Interleukin-2 (IL-2) has been shown to enhance natural cell-mediated cytotoxicity and other cellular immune functions in vitro and in vivo. The gene for the human lymphokine has been cloned, and recombinant IL-2 is now available for clinical trials. In the proposed investigation, recombinant IL-2 will be administered by intravenous injection to patients with advanced refractory malignancies in order to determine its effect on cellular immunity, its toxicity, and its potential as an antineoplastic agent. The aberrant amino acid sequence of the Interleukin-2 to be used in clinical trials and other properties of the molecule have raised the possibility that IL-2 may be immunogenic, and serum from recipient patients will be monitored for the development of anti-IL-2 antibodies with a sensitive ELISA. Moreover, a series of experiments using an adsorbed affinity-purified neutralizing rabbit anti-IL-2 antiserum is proposed to determine the biological significance of such antibodies in humans. The association between IL-2 and the acute phase response will be documented and correlated with the dose of IL-2 administered. The mechanism by which high doses of IL-2 cause fever in humans and the role of IL-2 in the induction of IL-1 and prostaglandin E2 synthesis will be investigated. The relationship between the induction of the acute phase response and changes in cellular immune function will be studied and correlated with IL-2 dose and tumor response, if any, is observed. This proposal represents a comprehensive investigation of the in vivo effects of this potent biological response modifier which will delineate its potential role in the management of patients with immunodeficiency and neoplastic diseases.
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