Human interleukin 2 analogues that preferentially bind the intermediate-affinity interleukin 2 receptor lead to reduced secondary cytokine secretion: implications for the use of these interleukin 2 analogues in cancer immunotherapy.

作者：Keith M. Heaton, G Ju, Elizabeth A. Grimm · 发表于：PubMed · 年份：1993 · 被引用次数：68 · 研究领域：Immune Cell Function and Interaction、Immune Response and Inflammation、Immunotherapy and Immune Responses

Cancer patients undergoing interleukin (IL)-2-based immunotherapy frequently experience dose-limiting side effects believed to be caused by the actions of such cytokines as IL-1 beta, tumor necrosis factor (TNF)-alpha and -beta, and interferon-gamma (IFN-gamma). Human peripheral blood mononuclear cells (PBMC) or monocyte-depleted peripheral blood lymphocytes were stimulated for up to 7 days by either of 2 IL-2 analogues (R38A or F42K) that bind to the intermediate-affinity IL-2 beta gamma receptor but have reduced abilities to bind the high-affinity IL-2 receptor. We previously reported that these IL-2 analogues retain the ability to generate lymphokine-activated killing by PBMC. In this study, we analyzed the cytokine content of supernatants from stimulated PBMC and peripheral blood lymphocyte cultures by enzyme-linked immunosorbent assay. The secretions of IL-1 beta, TNF-alpha, and -beta, and IFN-gamma induced by either R38A or F42K were markedly reduced compared with secretions produced in response to recombinant wild-type IL-2. In 4 experiments, secretion was reduced an average of 39% for IL-1 beta, 57% for TNF-alpha, 83% for TNF-beta, and 86% for IFN-gamma. Polymerase chain reaction analysis of recombinant wild-type IL-2 or analogue-stimulated PBMC did not reveal the presence of IL-2 mRNA; thus, differential production of endogenous IL-2 could not account for these findings. These data suggest the interaction of IL-2 and the high-affinity IL-2 receptor on human PBMC or p...