Gamma-Irradiated Bacille Calmette-Guérin Vaccination Does Not Modulate the Innate Immune Response during Experimental Human Endotoxemia in Adult Males

Hamers, L.A.C.; Kox, Matthijs; Arts, Rob J. W.; Blok, Bastiaan A.; Leentjens, Jenneke; Netea, Mihai G.; Pickkers, Peter

doi:10.1155/2015/261864

Cited by 9 publications

(7 citation statements)

References 34 publications

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“…In humans, c-irradiated BCG was studied as an alternative agonist to stimulate innate training both in vitro and in vivo. 38,39 An in vivo c-irradiated BCG vaccination in humans failed to alter cytokine expression when PBMCs were stimulated ex vivo with various agonists, 38 in contrast to previous studies with lvBCG. 3,40 In vitro c-irradiated BCG induces trained immunity but to a lesser degree than lvBCG; Arts et al 39 theorize that the reduced state of innate training with c-irradiated BCG compared to lvBCG may be due to changes to the immunostimulatory component of BCG (i.e., muramyl dipeptide) or that intracellular replication of live bacterium is necessary to induce trained immunity.…”

Section: Discussionmentioning

confidence: 94%

Differential induction of innate memory in porcine monocytes by β-glucan or bacillus Calmette-Guerin

2020

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Innate immunomodulation via induction of innate memory is one mechanism to alter the host’s innate immune response to reduce or prevent disease. Microbial products modulate innate responses with immediate and lasting effects. Innate memory is characterized by enhanced (training) or depressed (tolerance) innate immune responses, including pro-inflammatory cytokine production, to secondary exposure following a priming event. To investigate the ability of β-glucans and bacillus Calmette-Guerin to induce innate training or tolerance in pig cells, porcine monocytes were cultured with priming agonist (β-glucans or bacillus Calmette-Guerin) then re-stimulated 5 d later with a heterologous microbial agonist to determine induction of innate memory. Priming with β-glucan from Saccharomyces cerevisiae depressed IL-1β and TNF-α cytokine responses to re-stimulation with LPS, indicative of a tolerized state. However, bacillus Calmette-Guerin priming induced a trained state in porcine monocytes, as LPS re-stimulation enhanced IL-1β and TNF-α gene expression and protein production. We present the first evidence of innate memory in pig monocytes, with bacillus Calmette-Guerin (training) or Saccharomyces cerevisiae β-glucan (tolerance). Induction of a trained or tolerized state in vitro is a first step to identify agonists to alter the innate immune system at the animal level with the intent of enhancing disease resistance.

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Section: Discussionmentioning

confidence: 94%

Differential induction of innate memory in porcine monocytes by β-glucan or bacillus Calmette-Guerin

2020

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“…Moreover, in an experimental sepsis study in human volunteers, immunization with gamma-irradiated BCG 5 days prior to i.v. administration of LPS did not ameliorate the endotoxemia-induced immunoparesis, measured as a decrease in ex vivo cytokine responses (28).…”

Section: Discussionmentioning

confidence: 99%

The Effect of Inactivated Mycobacterium Paratuberculosis Vaccine on the Response to a Heterologous Bacterial Challenge in Pigs

et al. 2019

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Background: Vaccines may have non-specific effects, affecting resistance to heterologous pathogens. Veterinary vaccines have seldom been investigated for their non-specific effects. However, recent observational studies suggest that an inactivated paratuberculosis vaccine reduced all-cause mortality in goats and cattle. Aim: We tested if vaccination with a killed mycobacterial vaccine may have heterologous effects in swine (Sus domesticus), specifically on the pathogenic and clinical effects of a heterologous challenge with Actinobacillus pleuropneumoniae in young pigs. Methods: Newborn piglets were randomized to vaccination s.c. with the inactivated paratuberculosis vaccine Gudair (Zoetis Inc.) ( n = 17) or no vaccine ( n = 16). At 4–5 weeks after vaccination, all piglets were challenged intra-nasally with a high (Gudair: n = 8; control: n = 8) or a low (Gudair: n = 9; control: n = 8) dose of the gram-negative bacterium A. pleuropneumoniae causing acute porcine pleuropneumonia. The effect and severity of pathogen challenge was evaluated by measuring acute phase proteins C-reactive protein, haptoglobin and Porcine α1-acid glycoprotein, and by gross pathology 1 day post challenge. Specific and non-specific in vitro cytokine responses to vaccination were evaluated in whole blood before bacterial challenge. Results: The vaccine was immunogenic in the pigs as evidenced by increased IFN-γ responses to purified protein derivative of Mycobacterium paratuberculosis. However, Gudair vaccine did not affect IL-6 responses. The gross pathology of the lungs as well as the acute phase protein responses after the high A. pleuropneumoniae dose challenge was slightly increased in the vaccinated animals compared with controls, whereas this was not seen in the animals receiving the low-dose bacterial challenge. Conclusion: The inactivated paratuberculosis vaccine exacerbated the pathological and inflammatory effects of an experimental A. pleuropneumoniae infection in young pigs.

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“…Furthermore, the in vivo source of IFN-g remained elusive. Because only a subset of neutrophils express PD-L1, both in humans and mice [14,16], it is unlikely that systemic IFN-g production is responsible, also because systemic IFN-g levels during human endotoxemia remain very low [17,18]. In the present study, we sought to identify the source of IFNg production and its role in the generation of PD-L1 + -suppressive neutrophils.…”

Section: Introductionmentioning

confidence: 99%

Spleen-derived IFN-γ induces generation of PD-L1+-suppressive neutrophils during endotoxemia

Langereis

Pickkers

Kleijn

et al. 2017

Journal of Leukocyte Biology

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The immune inhibitory checkpoint molecule programmed death ligand (PD-L)-1 is increasingly recognized as an important player in the immune suppression observed in patients with sepsis, but its role has mainly been studied in monocytes. In an earlier study, we demonstrated that experimental human endotoxemia results in mobilization of a subset of PD-L1-expressing neutrophils displaying an IFN-γ-induced transcriptome profile. Herein, we identify the source of IFN-γ production during murine endotoxemia and its role in the generation of PD-L1-suppressive neutrophils. We demonstrate that, similar to what we found in humans, murine endotoxemia results in the influx of a subset of PD-L1 neutrophils in the circulation, and incubation of mouse neutrophils with recombinant IFN-γ profoundly increases PD-L1 expression. Furthermore, administration of anti-IFN-γ abrogated the generation of PD-L1 neutrophils in endotoxemic mice. The critical involvement of the spleen is illustrated by the fact that splenectomy nullified circulating IFN-γ levels and substantially reduced the abundance of PD-L1 neutrophils, whereas cotreatment with recombinant IFN-γ resulted in complete restoration of generation of PD-L1 neutrophils in splenectomized mice. Finally, the functional importance of spleen-derived PD-L1 neutrophils is exemplified by the finding that the profound decrease in T-lymphocyte proliferation observed in cells from endotoxemic mice was attenuated in cells from splenectomized animals. We demonstrated that spleen-derived IFN-γ induces generation of PD-L1-suppressive neutrophils, implying that the spleen is critically involved in immune suppression during inflammatory diseases such as sepsis. Furthermore, our data suggest that IFN-γ plays a dual role by enhancing innate immunity and at the same time suppressing adaptive immune responses.

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Gamma-Irradiated Bacille Calmette-Guérin Vaccination Does Not Modulate the Innate Immune Response during Experimental Human Endotoxemia in Adult Males

Cited by 9 publications

References 34 publications

Differential induction of innate memory in porcine monocytes by β-glucan or bacillus Calmette-Guerin

Differential induction of innate memory in porcine monocytes by β-glucan or bacillus Calmette-Guerin

The Effect of Inactivated Mycobacterium Paratuberculosis Vaccine on the Response to a Heterologous Bacterial Challenge in Pigs

Spleen-derived IFN-γ induces generation of PD-L1+-suppressive neutrophils during endotoxemia

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