Cytokine responses to intraventricular injection of interleukin 2 into patients with leptomeningeal carcinomatosis: rapid induction of tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, gamma-interferon, and soluble interleukin 2 receptor (Mr 55,000 protein).
Interleukin 2 (IL-2) is a potent immunostimulant that causes the release of secondary cytokines and the production of lymphokine-activated killer cells. We investigated the cellular and cytokine responses to injection of recombinant human IL-2 into the human cerebrospinal fluid of 11 patients with metastatic tumors involving the spinal or cerebral leptomeninges. After initial intraventricular IL-2 administration (1.25 x 10(5) to 2 x 10(6) Cetus units/injection), cerebrospinal fluid samples were collected at intervals from 0 to 24 h. Enzyme-linked immunosorbent assay results indicated that IL-2 levels gradually decreased during the first 24 h, with an average t1/2 between 4 and 8 h. Induction of tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, gamma-interferon, and interleukin 2 receptor (p55) was also assessed by enzyme-linked immunosorbent assay. Tumor necrosis factor alpha and interleukin 6 levels peaked at 2 to 4 h and 4 to 6 h, with concentrations between 71 to 1,714 pg/ml and 942 to 10,500 pg/ml, respectively. Interleukin 1 beta, gamma-interferon, and soluble IL-2 receptor peaked later, during 6 to 12 h; the levels achieved were 234 pg/ml, 25 NIH units/ml, and 207 units/ml, respectively. All cytokine concentrations returned to near baseline between 12 and 24 h; however, the soluble IL-2 receptor levels remained elevated. Additional observations included a rapid influx of neutrophilic leukocytes, followed by a prolonged presence of lymphocytes. These data indicate a broad and complex potential of the immune response in the central nervous system, as well as further define the cytokine cascade in response to IL-2 alone.
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J
J
Department of Tumor Biology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Moser
R P
RP
Steuer
M
M
Loudon
W G
WG
Blacklock
J B
JB
Grimm
E A
EA
D000230:Adenocarcinoma / Q000134:cerebrospinal fluid* / Q000556:secondary / Q000628:therapy; D000328:Adult; D005260:Female; D006801:Humans; D007276:Injections, Intraventricular; D007375:Interleukin-1 / Q000134:cerebrospinal fluid*; D007376:Interleukin-2 / Q000008:administration & dosage / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics / Q000494:pharmacology*; D015850:Interleukin-6 / Q000134:cerebrospinal fluid*; D015979:Killer Cells, Lymphokine-Activated; D007958:Leukocyte Count; D008175:Lung Neoplasms; D016131:Lymphocyte Subsets; D008297:Male; D008545:Melanoma / Q000134:cerebrospinal fluid* / Q000556:secondary / Q000628:therapy; D008577:Meningeal Neoplasms / Q000134:cerebrospinal fluid* / Q000556:secondary / Q000628:therapy; D008875:Middle Aged; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000134:cerebrospinal fluid*
D007375:Interleukin-1; D007376:Interleukin-2; D015850:Interleukin-6; D015375:Receptors, Interleukin-2; D014409:Tumor Necrosis Factor-alpha