Blood, Vol. 93 No. 10 (May 15), 1999:
pp. 3467-3472
Additive Effects of Human Recombinant Interleukin-11 and Granulocyte
Colony-Stimulating Factor in Experimental Gram-Negative Sepsis
Steven M. Opal,
Jhung W. Jhung,
James C. Keith Jr,
Samuel J. Goldman,
John E. Palardy, and
Nicolas A. Parejo
From the Infectious Disease Division and the Pathology Department,
Memorial Hospital of Rhode Island and Brown University School of
Medicine, Providence, RI; and Genetics Institute, Cambridge, MA.
Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is
widely used to promote granulocyte recovery from a variety of
pathologic states. Recombinant human interleukin-11 (rhIL-11) has
recently become available clinically as a platelet restorative agent
after myelosuppressive chemotherapy. Preclinical data has shown that
rhIL-11 limits mucosal injury after chemotherapy and attenuates the
proinflammatory cytokine response. The potential efficacy of
combination therapy with recombinant human forms of rhIL-11 and rhG-CSF
was studied in a neutropenic rat model of Pseudomonas
aeruginosa sepsis. At the onset of neutropenia, animals were
randomly assigned to receive either rhG-CSF at a dose of 200 µg/kg subcutaneously every 24 hours for 7 days; rhIL-11 at 200 µg/kg subcutaneously every 24 hours for 7 days; the combination of
both rhG-CSF and rhIL-11; or saline control. Animals were orally colonized with Pseudomonas aeruginosa 12.4.4 and then given a myelosuppressive dose of cyclophosphamide. rhG-CSF resulted in a slight
increase in absolute neutrophil counts (ANC), but did not provide a
survival advantage (0 of 12, 0% survival) compared with the placebo
group (1 of 12 , 8% survival). rhIL-11 was partially protective (4 of
10, 40% survival); the combination of rhG-CSF and rhIL-11 resulted in
a survival rate of 80% (16 of 20; P < .001). rhIL-11 alone
or in combination with rhG-CSF resulted in preservation of
gastrointestinal mucosal integrity (P < .001), lower
circulating endotoxin levels (P < .01), and reduced
quantitative levels of P. aeruginosa in quantitative organ
cultures. These results indicate that the combination of rhIL-11 and
rhG-CSF is additive as a treatment strategy in the prevention and
treatment of experimental Gram-negative sepsis in immunocompromised
animals. This combination may prove to be efficacious in the prevention of severe sepsis in neutropenic patients.
