ABSTRACT
This chapter discusses the exception of the phase III study of the Roche tumor necrosis factor (TNF) Receptor-IgG1:Fc, which is still underway, all the major clinical studies of immunomodulators in sepsis have failed. Infections begin when bacteria penetrate host barriers such as skin and mucosa, sometimes overwhelming host defenses and releasing toxic bacterial products that activate plasma factors as well as cells of the immune system. Central to the process was the discovery that macrophages and polymorphonuclear leukocytes activated by lipopolysaccharide (LPS) release numerous mediators by the interaction of LPS with the CD 14 receptor, a process influenced by LPS-binding protein. Among pro-inflammatory cytokines, TNF stands as the most toxic molecule, and the pioneering work of Beutler and colleagues has opened a new avenue in the limited repertoire of therapies for septic shock, since this work was the first demonstration that anticytokine therapies might be a useful approach to treat the disease.
