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Tolerance-like innate immunity and spleen injury: a novel discovery via the weekly administrations and consecutive injections of PEGylated emulsions.

Wang L, Wang C, Jiao J, Su Y, Cheng X, Huang Z, Liu X, Deng Y - Int J Nanomedicine (2014)

Bottom Line: Innate immunity tolerance was induced by PE, regardless of the mode of administration.Further study of this mechanism suggested that monocytes play an essential role in the suppression of innate immunity.These findings provide novel insights into the understanding of the innate immune system.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.

ABSTRACT
There has been an increasing interest in the study of the innate immune system in recent years. However, few studies have focused on whether innate immunity can acquire tolerance. Therefore, in this study, we investigated tolerance in the innate immune system via the consecutive weekly and daily injections of emulsions modified with polyethylene glycol (PEG), referred to as PEGylated emulsions (PE). The effects of these injections of PE on pharmacokinetics and biodistribution were studied in normal and macrophage-depleted rats. Additionally, we evaluated the antigenic specificity of immunologic tolerance. Immunologic tolerance against PE developed after 21 days of consecutive daily injections or the fourth week of PE administration. Compared with a single administration, it was observed that the tolerant rats had a lower rate of PE clearance from the blood, which was independent of the stress response. In addition, weekly PE injections caused injury to the spleen. Furthermore, the rats tolerant to PEs with the methoxy group (-OCH3) of PEG, failed to respond to the PEs with a different terminal group of PEG or to non-PEG emulsions. Innate immunity tolerance was induced by PE, regardless of the mode of administration. Further study of this mechanism suggested that monocytes play an essential role in the suppression of innate immunity. These findings provide novel insights into the understanding of the innate immune system.

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The antigenic specificity to terminal group of PEG in the tolerant rats induced by PE-OCH3.Notes: (A1 and A2) Blood clearance. (B1 and B2) Hepatic and splenic accumulation 12 hours after intravenous injection of the test dose. (A1 and B1) Intravenous injection of PE-NH2. (A2 and B2) Intravenous injection of PE-COOH. Data are shown as mean ± SD, n=3; *P<0.05.Abbreviations: PE, PEGylated emulsion; PEG, polyethylene glycol; SD, standard deviation; PE-OCH3, PEGylated emulsions modified with the methoxy group of DSPE-PEG; PE-NH2, PEGylated emulsions modified with the amino group of DSPE-PEG; PE-COOH, PEGylated emulsions modified with the carboxyl group of DSPE-PEG; DSPE, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine.
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f4-ijn-9-3645: The antigenic specificity to terminal group of PEG in the tolerant rats induced by PE-OCH3.Notes: (A1 and A2) Blood clearance. (B1 and B2) Hepatic and splenic accumulation 12 hours after intravenous injection of the test dose. (A1 and B1) Intravenous injection of PE-NH2. (A2 and B2) Intravenous injection of PE-COOH. Data are shown as mean ± SD, n=3; *P<0.05.Abbreviations: PE, PEGylated emulsion; PEG, polyethylene glycol; SD, standard deviation; PE-OCH3, PEGylated emulsions modified with the methoxy group of DSPE-PEG; PE-NH2, PEGylated emulsions modified with the amino group of DSPE-PEG; PE-COOH, PEGylated emulsions modified with the carboxyl group of DSPE-PEG; DSPE, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine.

Mentions: To investigate the antigenic specificity to the terminal group of PEG, the tolerant rats, which were immunized with PEs with the methoxy group of PEG (PE-OCH3), were injected with PEs with the amino group (PE-NH2) and carboxyl group (PE-COOH) of PEG. As shown in Figure 4, the plasma concentration of PE-NH2 and PE-COOH in the PE group increased correspondingly, especially within 1 hour. The AUC(0–1 h) of PE-NH2 and PE-COOH administered in the normal rats, the 5% Glu group, and the PE group was 10.40, 15.42, and 34.18, and 40.51, 37.10, and 53.47 mg/L·hour, respectively. The results demonstrate that PE-OCH3-tolerant rats failed to respond to PE-NH2 and PE-COOH. A large increase in splenic accumulation was observed in the tolerant rats that received PE-NH2 (P<0.05). There were no remarkable differences in rats that received weekly injections of 5% Glu.


Tolerance-like innate immunity and spleen injury: a novel discovery via the weekly administrations and consecutive injections of PEGylated emulsions.

Wang L, Wang C, Jiao J, Su Y, Cheng X, Huang Z, Liu X, Deng Y - Int J Nanomedicine (2014)

The antigenic specificity to terminal group of PEG in the tolerant rats induced by PE-OCH3.Notes: (A1 and A2) Blood clearance. (B1 and B2) Hepatic and splenic accumulation 12 hours after intravenous injection of the test dose. (A1 and B1) Intravenous injection of PE-NH2. (A2 and B2) Intravenous injection of PE-COOH. Data are shown as mean ± SD, n=3; *P<0.05.Abbreviations: PE, PEGylated emulsion; PEG, polyethylene glycol; SD, standard deviation; PE-OCH3, PEGylated emulsions modified with the methoxy group of DSPE-PEG; PE-NH2, PEGylated emulsions modified with the amino group of DSPE-PEG; PE-COOH, PEGylated emulsions modified with the carboxyl group of DSPE-PEG; DSPE, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4128795&req=5

f4-ijn-9-3645: The antigenic specificity to terminal group of PEG in the tolerant rats induced by PE-OCH3.Notes: (A1 and A2) Blood clearance. (B1 and B2) Hepatic and splenic accumulation 12 hours after intravenous injection of the test dose. (A1 and B1) Intravenous injection of PE-NH2. (A2 and B2) Intravenous injection of PE-COOH. Data are shown as mean ± SD, n=3; *P<0.05.Abbreviations: PE, PEGylated emulsion; PEG, polyethylene glycol; SD, standard deviation; PE-OCH3, PEGylated emulsions modified with the methoxy group of DSPE-PEG; PE-NH2, PEGylated emulsions modified with the amino group of DSPE-PEG; PE-COOH, PEGylated emulsions modified with the carboxyl group of DSPE-PEG; DSPE, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine.
Mentions: To investigate the antigenic specificity to the terminal group of PEG, the tolerant rats, which were immunized with PEs with the methoxy group of PEG (PE-OCH3), were injected with PEs with the amino group (PE-NH2) and carboxyl group (PE-COOH) of PEG. As shown in Figure 4, the plasma concentration of PE-NH2 and PE-COOH in the PE group increased correspondingly, especially within 1 hour. The AUC(0–1 h) of PE-NH2 and PE-COOH administered in the normal rats, the 5% Glu group, and the PE group was 10.40, 15.42, and 34.18, and 40.51, 37.10, and 53.47 mg/L·hour, respectively. The results demonstrate that PE-OCH3-tolerant rats failed to respond to PE-NH2 and PE-COOH. A large increase in splenic accumulation was observed in the tolerant rats that received PE-NH2 (P<0.05). There were no remarkable differences in rats that received weekly injections of 5% Glu.

Bottom Line: Innate immunity tolerance was induced by PE, regardless of the mode of administration.Further study of this mechanism suggested that monocytes play an essential role in the suppression of innate immunity.These findings provide novel insights into the understanding of the innate immune system.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.

ABSTRACT
There has been an increasing interest in the study of the innate immune system in recent years. However, few studies have focused on whether innate immunity can acquire tolerance. Therefore, in this study, we investigated tolerance in the innate immune system via the consecutive weekly and daily injections of emulsions modified with polyethylene glycol (PEG), referred to as PEGylated emulsions (PE). The effects of these injections of PE on pharmacokinetics and biodistribution were studied in normal and macrophage-depleted rats. Additionally, we evaluated the antigenic specificity of immunologic tolerance. Immunologic tolerance against PE developed after 21 days of consecutive daily injections or the fourth week of PE administration. Compared with a single administration, it was observed that the tolerant rats had a lower rate of PE clearance from the blood, which was independent of the stress response. In addition, weekly PE injections caused injury to the spleen. Furthermore, the rats tolerant to PEs with the methoxy group (-OCH3) of PEG, failed to respond to the PEs with a different terminal group of PEG or to non-PEG emulsions. Innate immunity tolerance was induced by PE, regardless of the mode of administration. Further study of this mechanism suggested that monocytes play an essential role in the suppression of innate immunity. These findings provide novel insights into the understanding of the innate immune system.

Show MeSH
Related in: MedlinePlus