Limits...
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

Blockade of either TLR2 or TLR4 improves inflammatory and infection indices in polymicrobial sepsis.Analysis of parameters of mice pre-treated (45 minutes before the CLP procedure) with individual anti-TLR2 or anti-TLR4 antibodies showed an increased neutrophil migration to the peritoneal cavity (A) and a decreased number of bacteria in peritoneum (B) and serum (C) 6 hours after sepsis compared to negative isotype IgG antibody treatment (black bar). The combined treatment with both anti-TLR2 and anti-TLR4 showed a similar inflammatory response compared to the negative control isotype IgG treated-group (CLP). * p<0.05 between the CLP and Sham groups. # p<0.05 between individual antibody treatments and negative control isotype IgG treated-group. Antibody dose (1 mg/animal). Horizontal bars in Fig 2A/2B represent median value. Used 6 animals/group, except isotype IgG antibody treated group (n = 10). Missing points in Figs reflect number of bacteria below detection limit.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4492955&req=5

pone.0132336.g002: Blockade of either TLR2 or TLR4 improves inflammatory and infection indices in polymicrobial sepsis.Analysis of parameters of mice pre-treated (45 minutes before the CLP procedure) with individual anti-TLR2 or anti-TLR4 antibodies showed an increased neutrophil migration to the peritoneal cavity (A) and a decreased number of bacteria in peritoneum (B) and serum (C) 6 hours after sepsis compared to negative isotype IgG antibody treatment (black bar). The combined treatment with both anti-TLR2 and anti-TLR4 showed a similar inflammatory response compared to the negative control isotype IgG treated-group (CLP). * p<0.05 between the CLP and Sham groups. # p<0.05 between individual antibody treatments and negative control isotype IgG treated-group. Antibody dose (1 mg/animal). Horizontal bars in Fig 2A/2B represent median value. Used 6 animals/group, except isotype IgG antibody treated group (n = 10). Missing points in Figs reflect number of bacteria below detection limit.

Mentions: Neutrophils play a crucial role in bacterial sepsis, as they have a series of effector functions that are relevant to bacterial clearance [20]. A previous study from our group has demonstrated that the failure of neutrophils to migrate early in response to an infectious challenge contributes substantially to the pathogenesis of polymicrobial sepsis induced by CLP [12]. Strategies which ameliorate neutrophil influx following CLP commonly induce better control of infection resulting in diminished lethality rates [20–22]. Pre-treatment of mice with either anti-TLR2 or anti-TLR4 resulted in an increase in the influx of neutrophils to the peritoneal cavity of mice subjected to severe CLP (Fig 2A). The increased neutrophil influx was associated with decreased numbers of bacteria in the peritoneal cavity (Fig 2B) and decreased spread of bacteria to the blood (Fig 2C). Co-treatment of mice with both mAbs prior to induction of CLP neither induced a significant increase in neutrophil accumulation nor altered bacterial growth in the peritoneal cavity, when compared to the control group (Fig 2A and 2B). Interestingly, there were significantly more bacteria in the blood of animals treated with the combination of anti-TLR2 and anti-TLR4 mAb than control antibody-treated animals (Fig 2C).


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)

Blockade of either TLR2 or TLR4 improves inflammatory and infection indices in polymicrobial sepsis.Analysis of parameters of mice pre-treated (45 minutes before the CLP procedure) with individual anti-TLR2 or anti-TLR4 antibodies showed an increased neutrophil migration to the peritoneal cavity (A) and a decreased number of bacteria in peritoneum (B) and serum (C) 6 hours after sepsis compared to negative isotype IgG antibody treatment (black bar). The combined treatment with both anti-TLR2 and anti-TLR4 showed a similar inflammatory response compared to the negative control isotype IgG treated-group (CLP). * p<0.05 between the CLP and Sham groups. # p<0.05 between individual antibody treatments and negative control isotype IgG treated-group. Antibody dose (1 mg/animal). Horizontal bars in Fig 2A/2B represent median value. Used 6 animals/group, except isotype IgG antibody treated group (n = 10). Missing points in Figs reflect number of bacteria below detection limit.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0132336.g002: Blockade of either TLR2 or TLR4 improves inflammatory and infection indices in polymicrobial sepsis.Analysis of parameters of mice pre-treated (45 minutes before the CLP procedure) with individual anti-TLR2 or anti-TLR4 antibodies showed an increased neutrophil migration to the peritoneal cavity (A) and a decreased number of bacteria in peritoneum (B) and serum (C) 6 hours after sepsis compared to negative isotype IgG antibody treatment (black bar). The combined treatment with both anti-TLR2 and anti-TLR4 showed a similar inflammatory response compared to the negative control isotype IgG treated-group (CLP). * p<0.05 between the CLP and Sham groups. # p<0.05 between individual antibody treatments and negative control isotype IgG treated-group. Antibody dose (1 mg/animal). Horizontal bars in Fig 2A/2B represent median value. Used 6 animals/group, except isotype IgG antibody treated group (n = 10). Missing points in Figs reflect number of bacteria below detection limit.
Mentions: Neutrophils play a crucial role in bacterial sepsis, as they have a series of effector functions that are relevant to bacterial clearance [20]. A previous study from our group has demonstrated that the failure of neutrophils to migrate early in response to an infectious challenge contributes substantially to the pathogenesis of polymicrobial sepsis induced by CLP [12]. Strategies which ameliorate neutrophil influx following CLP commonly induce better control of infection resulting in diminished lethality rates [20–22]. Pre-treatment of mice with either anti-TLR2 or anti-TLR4 resulted in an increase in the influx of neutrophils to the peritoneal cavity of mice subjected to severe CLP (Fig 2A). The increased neutrophil influx was associated with decreased numbers of bacteria in the peritoneal cavity (Fig 2B) and decreased spread of bacteria to the blood (Fig 2C). Co-treatment of mice with both mAbs prior to induction of CLP neither induced a significant increase in neutrophil accumulation nor altered bacterial growth in the peritoneal cavity, when compared to the control group (Fig 2A and 2B). Interestingly, there were significantly more bacteria in the blood of animals treated with the combination of anti-TLR2 and anti-TLR4 mAb than control antibody-treated animals (Fig 2C).

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