Limits...
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.

Show MeSH

Related in: MedlinePlus

The summary of the findings and possible mechanisms associated with innate immune tolerance with PE.Note: PE-n represents the nth-week PE injection, n days represent the nth-day PE injection.Abbreviations: PE, PEGylated emulsion; PEG, polyethylene glycol.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4128795&req=5

f9-ijn-9-3645: The summary of the findings and possible mechanisms associated with innate immune tolerance with PE.Note: PE-n represents the nth-week PE injection, n days represent the nth-day PE injection.Abbreviations: PE, PEGylated emulsion; PEG, polyethylene glycol.

Mentions: In the present study, we first proposed that innate immunity tolerance was induced by the consecutive injections and weekly administrations of PE in rats (Figure 9). This generalized tolerance feature of the innate immune system is defined as decreased recognition and clearance of invading pathogens, even of the infectious and inflammatory diseases. The results reported here provide a novel insight into the understanding of the relationship between innate and adaptive immune systems and further supplement the classical theory of immunology. Furthermore, our results have potential implications for the clinical application of PEs. The unexpected inhibition of the innate immune system was undesirable. The induced innate immunity tolerance has a marked effect on PE, even conventional fat emulsions in clinical situations, and the decreased blood clearance of the drug formulations can compromise their safety and therapeutic efficacy. In addition, if emulsions contain toxic drugs with a small therapeutic window, the increased concentration in the blood could cause adverse systemic toxicity. The immunologic tolerance was a key mechanism for maintaining the stability of the body based on antigen-specific and immune memory. The possible suppression of the innate immunity function led to a risk of infection, which is a negative effect for the treatment of diseases. The dysfunction of the immune system was the direct cause of the induced infectious disease or tumors.40,41 These findings may provide new perspectives regarding our understanding of the clinical application of PE.


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 summary of the findings and possible mechanisms associated with innate immune tolerance with PE.Note: PE-n represents the nth-week PE injection, n days represent the nth-day PE injection.Abbreviations: PE, PEGylated emulsion; PEG, polyethylene glycol.
© Copyright Policy
Related In: Results  -  Collection

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

f9-ijn-9-3645: The summary of the findings and possible mechanisms associated with innate immune tolerance with PE.Note: PE-n represents the nth-week PE injection, n days represent the nth-day PE injection.Abbreviations: PE, PEGylated emulsion; PEG, polyethylene glycol.
Mentions: In the present study, we first proposed that innate immunity tolerance was induced by the consecutive injections and weekly administrations of PE in rats (Figure 9). This generalized tolerance feature of the innate immune system is defined as decreased recognition and clearance of invading pathogens, even of the infectious and inflammatory diseases. The results reported here provide a novel insight into the understanding of the relationship between innate and adaptive immune systems and further supplement the classical theory of immunology. Furthermore, our results have potential implications for the clinical application of PEs. The unexpected inhibition of the innate immune system was undesirable. The induced innate immunity tolerance has a marked effect on PE, even conventional fat emulsions in clinical situations, and the decreased blood clearance of the drug formulations can compromise their safety and therapeutic efficacy. In addition, if emulsions contain toxic drugs with a small therapeutic window, the increased concentration in the blood could cause adverse systemic toxicity. The immunologic tolerance was a key mechanism for maintaining the stability of the body based on antigen-specific and immune memory. The possible suppression of the innate immunity function led to a risk of infection, which is a negative effect for the treatment of diseases. The dysfunction of the immune system was the direct cause of the induced infectious disease or tumors.40,41 These findings may provide new perspectives regarding our understanding of the clinical application of PE.

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