Potentia Hazards of Combination Immunotherapy in the Treatment of Experimental Septic Shock

Abstract

Using an actual infection model of Pseudomonas aeruginosa sepsis in neutropenic rats, the potential utility of a combination anticytokine approach for the treatment of sepsis was tested. A dimeric tumor necrosis factor binding protein (TNF-BP) consisting of two soluble recombinant human TNF type 1 receptors linked with polyethylene glycol was used with recombinant human interleukin-1 receptor antagonist (IL-1ra). Despite having levels of bacteremia and endotoxemia similar to the control group (survivors, 0/18), 30% of IL-1ra-treated animals survived (P < .05); 31% of TNF-BP-treated animals survived (P < .01). Unexpectedly, the combination of IL-1ra plus TNF-BP proved to be uniformly fatal (survivors, 0/20). Endotoxin (P < .0001) and bacteremia (P < .01) levels were >10-fold higher than levels in animals treated with IL-1ra alone, TNF-BP alone, or placebo. Disseminated microabscesses in major organs were found in animals treated with combination immunotherapy. Combination anticytokine therapy may exacerbate systemic infection and worsen outcome in experimental sepsis.

Recombinant Human Interleukin‐11 Has Anti‐inflammatory Actions Yet Does Not Exacerbate SystemicListeriaInfection

“…Despite the difficulty in measuring systemic levels of TNF in the animals, the removal of TNF activity greatly exacerbated L. monocytogenes infection. These observations were previously observed with inhibitors of TNF [7] and with other inhibitors of the proinflammatory immune response [8][9][10]. The increase in colony counts in the anti-IL-11 MAb group remains unexplained and is the focus of further investigation.…”

“…Inhibition of tumor necrosis factor (TNF) [7], IL-1 activity [8], combinations of inhibitors [9], and administration of other antiinflammatory cytokines [10] can potentiate systemic infections.…”

First-Generation Adenovirus Vectors Shorten Survival Time in a Murine Model of Sepsis

“…Many studies have focused on techniques to reduce systemic TNF-␣ in the setting of sepsis, in that it is likely an early contributor to systemic injury (41,45). However, techniques that limit the immune response in sepsis may render the patient more susceptible to infection (46,47).…”

Pneumonia Models and Innate Immunity to Respiratory Bacterial Pathogens

“…TNF receptor I-and IL-1 receptor-deficient mice demonstrated improved bacterial clearance after induction of P. aeruginosa pneumonia (44,45). Likewise, the outcome in neutropenic rats suffering from P. aeruginosa sepsis significantly improved after treatment with IL-1ra or TNF-binding protein (46). Of great interest, the combination of IL-1ra and TNF-binding protein not only worsened outcome of septic rats, but was also associated with diffuse bacterial microabscesses throughout the lungs (46).…”