Peripheral blood lymphocytes (PBLs) cultured in the presence of recombinant human interleukin-2 (rhIL-2) develop a natural killer (NK) cell phenotype (CD16+, CD56+, CD3-) and are referred to as lymphokine- activated killer cells (LAK). In developing the LAK phenotype, enhanced adherence to matrix components and endothelial cells have been described. In this report we investigated the functional behavior of adhesion receptors in rhIL-2-activated PBLs by in vitro adhesion assay and by flow cytometry. Compared to PBLs, IL-2-activated PBLs had increased integrin-mediated adherence to: (1) fibronectin (FN), (2) human umbilical vein endothelial (HUVE) cells, and (3) cultured melanoma and pancreatic tumor cell lines. This increase in adherence was mediated by increased surface expression of members of the beta 1 and beta 2 integrin subfamilies, as determined by flow cytometric analysis. No induction of an activation-dependent beta 1 (CD29) epitope was detected. We also investigated the effects of the methylxanthine derivative pentoxifylline (PTX) on PBLs and rhIL-2-activated PBL adhesion. PBLs co-cultivated in the presence of rhIL-2 (1,000 U/mL) and PTX exhibited reduced adherence to FN, HUVE and cultured tumor cell lines. This inhibition by PTX was concentration- and time-dependent. The increased expression of integrins induced by rhIL-2 was only in part inhibited by PTX, suggesting that PTX induced a subpopulation of integrins that are expressed but functionally inactive.
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-12r1 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 12r1 chain. 27 of PBL expressing IL-12 receptor 1 chainIn murine models, IL-12 has been shown to eradicate (IL-12r1) was higher in stem cell recipients than in some disseminated tumors. 30,31 Moreover, in...
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