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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

Therapeutic treatment with anti-TLR2 and anti-TLR4 improve sepsis.Mice were treated with individual anti-TLR2 or anti-TLR4 antibodies 3 hours after the CLP procedure. Treatment with both antibodies in combination decreased the number of bacteria in the peritoneum (A) and serum (B) as well as the levels of TNF-α in the peritoneum (C) and serum (D) 6 hours after sepsis compared to the negative control isotype IgG antibody treatment (CLP). * p<0.05 between CLP and Sham groups. # p<0.05 between the antibody treatment and negative control isotype IgG treated-group. Horizontal bars in Fig 5A/5B represent median value. Antibody dose (1 mg/animal). Used 6 animals/group, except isotype IgG antibody treated group (n = 10). Missing points in Figs reflect number of bacteria below detection limit.
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pone.0132336.g005: Therapeutic treatment with anti-TLR2 and anti-TLR4 improve sepsis.Mice were treated with individual anti-TLR2 or anti-TLR4 antibodies 3 hours after the CLP procedure. Treatment with both antibodies in combination decreased the number of bacteria in the peritoneum (A) and serum (B) as well as the levels of TNF-α in the peritoneum (C) and serum (D) 6 hours after sepsis compared to the negative control isotype IgG antibody treatment (CLP). * p<0.05 between CLP and Sham groups. # p<0.05 between the antibody treatment and negative control isotype IgG treated-group. Horizontal bars in Fig 5A/5B represent median value. Antibody dose (1 mg/animal). Used 6 animals/group, except isotype IgG antibody treated group (n = 10). Missing points in Figs reflect number of bacteria below detection limit.

Mentions: As shown in Fig 1, therapeutic treatment with either mAb 3 h after CLP induction decreased lethality rates by approximately 50%. In the next set of experiments, the bacterial load and inflammatory parameters were analyzed for these therapeutic regimens. Treatment with either anti-TLR-2 or anti-TLR4 mAbs significantly decreased bacterial growth and spread at 6 h (Fig 5A and 5B) which was associated with significantly lower levels of TNF-α in the peritoneum and serum (Fig 5C and 5D). Therefore, either preventive or therapeutic treatment with either anti-TLR2 or anti-TLR4 mAbs, but not in combination, diminished local and systemic inflammatory responses and protected against polymicrobial sepsis.


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)

Therapeutic treatment with anti-TLR2 and anti-TLR4 improve sepsis.Mice were treated with individual anti-TLR2 or anti-TLR4 antibodies 3 hours after the CLP procedure. Treatment with both antibodies in combination decreased the number of bacteria in the peritoneum (A) and serum (B) as well as the levels of TNF-α in the peritoneum (C) and serum (D) 6 hours after sepsis compared to the negative control isotype IgG antibody treatment (CLP). * p<0.05 between CLP and Sham groups. # p<0.05 between the antibody treatment and negative control isotype IgG treated-group. Horizontal bars in Fig 5A/5B represent median value. Antibody dose (1 mg/animal). 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.g005: Therapeutic treatment with anti-TLR2 and anti-TLR4 improve sepsis.Mice were treated with individual anti-TLR2 or anti-TLR4 antibodies 3 hours after the CLP procedure. Treatment with both antibodies in combination decreased the number of bacteria in the peritoneum (A) and serum (B) as well as the levels of TNF-α in the peritoneum (C) and serum (D) 6 hours after sepsis compared to the negative control isotype IgG antibody treatment (CLP). * p<0.05 between CLP and Sham groups. # p<0.05 between the antibody treatment and negative control isotype IgG treated-group. Horizontal bars in Fig 5A/5B represent median value. Antibody dose (1 mg/animal). Used 6 animals/group, except isotype IgG antibody treated group (n = 10). Missing points in Figs reflect number of bacteria below detection limit.
Mentions: As shown in Fig 1, therapeutic treatment with either mAb 3 h after CLP induction decreased lethality rates by approximately 50%. In the next set of experiments, the bacterial load and inflammatory parameters were analyzed for these therapeutic regimens. Treatment with either anti-TLR-2 or anti-TLR4 mAbs significantly decreased bacterial growth and spread at 6 h (Fig 5A and 5B) which was associated with significantly lower levels of TNF-α in the peritoneum and serum (Fig 5C and 5D). Therefore, either preventive or therapeutic treatment with either anti-TLR2 or anti-TLR4 mAbs, but not in combination, diminished local and systemic inflammatory responses and protected against polymicrobial sepsis.

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