Our understanding of the pathogenesis of sepsis has been oversimplified during the past decades and, as a result, many clinical trials addressed the proinflammatory side when there was no evidence that hyperinflammation was dominant in patients. Some issues remain before we gain a complete picture of events leading to immunosuppression: Are the major sepsis-induced inhibitory mechanisms all established? What is the physician-caused part of immunosuppression, because sedatives, catecholamines, insulin-all immunosuppressive-are administered to the patient? Is the cellular energetic status crucial in maintaining immune functions? How important is the neuroendocrine-mediated part of immunosuppression? How preponderant is immune failure among other organ failures? Nonetheless, we can reasonably state that patients with sepsis present with features consistent with immunoparalysis. Consequently, stimulating the patient’s immune system may become a promising therapeutic strategy. As presented in this review, we delineate four types of therapeutic interventions: blocking soluble antiinflammatory mediators, restoring antigen-presenting cell function, restoring T lymphocyte function, and blocking apoptosis (). In order not to repeat the mistakes from the past, we should keep in mind that targeting a single mediator/function among many immune dysfunctions may be inefficient.
Putative target-directed therapies for restoring immune function during sepsis-induced immunosuppression based on biological staging.
Regarding an eventual blockade of IL-10 function, we presently lack enough consistent data in the human setting, and studies in animal models have provided contrasting results. AS101, with the capacity to inhibit IL-10, has been demonstrated to increase survival in septic mice (185
), whereas anti-IL-10 antibodies did not improve bacterial clearance and mortality in murine models (186
). That said, we may speculate that blocking a single mediator in a context where many inhibitory pathways are involved/activated, would remain inefficient (as was targeting a single proinflammatory mediator during the early cytokine cascade in septic shock). However, AS101 might still be interesting because it acts through different mechanisms (inhibition of IL-10, activation of macrophage functions, inhibition of IL-1β converting enzyme). Further investigations are required.
Several molecules (IFN-γ, G-CSF, GM-CSF) have been used to stimulate monocyte functions and gave interesting preliminary ex vivo results (increase in mHLA-DR expression, restoration of cytokine production). Several prospective randomized multicenter trials using IFN-γ have been conducted in trauma patients. However, despite interesting results regarding secondary end points in some subgroups of patients (decreased severity in nosocomial infections, decreased mortality in infected patients), they remained inconclusive regarding overall mortality or infection rates (187
). Presneill et al. (189
) presented preliminary GM-CSF data in 10 patients with sepsis-induced respiratory failure. They observed modest improvement in gas exchange, ARDS resolution, and alveolar leukocyte phagocytic functions, but it was not accompanied by enhanced survival. In a prospective, randomized, placebo-controlled trial, Rosenbloom et al. (190
) investigated whether GM-CSF treatment can improve leukocyte functions and mortality in 40 septic patients. They observed a higher leukocyte count, increased mHLA-DR, and better cure/improvement of infection in the treated group but no difference in mortality. Nevertheless, it should be noted that these trials were designed without patient stratification, whereas drug efficacy should be assessed only in patients with established impairment in monocyte function. To our knowledge, only two studies stratified septic and trauma patients with respect to mHLA-DR. Because of the small number of patients included, it is not yet possible to reach conclusions on the impact of IFN-γ treatment in septic patients, but promising results have shown a decrease in mortality and/or rate of nosocomial infection (107
). A randomized, double-blind, placebo-controlled phase II trial using GM-CSF has just been completed in patients with severe sepsis and septic shock; results are still not available (www.clinicaltrials.gov/ct2/show/NCT00252915
). Given the central role of DCs in both innate and adaptive immune responses, increasing their number and restoring their function might constitute another potential treatment. In particular, the use of FLT3-L-known to activate and expand DCs-was shown to reverse immunoparalysis in a mouse model of endotoxin tolerance (77
) and to increase resistance to P. aeruginosa
opportunistic infections in burned mice (76
). In human patients, phase II/III trials have been conducted in cancer patients, but not yet in sepsis. Interestingly, GM-CSF and FLT3-L have synergistic effects on the DC maturation process. Activation of TLRs may also allow upregulation of specific antimicrobial defenses; this approach is currently under investigation (192
Augmenting T-cell function and fighting lymphopenia may represent another therapeutic strategy. For example, IL-7 is an essential cytokine for T-lymphocyte development, survival, expansion, and maturation in humans. Phase I clinical trials in cancer patients and HIV-infected patients have shown that T-cell expansion can be achieved at doses that are well tolerated (193
). The use of ligands of co-activator receptors for effector T lymphocytes may also have beneficial effects. As an example, recent results by Scumpia et al. (128
) have shown that anti-GITR agonistic antibodies were able to restore lymphocyte proliferation, prevent CD3 downmodulation, decrease bacteremia, and increase survival in a mouse model of sepsis. Intravenous use of immunoglobin therapy has also been proposed as an adjuvant treatment for sepsis, but its benefits remain unclear. The authors of recent meta-analyses recommend conducting larger clinical trials with patient stratification (195
Finally, strategies designed at blocking apoptosis, including caspase inhibitors, overexpression of Bcl-2, and inhibition of Fas/FasL signaling, have demonstrated survival improvement in animal models of sepsis as well (13
). That said, no therapeutic strategy is sufficiently developed for clinical use. An alternative might be provided by HIV protease inhibitors, whose activity is partly mediated through anti-apoptotic effects. Administration of ritonavir improved survival in a murine model of sepsis, even when given after the onset of the disease (197
). As these protease inhibitors are well tolerated in patients, we may expect enticing possibilities in sepsis. A phase I trial is currently underway, investigating in healthy volunteers the effects of these drugs in boosting the immune system (www.clinicaltrials.gov/ct2/show/NCT00346619
). Of note, drugs aimed at blocking apoptosis may be used as adjunctive agents in association with molecules targeting monocytes or leukocytes.
In summary, both arms of immunity, innate and adaptive, are severely dysfunctional in septic patients. This very likely contributes to the development of nosocomial infections and patients’ inability to clear primary infections. Consequently, therapies capable of restoring immune function represent a new worthwhile strategy. Although we cannot predict that these therapies will be efficacious, they surely deserve to be fully investigated, considering the high mortality that has characterized septic syndromes for 25 years. In order not to repeat the mistakes from the past, an absolute prerequisite for clinical trials is to systematically assess patients’ immune functions to be able to define individualized immunotherapy.