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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

Blockade of either TLR2 or TLR4 reduces TNF-α and CXCL1 levels after polymicrobial sepsis.Mice were pre-treated with individual or combined anti-TLR2 or anti-TLR4 antibodies (45 minutes before the CLP procedure). Single treatment resulted in lower levels of TNF-α and CXCL1 (A and B, respectively) in the peritoneal cavity (PL: peritoneum lavage) and in serum (C and D, respectively) 6 hours after sepsis compared to the negative control isotype IgG antibody treatment (black bar). The combined treatment with both anti-TLR2 and anti-TLR4 presented similar response compared to negative isotype IgG treated-group. * p<0.05 between the CLP and Sham groups. # p<0.05 between the antibody treatment groups and negative control isotype IgG treated-group. Antibody dose (1 mg/animal). Used 6 animals/group, except isotype IgG antibody treated group (n = 10).
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pone.0132336.g003: Blockade of either TLR2 or TLR4 reduces TNF-α and CXCL1 levels after polymicrobial sepsis.Mice were pre-treated with individual or combined anti-TLR2 or anti-TLR4 antibodies (45 minutes before the CLP procedure). Single treatment resulted in lower levels of TNF-α and CXCL1 (A and B, respectively) in the peritoneal cavity (PL: peritoneum lavage) and in serum (C and D, respectively) 6 hours after sepsis compared to the negative control isotype IgG antibody treatment (black bar). The combined treatment with both anti-TLR2 and anti-TLR4 presented similar response compared to negative isotype IgG treated-group. * p<0.05 between the CLP and Sham groups. # p<0.05 between the antibody treatment groups and negative control isotype IgG treated-group. Antibody dose (1 mg/animal). Used 6 animals/group, except isotype IgG antibody treated group (n = 10).

Mentions: Induction of CLP was accompanied by significant increases in the levels of TNF-α, IL-1β and the neutrophil-active chemokines CXCL1 (Fig 3A and 3B) and CXCL2 (data not shown) in the peritoneum at 6 h post surgery. Also, an increase in systemic levels of TNF-α and CXCL1 (Fig 3C and 3D) was observed. Pre-treatment with either anti-TLR2 or anti-TLR4 mAbs alone prevented the increase of these cytokines and chemokines (Fig 3). In contrast, combined pre-treatment with both mAbs tended to have little effect on the levels of inflammatory mediators, with the exception of a significant fall in the levels of TNF-α in serum (Fig 3), which may account for the small decrease of lethality observed (Fig 1).


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 reduces TNF-α and CXCL1 levels after polymicrobial sepsis.Mice were pre-treated with individual or combined anti-TLR2 or anti-TLR4 antibodies (45 minutes before the CLP procedure). Single treatment resulted in lower levels of TNF-α and CXCL1 (A and B, respectively) in the peritoneal cavity (PL: peritoneum lavage) and in serum (C and D, respectively) 6 hours after sepsis compared to the negative control isotype IgG antibody treatment (black bar). The combined treatment with both anti-TLR2 and anti-TLR4 presented similar response compared to negative isotype IgG treated-group. * p<0.05 between the CLP and Sham groups. # p<0.05 between the antibody treatment groups and negative control isotype IgG treated-group. Antibody dose (1 mg/animal). Used 6 animals/group, except isotype IgG antibody treated group (n = 10).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0132336.g003: Blockade of either TLR2 or TLR4 reduces TNF-α and CXCL1 levels after polymicrobial sepsis.Mice were pre-treated with individual or combined anti-TLR2 or anti-TLR4 antibodies (45 minutes before the CLP procedure). Single treatment resulted in lower levels of TNF-α and CXCL1 (A and B, respectively) in the peritoneal cavity (PL: peritoneum lavage) and in serum (C and D, respectively) 6 hours after sepsis compared to the negative control isotype IgG antibody treatment (black bar). The combined treatment with both anti-TLR2 and anti-TLR4 presented similar response compared to negative isotype IgG treated-group. * p<0.05 between the CLP and Sham groups. # p<0.05 between the antibody treatment groups and negative control isotype IgG treated-group. Antibody dose (1 mg/animal). Used 6 animals/group, except isotype IgG antibody treated group (n = 10).
Mentions: Induction of CLP was accompanied by significant increases in the levels of TNF-α, IL-1β and the neutrophil-active chemokines CXCL1 (Fig 3A and 3B) and CXCL2 (data not shown) in the peritoneum at 6 h post surgery. Also, an increase in systemic levels of TNF-α and CXCL1 (Fig 3C and 3D) was observed. Pre-treatment with either anti-TLR2 or anti-TLR4 mAbs alone prevented the increase of these cytokines and chemokines (Fig 3). In contrast, combined pre-treatment with both mAbs tended to have little effect on the levels of inflammatory mediators, with the exception of a significant fall in the levels of TNF-α in serum (Fig 3), which may account for the small decrease of lethality observed (Fig 1).

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