REFERENCES
1. P. M. Preiss et al., Science 347, 1229 (2015). 2. M. Ben Dahan, E. Peik, J. Reichel, Y. Castin, C. Salomon, Phys. Rev. Lett. 76, 4508 (1996). 3. M. Karski et al., Science 325, 174 (2009). 4. A. N. Wenz et al., Science 342, 457 (2013). 5. A. M. Kaufman et al., Science 345, 306 (2014). 6. M. Greiner, C. A. Regal, D. S. Jin, Nature 426, 537 (2003). 7. M. W. Zwierlein, J. R. Abo-Shaeer, A. Schirotzek, C. H. Schunck, W. Ketterle, Nature 435, 1047 (2005). 8. T. Kinoshita, T. Wenger, D. S. Weiss, Science 305, 1125 (2004). 9. B. Paredes et al., Nature 429, 277 (2004). 10.1126/science.aaa6885
IMMUNOLOGY
Getting sepsis therapy right Is decreasing inflammation or increasing the host immune response the better approach? By Richard S. Hotchkiss1 and Edward R. Sherwood2
S
epsis—a complication of infection—is a factor in at least a third of all hospital deaths—a sobering statistic (1). Patients with sepsis frequently present with fever, shock, and multiorgan failure. Because of this dramatic clinical scenario, investigators have generally assumed that sepsis mortality is due to unbridled inflammation (2). Research in animal models, in which administration of the cytokines tumor necrosis factor–α (TNF-α) and interleukin-1 (IL-1) reproduced many features of sepsis, supported that assertion. Yet, over 40 clinical trials of agents that block cytokines, pathogen recognition, or inflammation-signaling pathways have universally failed (3, 4). However, on page 1260 of this issue, Weber et al. (5) show that blocking a cytokine—specifically, IL-3—can indeed be protective against sepsis. IL-3 is a pleiotropic cytokine that induces proliferation, differentiation, and enhanced function of a broad range of hemopoietic cells (blood cells derived from the bone marrow). Using a mouse abdominal sepsis model, Weber et al. identified IL-3 as a critical driving force of sepsis. The authors observed that the cytokine caused proliferation and mobilization of myeloid cells that generated excessive proinflammatory cytokines, thereby fueling systemic inflammation, organ injury, and death. Blocking IL-3 (by treating wild-type mice with an antibody that blocks the receptor for IL-3 or using IL-3–deficient mice) prevented sepsisinduced increases in the number of circulating neutrophils and inflammatory monocytes and decreased the amount of circulating inflammatory cytokines, thus ameliorating organ injury and improving survival. Additionally, the authors showed a correlation between mortality in septic patients and elevated blood IL-3 concentrations. The findings of Weber et al. are mechanistically analogous to that of another study in which intravenous injection of mesenchymal stem cells (also known as bone marrow stromal cells) into a mouse model of sepsis led to reprogramming of immune cells toward a less inflammatory phenotype, thereby decreasing organ injury and mortality (6). In this scenario, mesenchymal stem
SCIENCE sciencemag.org
cells released factors that reprogrammed monocytes and macrophages; the downstream effect was to prevent a damaging, unrestrained immune response. Thus, IL-3 blockade and mesenchymal stem cell–based therapy represent potential approaches for sepsis treatment because of their ability to broadly reshape early immune responses from a proinflammatory, damaging reaction to a more balanced and effective one. However, a few cautionary caveats should be considered before adopting this approach. A phase II clinical trial of granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine that increases production, maturation, and function of monocytes, macrophages, and neutrophils, thereby mimicking selected properties of IL-3, was efficacious in treating sepsis and, indeed, a large multicenter trial of GM-CSF in sepsis is under way (7). This is contrary to the findings of Weber et al. that blocking IL-3 can
“Which approach to sepsis… is correct? …there are several clues…” ameliorate sepsis. Two other highly promising agents that are likely to enter clinical trials in sepsis are IL-7 (which promotes CD4+ and CD8+ T lymphocyte proliferation and maturation) and an antibody to programmed death–ligand 1 [(PD-L1), an immunosuppressive protein] (8, 9). Both IL-7 and anti-PD-L1 antibody are immunostimulatory agents that reverse key immunologic defects in lymphocytes and monocytes from septic patients ex vivo and are highly effective in multiple animal models of sepsis (9). Emerging evidence shows correlations between lymphopenia (decrease in lymphocytes) and impaired leukocyte functions with late mortality in patients with sepsis (8, 9). Thus, there is rationale for using approaches that selectively enhance antimicrobial immunity during sepsis. 1
Department of Anesthesiology, Medicine, and Surgery, Washington University School of Medicine, St. Louis, MO, USA. 2Department of Anesthesiology and Pathology, Microbiology and Immunology. Vanderbilt University School of Medicine, Nashville, TN, USA. E-mail: [email protected]; [email protected] 13 MARCH 2015 • VOL 347 ISSUE 6227
Published by AAAS
1201
Downloaded from www.sciencemag.org on March 12, 2015
temperature, because all lower-lying energy levels are already occupied and thus further occupation is forbidden. For a measurement of position correlations, the antisymmetry of the wave function results in an apparent antibunching, where fermions seem to avoid each other. Bosons, in contrast, experience an increase in the probability of reaching a state already occupied by other bosons. That is, bosons tend to bunch together. For small systems of particles, the consequences of quantum statistics were exploited in fermionic (4) as well as bosonic (5) systems. Preiss et al. observe this effect of bunching in the position correlations of two identical atoms undergoing a quantum walk. Surprisingly, although this behavior due to quantum statistics seems to be fundamentally fixed, interactions between particles can in fact turn bosonic bunching into fermionic antibunching and vice versa. This has been seen, for example, by association of two fermionic atoms to a bosonic molecule that can undergo Bose-Einstein condensation (6), or pairing of fermions in a many-body system showing superfluid behavior similar to Cooper pairs in a superconductor (7). Preiss et al. go the other way: By increasing repulsive interaction more and more, the bosonic atoms under investigation start to mimic the behavior of weakly interacting fermions, as was observed in one-dimensional Bose gases in the so-called Tonks-Girardeau regime (8, 9). With their superb position resolution, Preiss et al. can track the crossover from the quantum statistics–dominated bosonic bunching to the interaction-dominated antibunching, again extracting position correlations of two atoms doing a quantum walk. The system presented by Preiss et al. allows the study of the interplay of all these aforementioned aspects in a rather simple, paradigmatic system comprising all these effects: two identical, interacting atoms. Beyond the illustration of quantum physics, their system can serve as a basic building block for a bottom-up approach to engineering of complex quantum states atom by atom. ■
INSIGHTS | P E R S P E C T I V E S
Immunoinfammatory response in sepsis Therapy Modulate immune response: anti-IL-3, mesenchymal stem cells
Balanced Exhausted immune response Impaired immunity
Therapy Enhance immunity: (IL-7, GM-CSF, anti-PD-L1, IFN-γ) Inflammatory response to sepsis. Potential immune therapies can modulate immune responses that provoke excessive inflammation or enhance immunity if there is an impaired immune response to microbial infection. IFN-γ, interferon-γ.
Which approach to sepsis—decreasing excessive inflammation versus boosting host immunity—is correct? The answer to this question is critical and there are several clues (see the figure). Immunologic status is highly dependent on the age and general health of the individual. Although young, previously healthy individuals acquire virulent infections, early inflammatory deaths are becoming less common in developed countries because of improved surveillance and advances in supportive care. In the United States, 75% of the deaths in sepsis occur in patients over the age of 65 (10). The immune system in the elderly is substantially impaired and renders them susceptible to infection. Patients with major comorbidities, including chronic renal and liver failure, also are immunosuppressed, rendering them more vulnerable to developing and dying from sepsis. Thus, the patient populations that represent the highest proportion of sepsis deaths are likely to require therapy that augments immunity. By contrast, the number of sepsis patients with overwhelming inflammation, who may benefit from therapies that reduce early hyper-release of proinflammatory cytokines (“cytokine storm”), is declining. Another caveat affecting treatment selection is timing (11). Patients rapidly transition from the initial cytokine storm to a predominant immunosuppressed state as sepsis persists. This shift to an immunosuppressed state occurs for many reasons, 1202
Early death (organ injury)
Pathogens eliminated
Survival
Pathogen not contained
Death (from primary infection)
Pathogen contained
Develop secondary infection
including massive sepsis-induced death of immune cells, development of T cell exhaustion, and generation of T regulatory and myeloid-derived suppressor cells. A postmortem study of intensive care unit patients, in which spleens and lungs were harvested rapidly after death, showed that compared to patients dying of causes other than sepsis, immune effector cells from septic patients were massively depleted (12). Most of the sepsis deaths occurred after a prolonged course in the intensive care unit. This protracted septic course is difficult to reproduce in animal models. For example, animal sepsis mortality reported by Weber et al. generally occurred within 24 to 48 hours after sepsis onset (during the hyperinflammatory phase) and is therefore not reflective of most clinical deaths in sepsis. Recent studies provide compelling evidence for this immunologic evolution. In patients admitted with sepsis, “late” positive blood and tissue cultures were detected in ~28% of patients, and over half of these infections were due to fungi or weakly virulent bacteria considered to be “opportunistic” pathogens (13). In addition, use of latent viral reactivation as a surrogate marker of loss of immunocompetence (14) showed that over 42% of septic patients had reactivation of two or more viruses. The amount of viral reactivation in septic patients was comparable to that occurring in organ transplant patients on immunosuppressive therapy, further evidence of the remarkable degree of impaired immunity in patients with sepsis. So, how should sepsis be treated? The cornerstone of sepsis therapy remains drainage and/or removal of the infected site, fluid resuscitation, and rapid antibiotic administra-
Late death (from secondary infection)
tion. Although anti-inflammatory therapies, such as blocking IL-3, may be beneficial in selected patients, history has not been kind to such approaches. It may be that restorative immunotherapy, in which adjuvants that stimulate host immunity would be the centerpiece for response modification, offers the most promise. To guide sepsis immunotherapy, new methods to determine the health of the various components of a patient’s immune system are being developed and may direct the application of targeted immuneadjuvant therapies in the future (15). ■ REF ERENCES AND NOTES
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
V. Liu et al., JAMA 312, 90 (2014). R. S. Hotchkiss, I. E. Karl, N. Engl. J. Med. 348, 138 (2003). J. Cohen et al., Lancet Infect. Dis. 12, 503 (2012). D. C. Angus, JAMA 306, 2614 (2011). G. F. Weber et al., Science 347, 1260 (2015). K. Németh et al., Nat. Med. 15, 42 (2009). C. Meisel et al., Am. J. Respir. Crit. Care Med. 180, 640 (2009). R. S. Hotchkiss et al., Lancet Infect. Dis. 13, 260 (2013). F. Venet et al., J. Immunol. 189, 10 (2012). G. S. Martin, D. M. Mannino, M. Moss, Crit. Care Med. 34, 15 (2006). J. Leentjens et al., Am. J. Respir. Crit. Care Med. 187, 1287 (2013). J. S. Boomer et al., JAMA 306, 2594 (2011). G. P. Otto et al., Crit. Care 15, R183 (2011). A. H. Walton et al., PLOS ONE 9, e98819 (2014). J. L. Vincent, L. Teixeira, Am. J. Respir. Crit. Care Med. 190, 1081 (2014).
ACKNOWL EDGMENTS
R.S.H. has been on the advisory boards of Bristol-Myers Squibb (BMS), GlaxoSmithKline (GSK), and Merck, on immunotherapy for sepsis (he speaks on the topics of IL-7, anti-PD-1, anti-PD-L1, IL-15, IFN-γ, and GM-CSF). He is a paid consultant to BMS, GSK, Merck, and MedImmune on immunotherapy for sepsis. He collaborates with Revimmune on a trial of IL-7 in sepsis and with BMS on a trial of anti-PD-L1 in sepsis. He receives funding from BMS and MedImmune for studies with anti-PD-1 and anti-PD-L1 and from GSK to test immunomodulators in sepsis. 10.1126/science.aaa8334
sciencemag.org SCIENCE
13 MARCH 2015 • VOL 347 ISSUE 6227
Published by AAAS
ILLUSTRATION: ADAPTED BY P. HUEY/SCIENCE
Excessive infammation
Microbial assault
Late death (smoldering infammation)
Getting sepsis therapy right Richard S. Hotchkiss and Edward R. Sherwood Science 347, 1201 (2015); DOI: 10.1126/science.aaa8334
This copy is for your personal, non-commercial use only.
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The following resources related to this article are available online at www.sciencemag.org (this information is current as of March 12, 2015 ): Updated information and services, including high-resolution figures, can be found in the online version of this article at: http://www.sciencemag.org/content/347/6227/1201.full.html A list of selected additional articles on the Science Web sites related to this article can be found at: http://www.sciencemag.org/content/347/6227/1201.full.html#related This article cites 15 articles, 1 of which can be accessed free: http://www.sciencemag.org/content/347/6227/1201.full.html#ref-list-1 This article appears in the following subject collections: Immunology http://www.sciencemag.org/cgi/collection/immunology
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2015 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS.
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Permission to republish or repurpose articles or portions of articles can be obtained by following the guidelines here.
1. P. M. Preiss et al., Science 347, 1229 (2015). 2. M. Ben Dahan, E. Peik, J. Reichel, Y. Castin, C. Salomon, Phys. Rev. Lett. 76, 4508 (1996). 3. M. Karski et al., Science 325, 174 (2009). 4. A. N. Wenz et al., Science 342, 457 (2013). 5. A. M. Kaufman et al., Science 345, 306 (2014). 6. M. Greiner, C. A. Regal, D. S. Jin, Nature 426, 537 (2003). 7. M. W. Zwierlein, J. R. Abo-Shaeer, A. Schirotzek, C. H. Schunck, W. Ketterle, Nature 435, 1047 (2005). 8. T. Kinoshita, T. Wenger, D. S. Weiss, Science 305, 1125 (2004). 9. B. Paredes et al., Nature 429, 277 (2004). 10.1126/science.aaa6885
IMMUNOLOGY
Getting sepsis therapy right Is decreasing inflammation or increasing the host immune response the better approach? By Richard S. Hotchkiss1 and Edward R. Sherwood2
S
epsis—a complication of infection—is a factor in at least a third of all hospital deaths—a sobering statistic (1). Patients with sepsis frequently present with fever, shock, and multiorgan failure. Because of this dramatic clinical scenario, investigators have generally assumed that sepsis mortality is due to unbridled inflammation (2). Research in animal models, in which administration of the cytokines tumor necrosis factor–α (TNF-α) and interleukin-1 (IL-1) reproduced many features of sepsis, supported that assertion. Yet, over 40 clinical trials of agents that block cytokines, pathogen recognition, or inflammation-signaling pathways have universally failed (3, 4). However, on page 1260 of this issue, Weber et al. (5) show that blocking a cytokine—specifically, IL-3—can indeed be protective against sepsis. IL-3 is a pleiotropic cytokine that induces proliferation, differentiation, and enhanced function of a broad range of hemopoietic cells (blood cells derived from the bone marrow). Using a mouse abdominal sepsis model, Weber et al. identified IL-3 as a critical driving force of sepsis. The authors observed that the cytokine caused proliferation and mobilization of myeloid cells that generated excessive proinflammatory cytokines, thereby fueling systemic inflammation, organ injury, and death. Blocking IL-3 (by treating wild-type mice with an antibody that blocks the receptor for IL-3 or using IL-3–deficient mice) prevented sepsisinduced increases in the number of circulating neutrophils and inflammatory monocytes and decreased the amount of circulating inflammatory cytokines, thus ameliorating organ injury and improving survival. Additionally, the authors showed a correlation between mortality in septic patients and elevated blood IL-3 concentrations. The findings of Weber et al. are mechanistically analogous to that of another study in which intravenous injection of mesenchymal stem cells (also known as bone marrow stromal cells) into a mouse model of sepsis led to reprogramming of immune cells toward a less inflammatory phenotype, thereby decreasing organ injury and mortality (6). In this scenario, mesenchymal stem
SCIENCE sciencemag.org
cells released factors that reprogrammed monocytes and macrophages; the downstream effect was to prevent a damaging, unrestrained immune response. Thus, IL-3 blockade and mesenchymal stem cell–based therapy represent potential approaches for sepsis treatment because of their ability to broadly reshape early immune responses from a proinflammatory, damaging reaction to a more balanced and effective one. However, a few cautionary caveats should be considered before adopting this approach. A phase II clinical trial of granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine that increases production, maturation, and function of monocytes, macrophages, and neutrophils, thereby mimicking selected properties of IL-3, was efficacious in treating sepsis and, indeed, a large multicenter trial of GM-CSF in sepsis is under way (7). This is contrary to the findings of Weber et al. that blocking IL-3 can
“Which approach to sepsis… is correct? …there are several clues…” ameliorate sepsis. Two other highly promising agents that are likely to enter clinical trials in sepsis are IL-7 (which promotes CD4+ and CD8+ T lymphocyte proliferation and maturation) and an antibody to programmed death–ligand 1 [(PD-L1), an immunosuppressive protein] (8, 9). Both IL-7 and anti-PD-L1 antibody are immunostimulatory agents that reverse key immunologic defects in lymphocytes and monocytes from septic patients ex vivo and are highly effective in multiple animal models of sepsis (9). Emerging evidence shows correlations between lymphopenia (decrease in lymphocytes) and impaired leukocyte functions with late mortality in patients with sepsis (8, 9). Thus, there is rationale for using approaches that selectively enhance antimicrobial immunity during sepsis. 1
Department of Anesthesiology, Medicine, and Surgery, Washington University School of Medicine, St. Louis, MO, USA. 2Department of Anesthesiology and Pathology, Microbiology and Immunology. Vanderbilt University School of Medicine, Nashville, TN, USA. E-mail: [email protected]; [email protected] 13 MARCH 2015 • VOL 347 ISSUE 6227
Published by AAAS
1201
Downloaded from www.sciencemag.org on March 12, 2015
temperature, because all lower-lying energy levels are already occupied and thus further occupation is forbidden. For a measurement of position correlations, the antisymmetry of the wave function results in an apparent antibunching, where fermions seem to avoid each other. Bosons, in contrast, experience an increase in the probability of reaching a state already occupied by other bosons. That is, bosons tend to bunch together. For small systems of particles, the consequences of quantum statistics were exploited in fermionic (4) as well as bosonic (5) systems. Preiss et al. observe this effect of bunching in the position correlations of two identical atoms undergoing a quantum walk. Surprisingly, although this behavior due to quantum statistics seems to be fundamentally fixed, interactions between particles can in fact turn bosonic bunching into fermionic antibunching and vice versa. This has been seen, for example, by association of two fermionic atoms to a bosonic molecule that can undergo Bose-Einstein condensation (6), or pairing of fermions in a many-body system showing superfluid behavior similar to Cooper pairs in a superconductor (7). Preiss et al. go the other way: By increasing repulsive interaction more and more, the bosonic atoms under investigation start to mimic the behavior of weakly interacting fermions, as was observed in one-dimensional Bose gases in the so-called Tonks-Girardeau regime (8, 9). With their superb position resolution, Preiss et al. can track the crossover from the quantum statistics–dominated bosonic bunching to the interaction-dominated antibunching, again extracting position correlations of two atoms doing a quantum walk. The system presented by Preiss et al. allows the study of the interplay of all these aforementioned aspects in a rather simple, paradigmatic system comprising all these effects: two identical, interacting atoms. Beyond the illustration of quantum physics, their system can serve as a basic building block for a bottom-up approach to engineering of complex quantum states atom by atom. ■
INSIGHTS | P E R S P E C T I V E S
Immunoinfammatory response in sepsis Therapy Modulate immune response: anti-IL-3, mesenchymal stem cells
Balanced Exhausted immune response Impaired immunity
Therapy Enhance immunity: (IL-7, GM-CSF, anti-PD-L1, IFN-γ) Inflammatory response to sepsis. Potential immune therapies can modulate immune responses that provoke excessive inflammation or enhance immunity if there is an impaired immune response to microbial infection. IFN-γ, interferon-γ.
Which approach to sepsis—decreasing excessive inflammation versus boosting host immunity—is correct? The answer to this question is critical and there are several clues (see the figure). Immunologic status is highly dependent on the age and general health of the individual. Although young, previously healthy individuals acquire virulent infections, early inflammatory deaths are becoming less common in developed countries because of improved surveillance and advances in supportive care. In the United States, 75% of the deaths in sepsis occur in patients over the age of 65 (10). The immune system in the elderly is substantially impaired and renders them susceptible to infection. Patients with major comorbidities, including chronic renal and liver failure, also are immunosuppressed, rendering them more vulnerable to developing and dying from sepsis. Thus, the patient populations that represent the highest proportion of sepsis deaths are likely to require therapy that augments immunity. By contrast, the number of sepsis patients with overwhelming inflammation, who may benefit from therapies that reduce early hyper-release of proinflammatory cytokines (“cytokine storm”), is declining. Another caveat affecting treatment selection is timing (11). Patients rapidly transition from the initial cytokine storm to a predominant immunosuppressed state as sepsis persists. This shift to an immunosuppressed state occurs for many reasons, 1202
Early death (organ injury)
Pathogens eliminated
Survival
Pathogen not contained
Death (from primary infection)
Pathogen contained
Develop secondary infection
including massive sepsis-induced death of immune cells, development of T cell exhaustion, and generation of T regulatory and myeloid-derived suppressor cells. A postmortem study of intensive care unit patients, in which spleens and lungs were harvested rapidly after death, showed that compared to patients dying of causes other than sepsis, immune effector cells from septic patients were massively depleted (12). Most of the sepsis deaths occurred after a prolonged course in the intensive care unit. This protracted septic course is difficult to reproduce in animal models. For example, animal sepsis mortality reported by Weber et al. generally occurred within 24 to 48 hours after sepsis onset (during the hyperinflammatory phase) and is therefore not reflective of most clinical deaths in sepsis. Recent studies provide compelling evidence for this immunologic evolution. In patients admitted with sepsis, “late” positive blood and tissue cultures were detected in ~28% of patients, and over half of these infections were due to fungi or weakly virulent bacteria considered to be “opportunistic” pathogens (13). In addition, use of latent viral reactivation as a surrogate marker of loss of immunocompetence (14) showed that over 42% of septic patients had reactivation of two or more viruses. The amount of viral reactivation in septic patients was comparable to that occurring in organ transplant patients on immunosuppressive therapy, further evidence of the remarkable degree of impaired immunity in patients with sepsis. So, how should sepsis be treated? The cornerstone of sepsis therapy remains drainage and/or removal of the infected site, fluid resuscitation, and rapid antibiotic administra-
Late death (from secondary infection)
tion. Although anti-inflammatory therapies, such as blocking IL-3, may be beneficial in selected patients, history has not been kind to such approaches. It may be that restorative immunotherapy, in which adjuvants that stimulate host immunity would be the centerpiece for response modification, offers the most promise. To guide sepsis immunotherapy, new methods to determine the health of the various components of a patient’s immune system are being developed and may direct the application of targeted immuneadjuvant therapies in the future (15). ■ REF ERENCES AND NOTES
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
V. Liu et al., JAMA 312, 90 (2014). R. S. Hotchkiss, I. E. Karl, N. Engl. J. Med. 348, 138 (2003). J. Cohen et al., Lancet Infect. Dis. 12, 503 (2012). D. C. Angus, JAMA 306, 2614 (2011). G. F. Weber et al., Science 347, 1260 (2015). K. Németh et al., Nat. Med. 15, 42 (2009). C. Meisel et al., Am. J. Respir. Crit. Care Med. 180, 640 (2009). R. S. Hotchkiss et al., Lancet Infect. Dis. 13, 260 (2013). F. Venet et al., J. Immunol. 189, 10 (2012). G. S. Martin, D. M. Mannino, M. Moss, Crit. Care Med. 34, 15 (2006). J. Leentjens et al., Am. J. Respir. Crit. Care Med. 187, 1287 (2013). J. S. Boomer et al., JAMA 306, 2594 (2011). G. P. Otto et al., Crit. Care 15, R183 (2011). A. H. Walton et al., PLOS ONE 9, e98819 (2014). J. L. Vincent, L. Teixeira, Am. J. Respir. Crit. Care Med. 190, 1081 (2014).
ACKNOWL EDGMENTS
R.S.H. has been on the advisory boards of Bristol-Myers Squibb (BMS), GlaxoSmithKline (GSK), and Merck, on immunotherapy for sepsis (he speaks on the topics of IL-7, anti-PD-1, anti-PD-L1, IL-15, IFN-γ, and GM-CSF). He is a paid consultant to BMS, GSK, Merck, and MedImmune on immunotherapy for sepsis. He collaborates with Revimmune on a trial of IL-7 in sepsis and with BMS on a trial of anti-PD-L1 in sepsis. He receives funding from BMS and MedImmune for studies with anti-PD-1 and anti-PD-L1 and from GSK to test immunomodulators in sepsis. 10.1126/science.aaa8334
sciencemag.org SCIENCE
13 MARCH 2015 • VOL 347 ISSUE 6227
Published by AAAS
ILLUSTRATION: ADAPTED BY P. HUEY/SCIENCE
Excessive infammation
Microbial assault
Late death (smoldering infammation)
Getting sepsis therapy right Richard S. Hotchkiss and Edward R. Sherwood Science 347, 1201 (2015); DOI: 10.1126/science.aaa8334
This copy is for your personal, non-commercial use only.
If you wish to distribute this article to others, you can order high-quality copies for your colleagues, clients, or customers by clicking here.
The following resources related to this article are available online at www.sciencemag.org (this information is current as of March 12, 2015 ): Updated information and services, including high-resolution figures, can be found in the online version of this article at: http://www.sciencemag.org/content/347/6227/1201.full.html A list of selected additional articles on the Science Web sites related to this article can be found at: http://www.sciencemag.org/content/347/6227/1201.full.html#related This article cites 15 articles, 1 of which can be accessed free: http://www.sciencemag.org/content/347/6227/1201.full.html#ref-list-1 This article appears in the following subject collections: Immunology http://www.sciencemag.org/cgi/collection/immunology
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in December, by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. Copyright 2015 by the American Association for the Advancement of Science; all rights reserved. The title Science is a registered trademark of AAAS.
Downloaded from www.sciencemag.org on March 12, 2015
Permission to republish or repurpose articles or portions of articles can be obtained by following the guidelines here.
