Immunotherapy for Sepsis: a new approach against an ancient foe

Septic shock has traditionally been viewed as an excessive systemic inflammatory reaction to invasive microbial pathogens, yet efforts to improve outcome in septic patients with inhibitors of pro-inflammatory cytokines and mediators have been unsuccessful. Occasional patients present with an overly exuberant immune response to highly virulent pathogens (e.g. meningococcemia, overwhelming post-splenectomy infection) and rapidly succumb from an exaggerated systemic inflammatory response. However, the vast majority of septic patients today survive their initial insult only to end up in the intensive care unit with sepsis-induced multi-organ dysfunction over the ensuing days to weeks. Sepsis-induced immunosuppression is increasingly recognized as the overriding immune dysfunction in these vulnerable patients.¹

The clinical relevance of this immunosuppressed state is evidenced by the frequent occurrence of infection by relatively avirulent and often multidrug-resistant bacterial, viral, and fungal pathogens (Stenotrophomonas, Acinetobacter and Pseudomonas spp., enterococci, cytomegalovirus and Candida spp. infections). In light of progressive antimicrobial resistance and the paucity of new antimicrobial agents entering the developmental pipeline, the management of these patients is increasingly challenging.² Sepsis can be considered a race to the death between the pathogens and the host immune response and pathogens seek an advantage by incapacitating various aspects of host defenses including inducing apoptotic depletion of immune effector cells, endotoxin reprogramming, reduced expression of MHC Class-2 molecules, increased expression of negative co-stimulatory molecules, production of anti-inflammatory cytokines, and increased T-regulatory and myeloid-derived suppressor cells (Figure 1). Prevention of sepsis-induced immunosuppression, or treatment of this process once it occurs, is a major research priority.

Figure 1. Reversal of Immunosuppression in Sepsis.

Many patients fail to eradicate the initial invading pathogens and progress to a prolonged phase of sepsis-induced immunosuppression characterized by failure to eradicate the primary infection and development of secondary nosocomial infections. The immunosuppression is mediated by multiple mechanisms including massive apoptosis-induced depletion of lymphocytes and dendritic cells, decreased expression of the cell surface antigen presenting complex HLA-DR, and increased expression of negative co-stimulatory molecules programmed death 1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), B and T lymphocyte attenuator (BTLA), and their corresponding ligands, e.g., (PD-L1). Furthermore, T-regulatory cells (T-regs) and myeloid-derived suppressor cells (MDSCs) are increased and there is a shift from an inflammatory Th1 phenotype to an anti-inflammatory Th2 lymphocyte phenotype with production of IL-10. The net result is a severely compromised innate and adaptive immune system with poorly functional “exhausted” CD8 and anergic CD4 T cells. Potential immunotherapeutic approaches (illustrated in red color) include agents that block apoptosis, block negative co-stimulatory molecules, decrease anti-inflammatory cytokines, increase HLA-DR expression, and reactivate “exhausted” or anergic T cells. Abbreviations: DC, dendritic cell; MAC, macrophage; PMN, polymorphonuclear leukocyte; FLT-3L, Fms-related tyrosine kinase 3 ligand, GM-CSF, granulocyte macrophage colony stimulating factor;

A recent study by Said et al³ provides remarkable insights into the basic molecular mechanisms contributing to immune depression following sustained inflammation such as occurs in patients with chronic viral infections or protracted sepsis. These investigators studied a critical monocyte/macrophage protein known as programmed death-1 (PD-1) in HIV infection. PD-1, a negative co-stimulatory molecule expressed on immune effector cells, is upregulated along with its cognate ligand PD-L1 during chronic HIV infection. Microbial mediators translocate across intestinal epithelium during chronic HIV-induced inflammation and are recognized by toll-like receptors. Persistent activation of the innate immune system upregulates PD-1/PD-L1 expression on immune cells. Importantly, PD-1 impairs immunity by inducing apoptosis, increasing production of IL-10, preventing T-cell proliferation, and causing T cells to become non-responsive (“exhausted”). Said et al. showed that PD-1 activation increased IL-10, a key anti-inflammatory cytokine increased in sepsis. Thus, blocking PD-1 may improve mortality in various chronic infections and, in this regard, animal studies demonstrate that inhibiting PD-1 improves survival in lethal fungal infections and in bacterial sepsis.⁴

Although it is possible that immunostimulatory therapy could exacerbate the hyper-inflammatory phase of sepsis or induce autoimmunity, clinical trials of interferon-γ, a potent immunostimulatory agent, and G-CSF and GM-CSF in patients with various systemic inflammatory states did not demonstrate unbridled inflammatory reactions. Most patients with refractory sepsis are so severely immunosuppressed that they are less likely to develop hyper-inflammation.

Given the extensive apoptosis-induced depletion of immune effector cells, one strategy that offers promise is use of the anti-apoptotic, immunostimulatory cytokines IL-7 and IL-15; both agents have shown efficacy in sepsis models. These cytokines not only prevent cell death but also thereby diminish the immunosuppressive effect that uptake of apoptotic cells has on phagocytic cells. IL-7 also restores lymphocyte effector function and improves lymphocyte trafficking by increasing integrins. It is currently in clinical trials in chronic hepatitis-C, HIV, and cancer and has been well-tolerated.

Peering into the future, immunotherapy will likely be individualized based upon specific laboratory and/or clinical findings. In a recent trial in septic patients, GM-CSF was tailored to those patients in whom monocyte HLA-DR expression was significantly depressed.⁵ Similarly, flow cytometric studies quantitating leukocyte expression of negative co-stimulatory molecules, e.g, PD-1/PD-L1, or rapid whole blood stimulation assays of cytokine secretion could be used to guide immunotherapeutic decisions. Finally, patients with CMV or HSV-1 reactivation and patients with sepsis due to opportunistic pathogens, e.g., Stenotrophomonas or Acinetobacter infection, are obvious candidates for immuno-enhancing therapy.

Advances in immunology and in understanding the pathophysiology of systemic inflammation provide new therapeutic opportunities in sepsis. As one old saying goes, “Desperate diseases are cured by desperate means or not at all”. Carefully designed trials of immunostimulatory agents with close monitoring of innate and adaptive immune function in patients with demonstrable immunosuppression should be undertaken. Many potentially beneficial imunomodulatory agents (Figure 1) are currently in clinical trials for other indications and have reasonable safety profiles. We speculate that such an approach would have wide ranging effects and could represent a major advance in the field of infectious disease.