In vivo production of interleukin-5, granulocyte-macrophage colony-stimulating factor, macrophages colony-stimulating factor, and interleukin-6 during intravenous administration of high-dose interleukin-2 in cancer patients.
Recombinant human interleukin-2 (IL-2), administered to cancer patients by continuous intravenous (IV) infusion (3 x 10(6) U/m2/d), was found to induce the in vivo production of colony-stimulating factors (CSF). Plasma obtained from patients during IL-2 treatment stimulated in vitro colony formation of normal human bone marrow cells, depleted of mononuclear phagocytes and T lymphocytes. This colony-stimulating activity (CSA) was identified as IL-5, granulocyte-macrophage CSF (GM-CSF), and macrophage CSF (M-CSF), by the ability of specific antibodies against these factors to neutralize their effects. The presence of IL-2-induced GM-CSF and M-CSF was also demonstrated by specific radioimmunoassays. During IL-2 treatment, plasma also contained detectable levels of IL-6, which was measured in a bioassay. Using a cDNA-polymerase chain reaction (PCR) with specific primer sets for the various CSF, we showed that IL-2 treatment induced the expression of mRNA for M-CSF, GM-CSF, IL-3, and IL-5, but not for granulocyte CSF (G-CSF) in peripheral blood mononuclear cells, suggesting differential expression of CSF in vivo in response to IL-2. Furthermore, no negative regulators of hematopoiesis, such as interferon gamma (IFN-gamma) or tumor necrosis factor-alpha (TNF-alpha), were found in plasma. These data illustrate that in vivo administration of high-dose IL-2 may result in a stimulatory effect on hematopoiesis. The induction of detectable levels of IL-5 and GM-CSF in the circulation may explain the eosinophilia and neutrophilia observed in these patients.
Schaafsma
M R
MR
Department of Hematology, University Medical Center, Leiden, The Netherlands.
Falkenburg
J H
JH
Landegent
J E
JE
Duinkerken
N
N
Osanto
S
S
Ralph
P
P
Kaushansky
K
K
Wagemaker
G
G
Van Damme
J
J
Willemze
R
R
D002292:Carcinoma, Renal Cell / Q000628:therapy*; D003115:Colony-Stimulating Factors / Q000235:genetics / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000097:blood; D007376:Interleukin-2 / Q000008:administration & dosage*; D007377:Interleukin-3 / Q000235:genetics / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism*; D015850:Interleukin-6 / Q000096:biosynthesis; D007680:Kidney Neoplasms / Q000628:therapy*; D007958:Leukocyte Count; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D011863:Radioimmunoassay; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D003115:Colony-Stimulating Factors; D007376:Interleukin-2; D007377:Interleukin-3; D015848:Interleukin-5; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor