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Recent insights in sepsis pathology have led to the view that not the initial hyperinflammatory state, but rather a profoundly suppressed state of the immune system, also called immunoparalysis, accounts for the majority of sepsis-related deaths. Therefore, reconstitution of immunocompetence in sepsis is emerging as a promising therapeutic target to improve outcome. Bacille Calmette-Guérin (BCG) vaccine not only protects against tuberculosis, but exerts beneficial effects on other infectious diseases as well. These non-specific effects of BCG seem to be mediated by potentiation of adaptive immunity through heterologous effects, as well as epigenetic functional reprogramming of innate immune cells to an enhanced phenotype, a process described as 'trained immunity', which has been shown in vitro, ex vivo, and in animal models. Therefore, BCG-vaccination could represent a novel therapeutic option to treat sepsis-induced immunoparalysis, although its immunomodulatory effects in humans in vivo have not yet been investigated. Furthermore, the live BCG vaccine presents a potential risk of disseminated disease in immunoparalyzed patients, which can be circumvented by inactivating the vaccine through gamma-irradiation.
To determine the effects of gamma-irradiated BCG-vaccination on the in vivo innate immune responses induced by human endotoxemia. Also, to determine the effects of gamma-irradiated BCG-vaccination on ex vivo responsiveness of leukocytes to various inflammatory stimuli.
In a randomized double blind placebo-controlled study, healthy male volunteers were vaccinated with gamma-irradiated BCG (n = 10) or placebo (n = 10) and received 1 ng/kg lipopolysaccharide (LPS) intravenously on day 5 after vaccination to assess the in vivo immune response. Peripheral blood mononuclear cells were stimulated with various related and unrelated pathogens 5, 8 to 10, and 25 to 35 days after vaccination to assess ex vivo immune responses.
LPS administration elicited a profound systemic immune response, characterized by increased levels of pro-and anti-inflammatory cytokines, hemodynamic changes, and flu-like symptoms. However, BCG neither modulated this in vivo immune response (Figure (Figure1),1), nor ex vivo leukocyte responses at any time-point (Figure (Figure22).
Gamma-irradiated BCG does not modulate the innate immune response in vivo in humans and is therefore unlikely to represent an effective treatment option to restore immunocompetence in patients with sepsis-induced immunoparalysis.
M.G.N. was supported by a Vici grant of the Netherlands Organization for Scientific Research and an ERC Consolidator Grant (#310372).