Immunotherapy for sepsis--a new approach against an ancient foe.

Septic shock is traditionally viewed as an excessive systemic inflammatory reaction to invasive microbial pathogens, yet efforts to improve the outcome of patients with sepsis by means of inhibitors of proinflammatory cytokines and mediators have been unsuccessful. Occasionally, patients present with an exaggerated systemic inflammatory response to highly virulent pathogens (such as in cases of meningococcemia) and rapidly succumb. However, the vast majority of patients with sepsis survive the initial insult, only to end up in the intensive care unit with sepsis-induced multiorgan dysfunction days or weeks later. Sepsisinduced 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 with relatively avirulent and often multidrug-resistant bacterial, viral, or fungal pathogens such as species of stenotrophomonas, acinetobacter, candida, pseudomonas, enterococcus, and cytomegalovirus. In light of progressive antimicrobial resistance and the paucity of new antimicrobial agents entering the developmental pipeline, the care of patients with sepsis is increasingly challenging.2 Sepsis can be considered to represent a race between the pathogens and the host immune response; pathogens seek an advantage by incapacitating various aspects of host defenses. For example, they induce the apoptotic depletion of immune effector cells, suppress the expression of major-histocompatibility-complex class II molecules, increase expression of negative costimulatory molecules, increase antiinflammatory cytokines, and augment levels of regulatory T cells and myeloid-derived suppressor cells (Fig. 1). The prevention of sepsis-induced immunosuppression, or its treatment if it occurs, is a research priority. A recent study by Said and colleagues3 provides insights into the molecular mechanisms that underlie immune depression following sustained inflammation, such as occurs in patients with either chronic viral infections or protracted sepsis. These investigators studied a critical monocyte–macrophage protein known as programmed death 1 (PD-1), which is found in patients infected with the human immunodeficiency virus (HIV). PD-1, a negative costimulatory molecule expressed on immune effector cells, is up-regulated along with its cognate ligand PD-L1 (also expressed on effector cells) during chronic HIV infection. Said and colleagues found that microbial mediators translocate across the intestinal epithelium in chronic HIV-induced inflammation and are recognized by toll-like receptors. Persistent activation of the innate immune system by these intestinally derived microbial products up-regulates the expression of PD-1 and PD-L1 on various immune cells. PD-1 impairs immunity by inducing apoptosis, increasing production of interleukin-10 (a key antiinflammatory cytokine increased in sepsis), preventing T-cell proliferation, and causing T cells to become nonresponsive (“exhausted”). Said and colleagues described a new mechanism by which the interaction between PD-1 and PD-L1 induces immunosuppression in patients with HIV. They found that PD-1 activation results in the increased production of interleukin-10 by monocytes from persons infected with HIV. Moreover, the PD-1– induced inhibition of CD4 T cells was itself inhibited by the blocking of the interleukin-10 receptor. Thus, PD-1 affects immunosuppression through its effect on interleukin-10 expression. These results suggest that blocking PD-1 may improve the prognosis of patients with any of a variety of chronic infections. These findings are consistent with the improved survival in mice with fungal infections, and in mice with bacterial sepsis, in which PD-1 was inhibited.4