Anti-tumor necrosis factor α F(ab')2 antibody fragments protect in murine polymicrobial sepsis: Concentration and early intervention are fundamental to the outcome

Abstract

These results suggest that in processes where excessive production of cytokines is involved, the aim should be to return them to their physiologically acting range but not to inhibit their production. The timing of initiating therapy should also be considered in order to maximize the possible benefits.

Enhanced survival from CLP-induced sepsis following late administration of low doses of anti-IFNγ F(ab′)2 antibody fragments

“…Consistent with our previous findings [10,26], TNF levels were found not to be elevated. This is not an odd result, since other groups have described the same phenomenon.…”

“…This could be explained by an excessive proinflammatory cytokine blockade by the higher doses, which in turn results in immunosuppression or even in enhancement of the anti-inflammatory cytokine network, similar to that seen in CARS; this suggests that the use of high doses of anti-cytokines to completely deplete circulating cytokines seems not to be the best strategy in the treatment of sepsis. In confirmation, we have reported that the administration of anti-TNF F(ab 0 ) 2 fragments at 10 mg/kg does not decrease mortality in murine CLP-induced sepsis; however, when it is used at doses of 1 mg/kg a significant decline in mortality is achieved [10].…”

“…Moreover, its direct infusion results in fever, neutrophilia, thrombocytosis, and acute-phase reactant production, but this cytokine itself is unable to induce shock [24]; hence, the exact role of IL-6 in the pathogenesis of sepsis remains unclear. In a previous report on the use of anti-TNF in a murine model of sepsis, survival was also related to increases in the concentration of IL-6, suggesting that this cytokine plays a major protective role in sepsis [10]. In this line of thought, the absence of IL-6 has been associated with higher circulating levels of TNF, IFNc, and granulocyte/monocyte colony stimulating factor (GM-CSF), while administration of rhIL-6 to healthy volunteers enhances plasmatic anti-inflammatory responses of IL-10, IL-1ra, and cortisol but not TNF [25].…”

“…There is growing evidence supporting the theory that therapeutic manipulation of cytokines strikingly decreases mortality in sepsis [5][6][7][8][9][10]. Almost all of these studies have focused on cytokines of the innate immunity.…”

C1 Inhibitor-Mediated Protection from Sepsis

“…Excessive production of these cytokines can result in dramatic pathologic sequelae, including a systemic capillary leak syndrome, tissue injury, shock, and fatal organ failure (6 -15). Evidence in mice, using the cecal ligation and puncture (CLP) 4 model, suggests that neutralization of TNF-␣ or IL-1␤ as a therapeutic approach was either ineffective (16,17) or, in one study, provided a modest benefit that was strain dependent, very sensitive to changes in dose, and effective only when given before CLP (18). In human sepsis, the anticytokine approach also has been ineffective (19 -21) or, in some instances, may have provided a slight, usually statistically insignificant, beneficial effect (22)(23)(24).…”