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Evaluation of microspheres containing cytokine neutralizing antibodies in endotoxemia
M J D'Souza1, C W Oettinger, G V Milton
1Department of Pharmaceutical Sciences, Southern School of Pharmacy, Mercer University, Atlanta, Georgia, USA.
Abstract:
Albumin microspheres are efficient carriers for delivering therapeutic agents to macrophages. In response to endotoxin, macrophages release tumor necrosis factor alpha (TNF alpha) and interleukin-1-beta (IL-1 beta). Blocking the effects of TNF alpha and IL-1 beta decreased lethality due to endotoxin-induced shock. In this study, we compared the efficacy of the microsphere form of TNF alpha and/or IL-1 beta neutralizing antibodies (NAs) with the free form of TNF alpha and/or IL-1 beta NA in preventing lethality due to endotoxemia and evaluated the duration of blockade by the microsphere form of TNF alpha and/or IL-1 beta NA on endotoxin-induced cytokine release. The results indicate that the microsphere form of TNF alpha and/or IL-1 beta NA protected 80% of the rats from lethal endotoxemia, while none of the rats that received the free from of TNF beta and/or IL-1 beta NA survived longer than 48 hr. The microsphere form of TNF alpha and/or IL-1 beta NA attenuated endotoxin-induced cytokine release more potently than the free form of TNF alpha and/or IL-1 beta NA in vivo. In vitro, the microsphere form of TNF alpha and/or IL-1 beta NA blocked endotoxin-induced cytokine release for at least 24 hr. Higher efficacy of the microsphere form of NA in reducing mortality and blocking cytokine release makes it more therapeutically advantageous than the free form of NA in the treatment of lethal endotoxemia.
Insights
Albumin microspheres carrying neutralizing antibodies (NAs) effectively protected rats from lethal endotoxemia by blocking tumor necrosis factor alpha and interleukin-1 beta. This microsphere delivery system offers a significant therapeutic advantage over free NAs for treating endotoxic shock.
Area of Science:
- Immunology
- Pharmacology
- Biotechnology
Background:
- Macrophages release tumor necrosis factor alpha (TNF α) and interleukin-1 beta (IL-1 β) in response to endotoxin.
- Blocking TNF α and IL-1 β reduces lethality in endotoxin-induced shock.
- Albumin microspheres are effective carriers for delivering therapeutic agents to macrophages.
Purpose of the Study:
- To compare the efficacy of microsphere-encapsulated TNF α and/or IL-1 β neutralizing antibodies (NAs) against free NAs in preventing endotoxemia lethality.
- To evaluate the duration of cytokine blockade by microsphere-form NAs in endotoxin-induced cytokine release.
Main Methods:
- Comparison of microsphere-form NAs versus free NAs in a rat model of lethal endotoxemia.
- In vivo and in vitro assessment of endotoxin-induced cytokine release.
- Evaluation of animal survival rates and duration of cytokine blockade.
Main Results:
- Microsphere-form NAs protected 80% of rats from lethal endotoxemia, while free NAs showed no survival benefit beyond 48 hours.
- Microsphere-form NAs more potently attenuated endotoxin-induced cytokine release in vivo compared to free NAs.
- In vitro, microsphere-form NAs blocked endotoxin-induced cytokine release for at least 24 hours.
Conclusions:
- Microsphere-encapsulated TNF α and/or IL-1 β NAs demonstrate superior efficacy in reducing mortality during lethal endotoxemia.
- The microsphere delivery system provides a more therapeutically advantageous approach for blocking endotoxin-induced cytokine release compared to free NAs.