Differential inhibition of lymphokine-activated killing, proliferation, and cytokine secretion by humanized antibodies against the low- and intermediate-affinity interleukin-2 receptors. A novel model for activation of human peripheral blood mononuclear cells by interleukin 2.
Human PBMCs generate LAK, proliferate, and secrete secondary cytokines in response to IL-2. We assessed the roles of the various receptor complexes in these responses to IL-2 using antibodies that block the interaction of IL-2 with the intermediate-affinity IL-2R (humanized Mik beta 1) and high- and low-affinity interactions (HTac). The HTac antibody produced dramatic reductions in proliferation (27%) and in the secretion of cytokines (TNF)-alpha and -beta and IFN-gamma inhibited 68%, 72%, and 80%, respectively) with no decrease in LAK. HMik inhibited LAK activation by 65% and proliferation by 60% but had little effect on cytokine secretion. The combination of the two antibodies completely inhibited all proliferative, cytolytic, and secretory activity. These data suggest a novel model for the activation of human PBMCs by IL-2. Whereas induction of LAK activity is mediated through the intermediate-affinity IL-2R and cytokine secretion is mediated through the high-affinity complex, interaction between IL-2 and both of these receptor complexes is required for the induction and maintenance of proliferative activities in human PBMCs.
Heaton
K M
KM
Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Grimm
E A
EA
D000911:Antibodies, Monoclonal; D016207:Cytokines / Q000276:immunology* / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology
D000911:Antibodies, Monoclonal; D016207:Cytokines; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins