Jos W. M. van der Meer

Recombinant Murine Granulocyte Colony-Stimulating Factor Protects against Acute Disseminated Candida albicans Infection in Nonneutropenic Mice

The effect of recombinant granulocyte colony-stimulating factor (rG-CSF) on acute disseminated Candida albicans infection in nonneutropenic mice was investigated. Mice treated with a single dose of rG-CSF showed a significantly reduced mortality (28% vs. 90%; P < .001). The outgrowth of C. albicans from the kidneys, spleens, and livers of rG-CSF-treated mice was significantly reduced (log cfu/g of kidney, 5.54 vs. 7.13; P < .001), as were circulating tumor necrosis factor-alpha and interleukin-1beta. After rG-CSF, the kidneys showed fewer infectious infiltrates, enhanced granulocyte influx, and almost complete absence of hyphal outgrowth. During peritoneal C. albicans infection, rG-CSF enhanced influx of granulocytes to the site of infection, and exudate granulocytes showed increased oxygen radical production. These results indicate that rG-CSF enhances host resistance to disseminated candidiasis in nonneutropenic mice through activation of granulocytes and their recruitment to the site of infection.

Defects in Host-Defense Mechanisms

Under normal conditions, large areas of the human body surfaces are colonized with microorganisms. The skin and the mucous membranes of the oropharynx, nasopharynx, intestinal tract, and parts of the genital tract each have their own microflora.1 These patterns of colonization are determined by microbial factors, exogenous factors, and host factors.

Infusion of Lipoproteins into Volunteers Enhances the Growth of Candida albicans

Infusion of reconstituted high-density lipoproteins (rHDL) is being studied in clinical trials as an adjunctive therapy for gram-negative sepsis. Since no data are available on its possible effects in systemic candidiasis, we investigated the effect of rHDL infusion into volunteers on the growth of Candida albicans. C. albicans growth was 10- to 100-fold higher in the plasma of volunteers infused with 80 or 100 mg/kg rHDL than in plasma collected before infusion; administration of 60 mg/kg rHDL had marginal effects. In vitro, the isolated lipoprotein subfractions had a growth-promoting effect on C. albicans. These data suggest potential adverse effects of rHDL if infused into patients with systemic candidiasis. Thus, rHDL infusion into patients with sepsis caused by an unknown microorganism may be contraindicated.

Interleukin-1 and its Receptor Antagonist as Candidate Therapeutic Agents for Severe Infections

For the treatment of infections, nowadays a large armamentarium of antimicrobial drugs is available. Despite the availability of new antimicrobial drugs and new insights in how to apply antibiotics, it is clear that treatment of serious infections, such as Gram-negative septicemia still meets with high failure rates. It is highly questionable whether the success of antimicrobial treatment can be much more enhanced by still more potent antibiotics. An alternative would be to try to strengthen host defense. This is not a new thought. In this connection, George Bernard Shaw’s play “The Doctor’s Dilemma” published in 1906 is often quoted, in which Sir Ralph Bloomfield Bonington says: “There is at bottom only one genuinely scientific treatment for all diseases, and that is to stimulate the phagocytes”. In the beginning of this century the first animal experiments were performed demonstrating that pretreatment with bacterial products may leads to enhanced non-specific resistance to a variety of micro-organisms (1). Bacterial endotoxin, (lipopolysaccharide, LPS) was shown to be a major component responsible for the enhanced resistance to infection (1–3), but other substances derived from bacteria (such as muramylpeptides) (4,5) were also able to induce such protection. Since these bacterial immunostimulants were rather toxic, these treatment modalities did not become used in clinical medicine.