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Therapeutic Effects of Treatment with Anti-TLR2 and Anti-TLR4 Monoclonal Antibodies in Polymicrobial Sepsis.

Lima CX, Souza DG, Amaral FA, Fagundes CT, Rodrigues IP, Alves-Filho JC, Kosco-Vilbois M, Ferlin W, Shang L, Elson G, Teixeira MM - PLoS ONE (2015)

Bottom Line: Pre-treatment with anti-TLR2 or anti-TLR4 mAb alone showed significant protection from sepsis-associated death.Delayed administration of either mAb in combination with antibiotics resulted in additive protection.Although attempts to translate preclinical findings to clinical sepsis have failed so far, our preclinical experiments strongly suggest that there is a sufficient therapeutic window within which patients with ongoing sepsis could benefit from combined antibiotic plus anti-TLR2 or anti-TLR4 mAb treatment.

View Article: PubMed Central - PubMed

Affiliation: Faculdade de Medicina, Universidade Federal de Minas Gerais, Av. Prof. Alfredo Balena 190, sala 203, 30130-100, Belo Horizonte, MG, Brasil.

ABSTRACT

Introduction: Toll-like receptors (TLRs) play an important role in the recognition of microbial products and in host defense against infection. However, the massive release of inflammatory mediators into the bloodstream following TLR activation following sepsis is thought to contribute to disease pathogenesis.

Methods: Here, we evaluated the effects of preventive or therapeutic administration of monoclonal antibodies (mAbs) targeting either TLR2 or TLR4 in a model of severe polymicrobial sepsis induced by cecal ligation and puncture in mice.

Results: Pre-treatment with anti-TLR2 or anti-TLR4 mAb alone showed significant protection from sepsis-associated death. Protective effects were observed even when the administration of either anti-TLR2 or anti-TLR4 alone was delayed (i.e., 3 h after sepsis induction). Delayed administration of either mAb in combination with antibiotics resulted in additive protection.

Conclusion: Although attempts to translate preclinical findings to clinical sepsis have failed so far, our preclinical experiments strongly suggest that there is a sufficient therapeutic window within which patients with ongoing sepsis could benefit from combined antibiotic plus anti-TLR2 or anti-TLR4 mAb treatment.

No MeSH data available.


Related in: MedlinePlus

Combined effects of anti-TLR2, anti-TLR4 and antibiotics in polymicrobial sepsis.Mice were therapeutically treated with anti-TLR2, anti-TLR4 and antibiotics (metronidazole and ceftriaxone) separately or concomitantly 3 hours after the CLP procedure. The negative control isotype IgG antibody treatment was used as a control. n = 9–10 in each experimental group. * p<0.001 between use of the antibodies plus antibiotics and isotype IgG control and p<0.05 between individual use of antibodies or antibiotics. # p<0.05 between individual antibodies or antibiotics use and isotype IgG control. There was no difference in survival rates between mice given antibodies and antibiotics and the sham group (n = 10 animals/group). Antibody doses (1 mg/animal).
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pone.0132336.g006: Combined effects of anti-TLR2, anti-TLR4 and antibiotics in polymicrobial sepsis.Mice were therapeutically treated with anti-TLR2, anti-TLR4 and antibiotics (metronidazole and ceftriaxone) separately or concomitantly 3 hours after the CLP procedure. The negative control isotype IgG antibody treatment was used as a control. n = 9–10 in each experimental group. * p<0.001 between use of the antibodies plus antibiotics and isotype IgG control and p<0.05 between individual use of antibodies or antibiotics. # p<0.05 between individual antibodies or antibiotics use and isotype IgG control. There was no difference in survival rates between mice given antibodies and antibiotics and the sham group (n = 10 animals/group). Antibody doses (1 mg/animal).

Mentions: In the clinical situation, aggressive antibiotic therapy directed to the potential site of infection and initiated as soon as possible following diagnosis is recommended to treat septic patients [24]. In order to model this, antibiotics (metronidazole and ceftriaxone) were administered at different times (1, 3, 6, 12 and 24 h) post-induction of sepsis either alone or in combination with the various mAbs. A substantial protection was evident if treatments were administered until 3h after sepsis induction. Treatment after 3 h of sepsis initiation did not protect animals significantly (data not shown). As shown in Fig 6, antibiotic treatment alone decreased lethality rates to approximately 40%. These results were similar to those obtained with anti-TLR2 or anti-TLR4 mAbs alone in the absence of antibiotics (see Fig 1). The combination of antibiotics with anti-TLR2 or anti-TLR4 mAbs resulted in greater protection with approximately 75% of animals surviving at day-5 post-CLP induction (Fig 6). Interestingly, the combination of anti-TLR2 and anti-TLR4 mAbs in the presence of antibiotics also resulted in significant protection (75%) (Fig 6), which was in stark contrast to that observed in the absence of antibiotics (Fig 1). Overall, it is clear that administration of antibiotics with one of the antibodies (anti-TLR2 or anti-TLR4) provides better than or similar protection to administration antibiotics with both antibodies together. Delayed treatment also affected neutrophil recruitment; suggesting reversal of neutrophil paralysis is relevant for the mechanism of action of these molecules (data not shown).


Therapeutic Effects of Treatment with Anti-TLR2 and Anti-TLR4 Monoclonal Antibodies in Polymicrobial Sepsis.

Lima CX, Souza DG, Amaral FA, Fagundes CT, Rodrigues IP, Alves-Filho JC, Kosco-Vilbois M, Ferlin W, Shang L, Elson G, Teixeira MM - PLoS ONE (2015)

Combined effects of anti-TLR2, anti-TLR4 and antibiotics in polymicrobial sepsis.Mice were therapeutically treated with anti-TLR2, anti-TLR4 and antibiotics (metronidazole and ceftriaxone) separately or concomitantly 3 hours after the CLP procedure. The negative control isotype IgG antibody treatment was used as a control. n = 9–10 in each experimental group. * p<0.001 between use of the antibodies plus antibiotics and isotype IgG control and p<0.05 between individual use of antibodies or antibiotics. # p<0.05 between individual antibodies or antibiotics use and isotype IgG control. There was no difference in survival rates between mice given antibodies and antibiotics and the sham group (n = 10 animals/group). Antibody doses (1 mg/animal).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492955&req=5

pone.0132336.g006: Combined effects of anti-TLR2, anti-TLR4 and antibiotics in polymicrobial sepsis.Mice were therapeutically treated with anti-TLR2, anti-TLR4 and antibiotics (metronidazole and ceftriaxone) separately or concomitantly 3 hours after the CLP procedure. The negative control isotype IgG antibody treatment was used as a control. n = 9–10 in each experimental group. * p<0.001 between use of the antibodies plus antibiotics and isotype IgG control and p<0.05 between individual use of antibodies or antibiotics. # p<0.05 between individual antibodies or antibiotics use and isotype IgG control. There was no difference in survival rates between mice given antibodies and antibiotics and the sham group (n = 10 animals/group). Antibody doses (1 mg/animal).
Mentions: In the clinical situation, aggressive antibiotic therapy directed to the potential site of infection and initiated as soon as possible following diagnosis is recommended to treat septic patients [24]. In order to model this, antibiotics (metronidazole and ceftriaxone) were administered at different times (1, 3, 6, 12 and 24 h) post-induction of sepsis either alone or in combination with the various mAbs. A substantial protection was evident if treatments were administered until 3h after sepsis induction. Treatment after 3 h of sepsis initiation did not protect animals significantly (data not shown). As shown in Fig 6, antibiotic treatment alone decreased lethality rates to approximately 40%. These results were similar to those obtained with anti-TLR2 or anti-TLR4 mAbs alone in the absence of antibiotics (see Fig 1). The combination of antibiotics with anti-TLR2 or anti-TLR4 mAbs resulted in greater protection with approximately 75% of animals surviving at day-5 post-CLP induction (Fig 6). Interestingly, the combination of anti-TLR2 and anti-TLR4 mAbs in the presence of antibiotics also resulted in significant protection (75%) (Fig 6), which was in stark contrast to that observed in the absence of antibiotics (Fig 1). Overall, it is clear that administration of antibiotics with one of the antibodies (anti-TLR2 or anti-TLR4) provides better than or similar protection to administration antibiotics with both antibodies together. Delayed treatment also affected neutrophil recruitment; suggesting reversal of neutrophil paralysis is relevant for the mechanism of action of these molecules (data not shown).

Bottom Line: Pre-treatment with anti-TLR2 or anti-TLR4 mAb alone showed significant protection from sepsis-associated death.Delayed administration of either mAb in combination with antibiotics resulted in additive protection.Although attempts to translate preclinical findings to clinical sepsis have failed so far, our preclinical experiments strongly suggest that there is a sufficient therapeutic window within which patients with ongoing sepsis could benefit from combined antibiotic plus anti-TLR2 or anti-TLR4 mAb treatment.

View Article: PubMed Central - PubMed

Affiliation: Faculdade de Medicina, Universidade Federal de Minas Gerais, Av. Prof. Alfredo Balena 190, sala 203, 30130-100, Belo Horizonte, MG, Brasil.

ABSTRACT

Introduction: Toll-like receptors (TLRs) play an important role in the recognition of microbial products and in host defense against infection. However, the massive release of inflammatory mediators into the bloodstream following TLR activation following sepsis is thought to contribute to disease pathogenesis.

Methods: Here, we evaluated the effects of preventive or therapeutic administration of monoclonal antibodies (mAbs) targeting either TLR2 or TLR4 in a model of severe polymicrobial sepsis induced by cecal ligation and puncture in mice.

Results: Pre-treatment with anti-TLR2 or anti-TLR4 mAb alone showed significant protection from sepsis-associated death. Protective effects were observed even when the administration of either anti-TLR2 or anti-TLR4 alone was delayed (i.e., 3 h after sepsis induction). Delayed administration of either mAb in combination with antibiotics resulted in additive protection.

Conclusion: Although attempts to translate preclinical findings to clinical sepsis have failed so far, our preclinical experiments strongly suggest that there is a sufficient therapeutic window within which patients with ongoing sepsis could benefit from combined antibiotic plus anti-TLR2 or anti-TLR4 mAb treatment.

No MeSH data available.


Related in: MedlinePlus