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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 improves survival during polymicrobial sepsis.The survival rate was analyzed following CLP procedure comparing the effect of the treatment with isolated or combined anti-TLR2 and anti-TLR4 antibodies. The treatments were performed 45 minutes before (A) or 3 hours after (B) the CLP procedure. The combined treatment with both anti-TLR2 and anti-TLR4 showed a similar survival curve compared to the negative control isotype IgG treated-group (CLP) * P<0.001 between Individual antibody treatments and negative control (IgG). # p<0.05 between individual antibody treatments and negative control (IgG) Antibody dose (1 mg/animal). (n = 10/group).
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pone.0132336.g001: Blockade of either TLR2 or TLR4 improves survival during polymicrobial sepsis.The survival rate was analyzed following CLP procedure comparing the effect of the treatment with isolated or combined anti-TLR2 and anti-TLR4 antibodies. The treatments were performed 45 minutes before (A) or 3 hours after (B) the CLP procedure. The combined treatment with both anti-TLR2 and anti-TLR4 showed a similar survival curve compared to the negative control isotype IgG treated-group (CLP) * P<0.001 between Individual antibody treatments and negative control (IgG). # p<0.05 between individual antibody treatments and negative control (IgG) Antibody dose (1 mg/animal). (n = 10/group).

Mentions: Preventive treatment with mAbs targeting either TLR2 (T2.5) or TLR4 (1A6) caused a significant improvement in the survival rate during severe sepsis (Fig 1A) compared to the isotype control group, where 100% of the mice subjected to CLP succumbed within 24 hours. Mice pre-treated (45 minutes before CLP) with either antibody had significantly enhanced survival rates, with 75 and 65% survival after treatment with anti-TLR2 or anti-TLR4, respectively (Fig 1A). Therapeutic administration of either anti-TLR2 or anti-TLR4, i.e., 3 hours after the CLP procedure, also provided significant protective effects with delayed lethality and approximately 50% protection (Fig 1B). Of note, in this particular experiment, approximately 50% of control antibody-treated mice succumbed 12 h after CLP. Paradoxically, when both antibodies were administered simultaneously to mice subjected to CLP, either prophylactically or therapeutically, there was only partial protection which was significantly lower than that afforded by either antibody given alone (Fig 1). A series of experiments were then conducted to evaluate the effects of individual or combined pretreatment with antibodies on inflammatory and infection indices induced by CLP.


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 survival during polymicrobial sepsis.The survival rate was analyzed following CLP procedure comparing the effect of the treatment with isolated or combined anti-TLR2 and anti-TLR4 antibodies. The treatments were performed 45 minutes before (A) or 3 hours after (B) the CLP procedure. The combined treatment with both anti-TLR2 and anti-TLR4 showed a similar survival curve compared to the negative control isotype IgG treated-group (CLP) * P<0.001 between Individual antibody treatments and negative control (IgG). # p<0.05 between individual antibody treatments and negative control (IgG) Antibody dose (1 mg/animal). (n = 10/group).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0132336.g001: Blockade of either TLR2 or TLR4 improves survival during polymicrobial sepsis.The survival rate was analyzed following CLP procedure comparing the effect of the treatment with isolated or combined anti-TLR2 and anti-TLR4 antibodies. The treatments were performed 45 minutes before (A) or 3 hours after (B) the CLP procedure. The combined treatment with both anti-TLR2 and anti-TLR4 showed a similar survival curve compared to the negative control isotype IgG treated-group (CLP) * P<0.001 between Individual antibody treatments and negative control (IgG). # p<0.05 between individual antibody treatments and negative control (IgG) Antibody dose (1 mg/animal). (n = 10/group).
Mentions: Preventive treatment with mAbs targeting either TLR2 (T2.5) or TLR4 (1A6) caused a significant improvement in the survival rate during severe sepsis (Fig 1A) compared to the isotype control group, where 100% of the mice subjected to CLP succumbed within 24 hours. Mice pre-treated (45 minutes before CLP) with either antibody had significantly enhanced survival rates, with 75 and 65% survival after treatment with anti-TLR2 or anti-TLR4, respectively (Fig 1A). Therapeutic administration of either anti-TLR2 or anti-TLR4, i.e., 3 hours after the CLP procedure, also provided significant protective effects with delayed lethality and approximately 50% protection (Fig 1B). Of note, in this particular experiment, approximately 50% of control antibody-treated mice succumbed 12 h after CLP. Paradoxically, when both antibodies were administered simultaneously to mice subjected to CLP, either prophylactically or therapeutically, there was only partial protection which was significantly lower than that afforded by either antibody given alone (Fig 1). A series of experiments were then conducted to evaluate the effects of individual or combined pretreatment with antibodies on inflammatory and infection indices induced by CLP.

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