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Autophagy controls BCG-induced trained immunity and the response to intravesical BCG therapy for bladder cancer.

Buffen K, Oosting M, Quintin J, Ng A, Kleinnijenhuis J, Kumar V, van de Vosse E, Wijmenga C, van Crevel R, Oosterwijk E, Grotenhuis AJ, Vermeulen SH, Kiemeney LA, van de Veerdonk FL, Chamilos G, Xavier RJ, van der Meer JW, Netea MG, Joosten LA - PLoS Pathog. (2014)

Bottom Line: It has been recently proposed that the non-specific effects of BCG are mediated through epigenetic reprogramming of monocytes, a process called trained immunity.Single nucleotide polymorphisms (SNPs) in the autophagy genes ATG2B (rs3759601) and ATG5 (rs2245214) influenced both the in vitro and in vivo training effect of BCG upon restimulation with unrelated bacterial or fungal stimuli.These findings identify a key role of autophagy for the nonspecific protective effects of BCG.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands.

ABSTRACT
The anti-tuberculosis-vaccine Bacillus Calmette-Guérin (BCG) is the most widely used vaccine in the world. In addition to its effects against tuberculosis, BCG vaccination also induces non-specific beneficial effects against certain forms of malignancy and against infections with unrelated pathogens. It has been recently proposed that the non-specific effects of BCG are mediated through epigenetic reprogramming of monocytes, a process called trained immunity. In the present study we demonstrate that autophagy contributes to trained immunity induced by BCG. Pharmacologic inhibition of autophagy blocked trained immunity induced in vitro by stimuli such as β-glucans or BCG. Single nucleotide polymorphisms (SNPs) in the autophagy genes ATG2B (rs3759601) and ATG5 (rs2245214) influenced both the in vitro and in vivo training effect of BCG upon restimulation with unrelated bacterial or fungal stimuli. Furthermore, pharmacologic or genetic inhibition of autophagy blocked epigenetic reprogramming of monocytes at the level of H3K4 trimethylation. Finally, we demonstrate that rs3759601 in ATG2B correlates with progression and recurrence of bladder cancer after BCG intravesical instillation therapy. These findings identify a key role of autophagy for the nonspecific protective effects of BCG.

No MeSH data available.


Related in: MedlinePlus

SNP in ATG2B affects the efficacy of in vivo BCG-induced trained immunity.(a–b) Monocytes isolated before and 3 months after vaccination of 16 naïve (nonexposed) volunteers were stimulated in vitro with B. burgdorferi. Proinflammatory cytokine production (IL-1β [a], TNF-α [b]) was assessed by ELISA in the supernatants. (c–d) Kaplan-Meier curves for recurrence-free (c) and progression-free (d) survival according to rs3759601 SNP genotype of 192 patients suffering from non-muscle invasive bladder cancer treated with ≥6 intravesical instillations of BCG. Each drop in a probability curve indicates one or more events in that group. Vertical lines indicate censored patients, i.e. those who reached the end of their follow-up without experiencing the event. Total number of patients and number of events (between brackets) per genotype category are indicated next to the corresponding curve. Numbers of patients at risk at selected time points for each genotype category are given below the plots. (e–g) Monocytes of bladder cancer patients isolated before and after 6 intravesical BCG instillations as initial treatment were stimulated in vitro with LPS. Proinflammatory cytokine production (IL-1β [e], IL-6 [f], TNF-α [g]) was assessed by ELISA in the supernatants *P<0.05, **P<0.01.
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ppat-1004485-g004: SNP in ATG2B affects the efficacy of in vivo BCG-induced trained immunity.(a–b) Monocytes isolated before and 3 months after vaccination of 16 naïve (nonexposed) volunteers were stimulated in vitro with B. burgdorferi. Proinflammatory cytokine production (IL-1β [a], TNF-α [b]) was assessed by ELISA in the supernatants. (c–d) Kaplan-Meier curves for recurrence-free (c) and progression-free (d) survival according to rs3759601 SNP genotype of 192 patients suffering from non-muscle invasive bladder cancer treated with ≥6 intravesical instillations of BCG. Each drop in a probability curve indicates one or more events in that group. Vertical lines indicate censored patients, i.e. those who reached the end of their follow-up without experiencing the event. Total number of patients and number of events (between brackets) per genotype category are indicated next to the corresponding curve. Numbers of patients at risk at selected time points for each genotype category are given below the plots. (e–g) Monocytes of bladder cancer patients isolated before and after 6 intravesical BCG instillations as initial treatment were stimulated in vitro with LPS. Proinflammatory cytokine production (IL-1β [e], IL-6 [f], TNF-α [g]) was assessed by ELISA in the supernatants *P<0.05, **P<0.01.

Mentions: To corroborate the above data, we investigated BCG-induced training of monocytes in vivo by testing individuals carrying different ATG2B alleles. Monocytes were isolated from 16 healthy volunteers, before and 3 months after vaccination with BCG. Following stimulation with LPS (Figure S5a–b) or B. burgdorferi (Figure 4a–b), IL-1β and TNF-α production was significantly higher 3 months after vaccination in individuals who were bearing at least one G allele of the ATG2B SNP (n = 12), while monocytes isolated from individuals carrying the CC genotype (n = 4) showed no change in cytokine production after BCG vaccination.


Autophagy controls BCG-induced trained immunity and the response to intravesical BCG therapy for bladder cancer.

Buffen K, Oosting M, Quintin J, Ng A, Kleinnijenhuis J, Kumar V, van de Vosse E, Wijmenga C, van Crevel R, Oosterwijk E, Grotenhuis AJ, Vermeulen SH, Kiemeney LA, van de Veerdonk FL, Chamilos G, Xavier RJ, van der Meer JW, Netea MG, Joosten LA - PLoS Pathog. (2014)

SNP in ATG2B affects the efficacy of in vivo BCG-induced trained immunity.(a–b) Monocytes isolated before and 3 months after vaccination of 16 naïve (nonexposed) volunteers were stimulated in vitro with B. burgdorferi. Proinflammatory cytokine production (IL-1β [a], TNF-α [b]) was assessed by ELISA in the supernatants. (c–d) Kaplan-Meier curves for recurrence-free (c) and progression-free (d) survival according to rs3759601 SNP genotype of 192 patients suffering from non-muscle invasive bladder cancer treated with ≥6 intravesical instillations of BCG. Each drop in a probability curve indicates one or more events in that group. Vertical lines indicate censored patients, i.e. those who reached the end of their follow-up without experiencing the event. Total number of patients and number of events (between brackets) per genotype category are indicated next to the corresponding curve. Numbers of patients at risk at selected time points for each genotype category are given below the plots. (e–g) Monocytes of bladder cancer patients isolated before and after 6 intravesical BCG instillations as initial treatment were stimulated in vitro with LPS. Proinflammatory cytokine production (IL-1β [e], IL-6 [f], TNF-α [g]) was assessed by ELISA in the supernatants *P<0.05, **P<0.01.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4214925&req=5

ppat-1004485-g004: SNP in ATG2B affects the efficacy of in vivo BCG-induced trained immunity.(a–b) Monocytes isolated before and 3 months after vaccination of 16 naïve (nonexposed) volunteers were stimulated in vitro with B. burgdorferi. Proinflammatory cytokine production (IL-1β [a], TNF-α [b]) was assessed by ELISA in the supernatants. (c–d) Kaplan-Meier curves for recurrence-free (c) and progression-free (d) survival according to rs3759601 SNP genotype of 192 patients suffering from non-muscle invasive bladder cancer treated with ≥6 intravesical instillations of BCG. Each drop in a probability curve indicates one or more events in that group. Vertical lines indicate censored patients, i.e. those who reached the end of their follow-up without experiencing the event. Total number of patients and number of events (between brackets) per genotype category are indicated next to the corresponding curve. Numbers of patients at risk at selected time points for each genotype category are given below the plots. (e–g) Monocytes of bladder cancer patients isolated before and after 6 intravesical BCG instillations as initial treatment were stimulated in vitro with LPS. Proinflammatory cytokine production (IL-1β [e], IL-6 [f], TNF-α [g]) was assessed by ELISA in the supernatants *P<0.05, **P<0.01.
Mentions: To corroborate the above data, we investigated BCG-induced training of monocytes in vivo by testing individuals carrying different ATG2B alleles. Monocytes were isolated from 16 healthy volunteers, before and 3 months after vaccination with BCG. Following stimulation with LPS (Figure S5a–b) or B. burgdorferi (Figure 4a–b), IL-1β and TNF-α production was significantly higher 3 months after vaccination in individuals who were bearing at least one G allele of the ATG2B SNP (n = 12), while monocytes isolated from individuals carrying the CC genotype (n = 4) showed no change in cytokine production after BCG vaccination.

Bottom Line: It has been recently proposed that the non-specific effects of BCG are mediated through epigenetic reprogramming of monocytes, a process called trained immunity.Single nucleotide polymorphisms (SNPs) in the autophagy genes ATG2B (rs3759601) and ATG5 (rs2245214) influenced both the in vitro and in vivo training effect of BCG upon restimulation with unrelated bacterial or fungal stimuli.These findings identify a key role of autophagy for the nonspecific protective effects of BCG.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands.

ABSTRACT
The anti-tuberculosis-vaccine Bacillus Calmette-Guérin (BCG) is the most widely used vaccine in the world. In addition to its effects against tuberculosis, BCG vaccination also induces non-specific beneficial effects against certain forms of malignancy and against infections with unrelated pathogens. It has been recently proposed that the non-specific effects of BCG are mediated through epigenetic reprogramming of monocytes, a process called trained immunity. In the present study we demonstrate that autophagy contributes to trained immunity induced by BCG. Pharmacologic inhibition of autophagy blocked trained immunity induced in vitro by stimuli such as β-glucans or BCG. Single nucleotide polymorphisms (SNPs) in the autophagy genes ATG2B (rs3759601) and ATG5 (rs2245214) influenced both the in vitro and in vivo training effect of BCG upon restimulation with unrelated bacterial or fungal stimuli. Furthermore, pharmacologic or genetic inhibition of autophagy blocked epigenetic reprogramming of monocytes at the level of H3K4 trimethylation. Finally, we demonstrate that rs3759601 in ATG2B correlates with progression and recurrence of bladder cancer after BCG intravesical instillation therapy. These findings identify a key role of autophagy for the nonspecific protective effects of BCG.

No MeSH data available.


Related in: MedlinePlus