Thomas Hartung

Effect of filgrastim treatment on inflammatory cytokines and lymphocyte functions

Twenty‐four healthy male volunteers received either placebo or 75, 150, or 300 μg filgrastim (recombinant methionyl human granulocyte colony‐stimulating factor) for 12 days to study effects on monocytes and lymphocytes. In all filgrastim‐treated groups, tumor necrosis factor alpha (TNF‐α), interleukin‐12 (IL‐12), and interferon gamma (IFN‐γ) release by whole blood in response to endotoxin (lipopolysaccharide) was reduced. IL‐12 added in vitro to lipopolysaccharide‐stimulated blood of filgrastim‐treated donors restored IFN‐γ and TNF‐α release, suggesting that the anti‐inflammatory effect of granulocyte colony‐stimulating factor is exercised through IL‐12 suppression. Phytohemagglutinin‐ or anti‐CD3 antibody–induced lymphocyte proliferation ex vivo was reduced by 60% from day 5 to day 15, after a 50% increase at day 2 with concomitant doubled IL‐2 release. In vivo, filgrastim induced doubling of all T‐cell populations by day 8. Filgrastim decreased proinflammatory cytokine production and lymphocyte proliferation ex vivo throughout prolonged treatment at all doses. This indicates that endogenous granulocyte colony‐stimulating factor may counterregulate the inflammatory cytokine cascade and implies a potential indication for filgrastim in chronic inflammatory conditions.

Growth Factors G-CSF and GM-CSF : Clinical Options

The bodys immediate response to bacterial infection becomes clinically evident as an inflammatory reaction accompanied by an acute-phase response in the liver and hyperthermia. Activation of the immune system must be counterregulated to curb these processes and to prevent (or at least minimize) damage to the host tissue. The major part of this intricate regulation is performed by the cytokine mediator network, a relay of glycoprotein signals that first activate proliferation and host defense functions of immune cells and then control the return to a state of readiness when the infection is under control. Septic shock encompasses fulminant, and self-destructive activation of the defense system that is now understood as a systemic inflammatory reaction followed by multiple organ failure. This extreme activation of the nonspecific immune system is followed, provided the patient can be stabilized by intensive medical care, by corresponding massive counterreguxad lation. The patient, whose immune system is exhausted, is left almost defenseless in a state termed immune paralysis, or anergy. A patient in this state is particularly susceptible to lifexad threatening secondary infections. Granulocyte (G-CSF) and granulocyte/macrophage colonyxad stimulating factors (GM-CS!; (Table 64.1), central mediators of the endogenous response to infection and inflammation, have been cloned and are commercially available in forms approved for clinical use (Table 64.2). Both stimulate the proliferation and release of immune cells from the bone marrow, and so they were originally approved for the treatment of leukopenia. G-CSF, when given prophylactically or as substitution in situations of deficiency, has also been attributed with improved host defense paired with antiinflammatory effects. GM-CSF, on the other hand, is considered a potent immunostimulator and proinflamxad matory agent. Evidence from many animal studies and some clinical studies suggests that prophylactic treatment with G-CSF at the time a risk can be anticipated, such as before an operation, may offer protection from infections and lower the incidence of sepsis. GM-CSF therapy may find a place in reactivating the immune system of patients in a state of immune paralysis following septic shock, thereby reinforcing the patients impaired defense system against secondary infections. (See Table 64.3 for approved and experimental indications.)