Interleukin-2 toxicity

Anderson, James Ainslie (1997) Interleukin-2 toxicity. University of Southampton, Doctoral Thesis.

Abstract

Interleukin-2 (IL-2) is a 15.5 kDa protein produced by activated T lymphocytes whose function is to stimulate the proliferation of certain lymphocyte subsets, as part of the immune response to foreign antigen. Pharmacological doses of this cytokine, administered alone or in combination with activated lymphocytes, have been able to cause the regression of certain malignancies. Widespread use of IL-2 has been limited by severe dose-dependent toxicities, which can be divided into the acute vascular leak syndrome and the more chronic organ dysfunction which is associated with infiltration of activated lymphocytes.

The role of tumour necrosis factor in the acute vascular leak syndrome was studied using the rat cremaster microcirculation model. Leakage was found to be extremely dose specific, and did not involve neutrophils or mast cells.

The subcutaneous route of administration in a tumoured murine model was found to be ineffective at inhibiting tumour growth over a wide range of doses.

The mechanisms of IL-2 induced lymphocytic infiltration were studied in a murine model, using reverse transcription polymerase chain reaction, immunohistochemistry and flow cytometry: The cytokines TNF-α and IL-1β, and the adhesion molecules LFA-1, VLA-4, ICAM-1 and VCAM-1 are involved in lymphocytic infiltration secondary to IL-2. Pentoxifylline was unable to reduce IL-2 toxicity in this model.

A phase I study of the effect of oral pentoxifylline on IL-2 induced toxicity in patients with metastatic renal cell carcinoma showed no significant benefit to concomitant pentoxifylline administration, but an additional toxic effect of the pentoxifylline itself was observed.

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