Evidence for eosinophil activation in cancer patients receiving recombinant interleukin-4: effects of interleukin-4 alone and following interleukin-2 administration.
Interleukin-4 (IL-4) is a T-cell-derived cytokine that may mediate murine tumor rejection through the activation of host eosinophils. In association with a Phase I clinical trial of IL-4 in cancer patients, we have examined changes in eosinophil counts and characterized systemic eosinophil degranulation. As previously reported, IL-4 administration induced a modest eosinophilia in all 17 evaluated patients. Here, we report that IL-4 therapy induced systemic eosinophil degranulation based on increases in serum major basic protein (MBP) (P = 0.018) and urine MBP (P = 0.031). The increase in serum MBP was IL-4 dose dependent (P = 0.001). Following the highest dose (600 microgram/m2/day) of IL-4 administered, mean serum MBP levels were >2000 ng/ml. Skin biopsies of rashes from patients receiving IL-4 revealed MBP deposition. Sera from eight patients receiving IL-4 at 360 and 600 microgram/m2/day exhibited eosinophil survival-enhancing activity (on days 3, 5, 7, and 9) significantly above pretreatment (on day 1) activity (P values 0. 0469, 0.0039, 0.0395, and 0.0313, respectively). This enhanced eosinophil survival could be neutralized by antibodies to IL-5, granulocyte-macrophage-colony-stimulating factor, and IL-3. The eosinophil activation demonstrated in this trial may be relevant to the clinical effects of IL-4 in cancer patients. Furthermore, an association between IL-4 and eosinophil activation should be explored in other disease states.
Sosman
J A
JA
Division of Hematology/Oncology, Department of Obstetrics/Gynecology Loyola University Medical Center, Maywood, Illinois 60153, USA.
Bartemes
K
K
Offord
K P
KP
Kita
H
H
Fisher
S G
SG
Kefer
C
C
Ellis
T A
TA
Fisher
R I
RI
Higgins
T J
TJ
Gleich
G J
GJ
D000704:Analysis of Variance; D001798:Blood Proteins / Q000378:metabolism / Q000652:urine; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D047091:Eosinophil Granule Proteins; D004804:Eosinophils / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D006801:Humans; D007376:Interleukin-2 / Q000009:adverse effects / Q000627:therapeutic use*; D015847:Interleukin-4 / Q000009:adverse effects / Q000627:therapeutic use*; D007958:Leukocyte Count; D009369:Neoplasms / Q000097:blood / Q000628:therapy* / Q000652:urine; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D012260:Ribonucleases; D012867:Skin / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
D001798:Blood Proteins; D047091:Eosinophil Granule Proteins; D007376:Interleukin-2; D011994:Recombinant Proteins; D015847:Interleukin-4; D012260:Ribonucleases