Reversible anergy in circulating lymphocytes of cancer patients during interleukin-2 therapy.
Interleukin-2 plays a crucial role in enhancing the antitumor immune response. Clinical trials, mainly in renal cell carcinoma and melanoma patients, have been carried out with encouraging results. Recent reports demonstrated that interleukin-2 therapy may depress the immune response either in vitro or in vivo. We decided to monitor, in nine renal cancer patients, the proliferative responses and the parallel variations in Ca2+ homeostasis of peripheral blood lymphocytes collected before, during and after the first cycle of a 3-day interleukin-2 systemic administration. The proliferative response to phytohemagglutinin or concanavalin A significantly dropped early during interleukin-2 infusion. Consistently, an impairment in mobilizing Ca2+, either from internal stores or via influx from outside, was observed. Results obtained with a mAb-alpha CD3 molecular complex strongly suggested that the TCR/CD3 signal transduction pathway was defective. In contrast, no major variations were observed in the general machinery controlling Ca2+ homeostasis nor in the total Ca(2+)-releasable pool. Patients' lymphocytes, cultured in vitro for 3 days in medium alone, showed an almost complete recovery in their ability to respond to mitogens. In conclusion, we show that interleukin-2 administration in cancer patients induces a reversible state of anergy in circulating lymphocytes, assessed both by the reduction in the proliferative response and the block of the mitogen-activated intracellular Ca2+ signalling.
Clementi
E
E
Faculty of Pharmacy, University of Reggio Calabria, Catanzaro, Italy.
Bucci
E
E
Citterio
G
G
Landonio
G
G
Consogno
G
G
Fortis
C
C
D002118:Calcium / Q000097:blood / Q000502:physiology; D002292:Carcinoma, Renal Cell / Q000097:blood* / Q000188:drug therapy* / Q000276:immunology; D002478:Cells, Cultured; D003208:Concanavalin A / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007167:Immunotherapy; D007376:Interleukin-2 / Q000097:blood / Q000627:therapeutic use*; D015759:Ionomycin / Q000494:pharmacology; D007680:Kidney Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000502:physiology; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000502:physiology*; D016853:Muromonab-CD3 / Q000494:pharmacology; D010835:Phytohemagglutinins / Q000494:pharmacology; D011994:Recombinant Proteins / Q000627:therapeutic use; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013268:Stimulation, Chemical; D013729:Terpenes / Q000494:pharmacology; D019284:Thapsigargin
D007376:Interleukin-2; D016853:Muromonab-CD3; D010835:Phytohemagglutinins; D011994:Recombinant Proteins; D013729:Terpenes; D003208:Concanavalin A; D015759:Ionomycin; D019284:Thapsigargin; D002118:Calcium