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Interleukin-2 induced systemic toxicity: induction of mediators and immunopharmacologic intervention
L D Butler1, K M Mohler, N K Layman
1Department of Immunology, Lilly Research Laboratories, Indianapolis, Indiana 46285.
Abstract:
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.
Insights
Interleukin-2 (IL2) cancer therapy shows promise but causes severe toxicity. This study investigated IL2
Area of Science:
- Immunopharmacology
- Cancer Biology
- Toxicology
Background:
- Interleukin-2 (IL2) is an anti-cancer agent with observed severe toxic effects.
- The mechanisms underlying IL2 toxicity are poorly understood, hindering separation of therapeutic and toxic effects.
- Previous studies show IL2 enhances immune function in murine models.
Purpose of the Study:
- To investigate the immunopharmacologic regulation of IL2-induced mediator induction and toxicity syndrome.
- To compare IL2-induced toxicity with its immune-enhancing effects in murine systems.
- To identify potential strategies to mitigate IL2-related adverse events.
Main Methods:
- Treatment of mice with recombinant human interleukin-2 (IL2).
- Assessment of cellular TNF activity in lymphoid organs and serum cytokine levels (IL1, TNF).
- Measurement of serum corticosterone and histopathological examination of tissues.
- Evaluation of various immunosuppressive agents (cyclophosphamide, dexamethasone, anti-ASGM1, cyclosporin A, azathioprine) for their effects on survival, immune enhancement, TNF induction, ascites/hydrothorax, and lymphoid proliferation.
Main Results:
- IL2 treatment increased cellular TNF activity, which was blocked by an anti-TNF antibody.
- Continuous IL2 administration elevated serum corticosterone and caused histopathological changes in adrenal glands and other organs, coinciding with mortality.
- Fatal IL2 treatment resulted in ascites and hydrothorax, with widespread tissue damage.
- Cyclophosphamide, dexamethasone, and anti-ASGM1 antibody improved survival and inhibited immune enhancement but had differential effects on TNF induction and fluid accumulation.
- Cyclosporin A and azathioprine were less effective in improving survival.
Conclusions:
- IL2-induced toxicity is associated with TNF activity and elevated corticosterone levels, leading to significant organ damage and fluid accumulation.
- Specific immunosuppressive agents can mitigate IL2 toxicity and enhance survival, but their efficacy varies.
- Understanding the mechanisms of IL2-induced toxicity is crucial for separating therapeutic and adverse effects in cancer treatment.