Differential Effect of Human and Murine Polyclonal and Monoclonal Antisera on TNF-α Production by Human Monocytes

Abstract

The capacity of human and murine polyclonal and monoclonal antibodies to inhibit lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-alpha) release from human monocytes was investigated. Human pooled immunoglobulin G (IVIG), human IgM monoclonal antibody (HA-1A) directed against the lipid A moiety of LPS, and murine IgG monoclonal antibody (MT-1F) raised in mice against antibiotic-treated Escherichia coli O6:K- were either added simultaneously with LPS to monocytes or preincubated for 1 h at 37 degrees C before being added to monocytes. TNF-alpha content in the monocyte supernatants was then tested. Simultaneous addition of increasing concentrations of IVIG (from 0.3 to 2.5 mg/ml) and 10 micrograms/ml of LPS to monocytes induced an enhanced release of TNF-alpha by monocytes in a dose dependent fashion. Preincubation of IVIG with LPS abolished the additive effect, but did not inhibit LPS-induced TNF-alpha release by monocytes. The simultaneous addition of LPS and HA-1A to monocytes had no additive effect nor did it inhibit TNF-alpha release. On the other hand, inhibition of TNF-alpha release was observed when HA-1A was preincubated with LPS before being added to monocytes. In all instances MT-1F inhibited TNF-alpha release when the monocytes were stimulated with smooth type LPS, but not with LPS isolated from rough mutants.

Monoclonal Antibody Clearance

“…aggregation) of the WT or variant anti-TNF␣ molecules that could potentially modulate clearance (data not shown), it is not clear what alternative mechanisms could be involved in clearance in the primate. Because TNF␣ exists as a very small pool in normal animals (26,42,43), it is unlikely that clearance is driven by binding to antigen or clearance of antigen-antibody complex. However, the possibility that a nonspecific binding mechanism contributes disproportionately to the clearance of the anti-TNF␣ mAb in primates and masks the potential benefit of improved FcRn binding cannot be excluded.…”

IgM‐enriched solution BT086 improves host defense capacity and energy store preservation in a rabbit model of endotoxemia

“…12,23 The rationale for enrichment of IVIGs with IgM-type immunoglobulins is the unique ability of IgM to neutralize LPS in the early stage of antibodydependent host defense. 12 Specifically, IgM contributes to the opsonization of bacteria, 7 inhibits the LPS-triggered release of TNFa in mono- cytes, 6 and stimulates the production of antibodies against LPS, 7 which is one of the key activators of the complex anti-inflammatory cascade. 12,24 In this study, we evaluated an IVIG solution with an increased portion of IgM.…”

“…5 The IgM component of IVIG, in particular, appears to be critical for these properties. 6,7 The beneficial pathobiochemical effects of IVIG have been previously described. 8,9 The role of sepsis therapy using traditional IgGenriched IVIGs for improving survival in severe sepsis and septic shock in humans remains controversial.…”

“…Intravenous immunoglobulin (IVIG) has the potential to scavenge and neutralize endotoxins, which reduces the overall pro‐inflammatory reaction 5. The IgM component of IVIG, in particular, appears to be critical for these properties 6, 7…”