MONOCYTE DEACTIVATION IN SEPTIC PATIENTS - RESTORATION BY IFN-GAMMA TREATMENT

Neutralization of proinflammatory cytokines, such as tumor necrosis fa ctor-alpha. (TNF-alpha) or interleukin-1 (IL-1), decreases mortality i n several animal models of sepsis. However, recent clinical trials did not show an unequivocal improvement in survival. In contrast to anima ls, which succumb to shock during the first 72 hours, we found that ma ny patients die much later with signs of opportunistic infections acco mpanied by downregulation of their monocytic HLA-DR expression and red uced ability to produce lipopolysaccharide (LPS)-induced TNF-alpha in vitro(1-3). This phenomenon of monocyte deactivation in septic patient s with fatal outcome shows similarities to experimental monocytic refr actoriness induced by LPS desensitization or by pretreatment with its endogenous mediators IL-10 and transforming growth factor-beta (TCF-be ta)(4). In order to strengthen their antimicrobial defense, here we te sted whether interferon-gamma (IFN-gamma) can improve monocytic functi ons in these patients and in experimental monocytic deactivation. The considerably lowered in vitro levels of LPS-induced TNF-alpha in these situations were significantly enhanced by IFN-gamma, but did not reac h the extremely high levels of IFN-gamma primed naive cells from healt hy donors. Moreover, IFN-gamma applied to septic patients with low mon ocytic HLA-DR expression restored the deficient HLA-DR expression and in vitro LPS-induced TNF-alpha secretion. Recovery of monocyte functio n resulted in clearance of sepsis in eight of nine patients. These dat a suggest that IFN-gamma treatment in carefully selected septic patien ts is a novel therapeutic strategy worth pursuing.