Interleukin-12 induced cytolytic activity in lymphocytes from recipients of autologous and allogeneic stem cell transplants

Abstract

Summary:Stem cell transplantation for advanced hematologic Interleukin-12 (IL-12) has been reported to enhance the malignancies is limited largely by disease recurrence. 1-6 cytolytic activity of NK and activated T cells and toIntensification of chemotherapy and radiation has had little induce low levels of lymphokine-activated killer (LAK) impact on post-transplant relapses. 7 Immunotherapeutic activity in normal human lymphocytes. Therapy with approaches may not cross-react with chemoradiotherapy, IL-12 has induced tumor eradication in murine models.and, if administered early after transplantation, might eradiThese observations suggest that IL-12 might have a role cate any residual tumor cells which survived the preparative as treatment for minimal residual disease following regimen and/or were infused with the marrow. For transplantation. To determine whether PBL from example, interleukin-2 (IL-2) which has been reported to recipients of autologous (autoSCT) and allogeneic induce regression of hematologic malignancies in some (alloSCT) bone marrow or peripheral blood stem cell patients 8-11 is being explored as therapy early after autologtransplants respond to IL-12 with generation of LAK ous (AutoSCT) and allogeneic (AlloSCT) stem cell transactivity, PBL were incubated with IL-12 for 5 days, then plantation. 1,12-19 tested in a 51 Cr release assay for lysis of Daudi. PBL Interleukin-12 (IL-12), a 70-kDa heterodimeric cytokine, from 17 normal 'control' individuals were similarly induces immunomodulatory effects, some of which are tested and lysis was observed in only 3/17 (mean 16.9% similar to those induced by IL-2, but via independent pathof the three). By contrast, PBL from 10/12 patients ways. 20 In normal human PBL, IL-12 enhances the cytoobtained a median of 30 days after autoSCT, exhibited toxic activity of NK and activated T cells and can induce significant IL-12-induced LAK activity (mean lysis, very low levels of lymphokine-activated killer (LAK) 35.3%, P Ͻ 0.005 vs controls). PBL from 18 of 20 activity, mediated by CD56 + NK cells. [20][21][22][23][24][25] IL-12 also patients tested a median of 44 days after alloSCT also enhances IL-2-induced LAK activity. 22-26 A high affinity exhibited significant LAK activity (mean lysis, 30.0%, IL-12 receptor (IL-12r) has been identified on normal human P Ͻ 0.005 vs controls). In autoSCT recipients, IL-12 and NK and activated T cells and in some B cell lines. 27-29 A IL-2 at high concentrations (1000 U/ml each) were addisubunit of the IL-12r, the IL-12r␤1 chain, has been shown tive for induction of LAK activity, whereas low, suboptito be an essential component for the functional IL-12r since mal concentration of IL-12 (250 U/ml) and IL-2 (1 U/ml) the cytolytic activity is inhibited by antibodies to the ILwere synergistic in 3/5 experiments. The percentage 12r␤1 chain. 27 of PBL expressing IL-12 receptor ␤1 chainIn murine models, IL-12 has been shown to eradicate (IL-12r␤1) was higher in stem cell recipients than in some disseminated tumors. 30,31 Moreover, in...