Interleukin-2 induced systemic toxicity: induction of mediators and immunopharmacologic intervention.
Interleukin-2 has been tested as an anti-cancer agent, either alone or in combination with immune cells, but severe dose limiting adverse toxic effects have been observed. Because the pathogenesis of the toxicity has remained uncharacterized, it has not been possible to determine whether the therapeutic and the toxic events could be separated. We have examined immunopharmacologic regulation of IL2 induced mediator induction and toxicity syndrome and have compared this data with our earlier information on IL2 enhancement of immune function in murine systems. The results of this study have shown that treatment with recombinant human interleukin-2 induced increased cellular TNF activity in lymphoid organs and this activity was abrogated by an anti-TNF antibody. Additionally, continuous daily treatment with interleukin-2 also induced increases in serum corticosterone but no detectable increases in serum IL1 or TNF. The increases in serum corticosterone occurred later in the treatment process and coincided with histopathologic changes in the adrenal glands and other tissues. Animals that died as a result of IL2 treatment had ascites and hydrothorax. Histopathologic changes were noted in the lungs, liver, adrenals, kidneys, gastrointestinal tract, heart and lymphoid organs. Cyclophosphamide, dexamethasone and anti-ASGM1 antibody were most effective in increasing survival and inhibiting immune enhancement but differentially effective in inhibiting TNF induction (or in certain cases gamma interferon induction), decreasing ascites or hydrothorax or affecting lymphoid proliferation in the lungs and spleen. Cyclosporin A and azathioprine were not as effective in enhancing survival and had differential effects on the other parameters. Possible mechanisms of both therapeutic and toxic events are discussed.
Butler
L D
LD
Department of Immunology, Lilly Research Laboratories, Indianapolis, Indiana 46285.
Mohler
K M
KM
Layman
N K
NK
Cain
R L
RL
Riedl
P E
PE
Puckett
L D
LD
Bendele
A M
AM
D000311:Adrenal Glands / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000998:Antiviral Agents; D001685:Biological Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D002455:Cell Division / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D016207:Cytokines; D004305:Dose-Response Relationship, Drug; D005260:Female; D007376:Interleukin-2 / Q000633:toxicity*; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D010902:Pituitary Gland / Q000502:physiology; D013154:Spleen / Q000166:cytology; D015275:Tumor Lysis Syndrome / Q000503:physiopathology*
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D001685:Biological Factors; D016207:Cytokines; D007376:Interleukin-2; D003345:Corticosterone