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Prophylactic and therapeutic effects of a monoclonal antibody to tumor necrosis factor-alpha in experimental
A T Silva1, K F Bayston, J Cohen
1Department of Bacteriology, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom.
Abstract:
A monoclonal antibody to recombinant murine tumor necrosis factor-alpha (TNF alpha), TN3-19.12, was used to explore pathogenetic mechanisms and therapeutic strategies in gram-negative shock. In mice receiving an LD90 dose of Escherichia coli O111, TN3-19.12 prevented death if given 1.5 h before or 30 min after challenge. Less protection was conferred if the antibody was given 2.5 h after challenge. In control mice receiving an irrelevant antibody, L2-3D9, TNF alpha levels rose (less than or equal to 185.1 +/- 26.1 ng/ml) by 90 min and had returned to baseline by 5 h. Mice receiving TN3-19.12 did not have this response. TN3-19.12 was of limited benefit in mice receiving Pseudomonas aeruginosa but had no protective effect in cyclophosphamide-treated mice receiving Klebsiella pneumoniae. In L2-3D9-treated mice, TNF alpha levels were elevated to 61.8 +/- 27.9 and 49.7 +/- 5.1 ng/ml by 90 min in the two models, respectively. TNF alpha levels in TN3-19.12-treated mice in these two models were very low (3.9-5.5 ng/ml). TNF alpha is a mediator in gram-negative shock; antibody to TNF alpha can be of value in prophylaxis and treatment, but its clinical use remains to be established.
Insights
A monoclonal antibody targeting tumor necrosis factor-alpha (TNF alpha) showed protective effects against Escherichia coli-induced gram-negative shock in mice. Early administration of this TNF alpha antibody is crucial for therapeutic benefit.
Area of Science:
- Immunology
- Pathology
Background:
- Gram-negative shock is a life-threatening condition.
- Tumor necrosis factor-alpha (TNF alpha) is implicated as a key mediator in the pathogenesis of gram-negative shock.
Purpose of the Study:
- To investigate the pathogenetic mechanisms of gram-negative shock.
- To explore therapeutic strategies using a monoclonal antibody against TNF alpha.
Main Methods:
- Administration of a monoclonal antibody (TN3-19.12) targeting TNF alpha in murine models of gram-negative shock induced by Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae.
- Measurement of TNF alpha levels and survival rates in treated and control groups.
Main Results:
- TN3-19.12 significantly prevented death when administered before or shortly after Escherichia coli challenge.
- Antibody efficacy decreased with delayed administration.
- Limited benefit was observed with Pseudomonas aeruginosa, and no protection was seen with Klebsiella pneumoniae.
- TN3-19.12 effectively suppressed TNF alpha level elevations in response to bacterial challenge.
Conclusions:
- TNF alpha plays a critical role in the pathophysiology of gram-negative shock.
- Antibodies targeting TNF alpha demonstrate potential value in the prophylaxis and treatment of gram-negative shock.
- Further clinical studies are required to establish the efficacy and safety of TNF alpha antibodies in human patients.
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