Inhibition of Splenic Macrophage Tumor Necrosis Factor α Secretion In Vivo by Antilipopolysaccharide Monoclonal Antibodies

Richard J. Battafarano, Randall S. Burd, Karla M. Kurrelmeyer, Craig A. Ratz, David L. Dunn

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Objective: This study tried to determine whether administration of antilipopolysaccharide (LPS) murine monoclonal antibody (mAb) 2A3 to mice was associated with (1) protective capacity during experimental gram-negative bacterial sepsis, and (2) inhibition of tumor necrosis factor α (TNF-α) secretion in the systemic circulation and at the tissue level during experimental infection. Design: Mice received an initial intravenous injection of either saline or 100 μg of anti-LPS mAb 2A3, and 1 hour later underwent intraperitoneal inoculation of viable Escherichia coli 0111:B4. Mortality was assessed daily for 7 days. Separate groups of mice were treated similarly and plasma TNF-α concentrations were determined from blood samples obtained at 1, 3, 6, 10, and 16 hours after infection by enzyme-linked immunosorbent assay. Concurrently, splenocytes harvested from animals 3, 10, and 16 hours after infection were incubated in culture ex vivo and supernatant TNF-α levels were determined. Results: Pretreatment with anti- LPS mAb 2A3 prior to an intraperitoneal challenge of live E coli 0111:B4 was associated with the following: (1) significant protective capacity (100% vs 0% mortality, P<.001); (2) inhibition of plasma TNF-α levels 16 hours after infection (1257 ± 323 pg/mL vs 292 ± 254 pg/mL, P<.001); and (3) abrogation of TNF-α secretion derived from splenic macrophages isolated 16 hours after bacterial challenge (229 ± 12 pg/mL vs 107 ± 48 pg/mL, p<.05). Conclusions: These results strongly support the contention that inhibition of LPS-induced TNF-α secretion at both the tissue and systemic levels is a key mechanism by which anti-LPS mAbs provide protection during gram-negative bacterial peritonitis. We believe that in vivo monitoring of macrophage cytokine secretion will be critical for elucidating the precise role of a variety of mediators in the pathogenesis of gram-negative bacterial sepsis.

Original languageEnglish (US)
Pages (from-to)179-186
Number of pages8
JournalArchives of Surgery
Volume129
Issue number2
DOIs
StatePublished - Feb 1994

ASJC Scopus subject areas

  • Surgery

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