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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 lung inflammation 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 (A), IL-1β (B), CXCL1 (C) and myeloperoxidase in the lung 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 showed moderate improvement when compared to the control treatment-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.g004: Blockade of either TLR2 or TLR4 reduces lung inflammation 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 (A), IL-1β (B), CXCL1 (C) and myeloperoxidase in the lung 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 showed moderate improvement when compared to the control treatment-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: Inflammatory parameters in the lung, the target organ most commonly affected by systemic inflammatory responses [23], were also evaluated. Pre-treatment with either anti-TLR2 or anti-TLR4 mAbs diminished inflammation in the lung, as seen by the local production of IL-1β, TNF-α, and CXCL1, as well as the local accumulation of neutrophils (Fig 4). Again, and in contrast to the effects of individual treatment, combined pre-treatment with anti-TLR2 and anti-TLR4 mAbs failed to ameliorate pulmonary inflammation (Fig 4).


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 lung inflammation 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 (A), IL-1β (B), CXCL1 (C) and myeloperoxidase in the lung 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 showed moderate improvement when compared to the control treatment-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.g004: Blockade of either TLR2 or TLR4 reduces lung inflammation 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 (A), IL-1β (B), CXCL1 (C) and myeloperoxidase in the lung 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 showed moderate improvement when compared to the control treatment-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: Inflammatory parameters in the lung, the target organ most commonly affected by systemic inflammatory responses [23], were also evaluated. Pre-treatment with either anti-TLR2 or anti-TLR4 mAbs diminished inflammation in the lung, as seen by the local production of IL-1β, TNF-α, and CXCL1, as well as the local accumulation of neutrophils (Fig 4). Again, and in contrast to the effects of individual treatment, combined pre-treatment with anti-TLR2 and anti-TLR4 mAbs failed to ameliorate pulmonary inflammation (Fig 4).

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