.
22. Nakamoto N, Kaplan DE, Coleclough J, Li Y, Valiga ME, Kaminski M, Shaked A, Olthoff K, Gostick E, Price DA, et al.: Functional restoration of HCV-specific CD8 T-cells by PD-1
blockade is defined by PD-1
expression and compartmentalization. Gastroenterology 134 (7): 1927–1937, 2008.
23. Riley J: PD-1
signaling in primary T-cells. Immunol Rev 229 (1): 114–125, 2009.
24. Blank C, Mackensen A: Contribution of the PD-L1/PD-1
pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion. Cancer Immunol Immunother 56 (5): 739–745, 2007.
25. Said E, Dupuy FP, Trautmann L, Zhang Y, Shi Y, El-Far M, Hill BJ, Noto A, Ancuta P, Peretz Y, et al.: Programmed death-1 induced interleukin-10 production by monocytes impairs CD4+
T-cell activation during HIV infection. Nat Med 16 (4): 452–459, 2010.
26. Moore K, de Waal Malefyt R, Coffman RL, O’Garra A: Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19: 683–765, 2001.
27. Clark M, Plank LD, Connolly AB, Streat SJ, Hill AA, Gupta R, Monk DN, Shenkin A, Hill GL: Effect of a chimeric antibody to tumor necrosis factor-alpha on cytokine and physiologic response in patients with severe sepsis - a randomized clinical trial. Crit Care Med 26 (10): 1650–1659, 1998.
28. Brahmer J, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, Stankevich E, Pons A, Salay TM, McMiller TL, et al.: Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics and immunologic correlates. J Clin Oncol 28 (19): 3167–3175, 2010.
29. Gartman E, Casserly BP, Martin D, Ward NS: Using serial severity scores to predict death in ICU patients: a validation study and review of the literature. Curr Opin Crit Care 15 (6): 578–582, 2009.
30. Dossett L, Redhage LA, Sawyer RG, May AK: Revisiting the validity of APACHE II
in the trauma ICU: improved risk stratification in critically injured adults. Injury 40 (9): 993–998, 2009.
31. Rhee J-Y, Kwon KT, Ki HK, Shin SY, Jung DS, Chung DR, Ha BC, Peck KR, Song JH: Scoring systems for prediction of mortality in patients with intensive care unit acquired sepsis: a comparison of the Pitt bacteremia score and the Acute Physiology and Chronic Health Evaluation II scoring systems. Shock 31 (2): 146–150, 2009.
32. Heffernan DS, Inaba K, Arbabi S, Cotton B: Sympathetic hyperactivity after traumatic brain injury and the role of beta-blocker therapy. J Trauma 69 (6): 1602–1609, 2010.
33. Grzywnowicz M, Zaleska J, Mertens D, Tomczak W, Wlasiuk P, Kosior K, Piechnik A, Bojarska-Junak A, Dmoszynska A, Giannopoulos K: Programmed death-1 and its ligand are novel immunotolerant molecules expressed on leukemic B cells in chroinc lymphocytic leukemia. PLoS One 7 (4): e35178, 2012.
34. Hofmeyer K, Jeon H, Zang X: The PD-1
/PD-L1 (B7-H1) pathway in chronic infection-induced cytotoxic T Lymphocyte exhaustion. J Biomed Biotechnol 2011 (45): 451694, 2011.