IL-12 Synergizes with IL-2 to Induce Lymphokine-Activated Cytotoxicity and Perforin and Granzyme Gene Expression in Fresh Human NK Cells

DeBlaker-Hohe, D'Anna F.; Yamauchi, Aira; Yu, Cheng‐Rong; Horvath‐Arcidiacono, Judith A.; Bloom, Eda T.

doi:10.1006/cimm.1995.1184

Cited by 98 publications

(49 citation statements)

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“…43 Human peripheral blood mononuclear cells treated with IL-2 and IL-12 kill neuroblastoma target cells in vitro more effectively than either alone. 44 IL-2 and IL-12 synergize to stimulate NK activity in lymphocytes, 45 and to more efficiently generate tumor-specific cytolytic T lymphocytes. 46 In studies of the cytolytic responses of peripheral blood mononuclear cells, Rashleigh et al 47 showed that the combination of IL-2 and IL-12 consistently produced greater activation of cytolysis than either cytokine alone.…”

Section: Discussionmentioning

confidence: 99%

Efficient cotransduction of tumors by multiple herpes simplex vectors: Implications for tumor vaccine production

et al. 2000

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Many gene therapy strategies would be enhanced by efficient transfer of multiple genes into the same cell. Herpes simplex viral amplicon (HSV) vectors are good vehicles for gene transfer because they accommodate large pieces of foreign DNA and transfer genes rapidly and efficiently. The current studies examine whether efficient cotransduction of tumor cells can be accomplished using multiple HSV vectors in a manner useful for clinical gene therapy. Interleukin-12 (IL-12) exists as a heterodimer, with components (m35 and m40) coded for by genes on two separate chromosomes. We constructed HSV vectors carrying either IL12m35 (HSVm35) or IL12m40 (HSVm40) or both genes (HSVm75) separated by an internal ribosome entry site to assess whether gene transfer using a single HSV vector constructed to carry multiple genes has any advantage over gene transfer using multiple vectors that are each carrying single genes. Because IL-12 and IL-2 have been found to have synergistic antitumoral activity, we further analyzed the biologic activity of tumor cells cotransduced by separate HSV vectors carrying genes coding for these two cytokines. The results demonstrate that multiple genes can be inserted into the same cell efficiently using multiple HSV vectors, and that these vectors allow rapid production of tumor vaccines expressing multiple cytokine genes. Thus, gene transfer using HSV may not be limited by the size of the DNA that each vector can accommodate. Immunizations with tumors cotransduced with HSVm35 and HSVm40 were equally effective in eliciting a cytolytic T-lymphocyte response and in protecting against tumor growth in vivo as immunization with tumors treated with HSVm75. Immunization with tumors cotransduced with HSVm75 and HSVil2 was superior to immunization with tumors transduced with either alone. The combination of IL-2-and IL-12-secreting tumor cells may be used as an effective immunization strategy against solid tumors. Cancer Gene Therapy (2000) 7, 581-588

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Section: Discussionmentioning

confidence: 99%

Efficient cotransduction of tumors by multiple herpes simplex vectors: Implications for tumor vaccine production

et al. 2000

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“…of LAK activity, depending on the concentration of cytokines and/or culture conditions used. [21][22][23][24]26 Although low percentages of IL-12r␤1 expression were observed in PBL from some autoSCT recipients who were In this study, IL-12-induced LAK activity in PBL from healthy individuals was uncommon and weak. By contrast, not on immunosuppressants, the PBL which expressed the lowest percentage of IL-12r␤1 were from alloSCT patients IL-12-induced LAK activity in PBL from autoSCT recipients was common and strong.…”

Section: A High Percentage Of Cells Expressing Il-12r␤1 Is Associatedmentioning

confidence: 96%

“…NK been shown to upregulate the expression of IL-2r and IL12r, 22 to increase chemotaxis and adhesion ␤2 integrin cells capable of responding to IL-2 with LAK activity, are reconstituted early after transplantation. 17,34,39,40 This and CD18 in NK cells, 48 and to increase cytotoxic granule formation, 26 all of which may contribute to the observed addiother observations have stimulated clinical trials in which IL-2, with or without exogenous LAK cells, have been tive or synergistic effects of the two cytokines. The effector cells which mediate IL-12-induced lytic administered early after stem cell transplantation in an effort to reduce relapse.…”

Section: A High Percentage Of Cells Expressing Il-12r␤1 Is Associatedmentioning

confidence: 98%

“…[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][23][24][25][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.…”

Section: -6 Cytolytic Activity Of Nk and Activated T Cells And Tomentioning

confidence: 99%

“…Although PBL from some transuals. 23,25,26 Tests for additive or synergistic effects between IL-12 and IL-2 in the induction of LAK activity in normal plant recipients had a barely detectable percentage of cells expressing IL-12r␤1, but still exhibited detectable LAK human PBL have yielded conflicting results, including synergy, modest enhancement and even significant suppression activity, a high percentage of IL-12r␤1 expression was associated with greater IL-12-induced LAK activity. of LAK activity, depending on the concentration of cytokines and/or culture conditions used.…”

Section: A High Percentage Of Cells Expressing Il-12r␤1 Is Associatedmentioning

confidence: 99%

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

Robinson

et al. 1997

Bone Marrow Transplant

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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...

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Cytotoxicity and cytotoxic molecules in invertebrates

2000

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IL-12 Synergizes with IL-2 to Induce Lymphokine-Activated Cytotoxicity and Perforin and Granzyme Gene Expression in Fresh Human NK Cells

Cited by 98 publications

References 0 publications

Efficient cotransduction of tumors by multiple herpes simplex vectors: Implications for tumor vaccine production

Efficient cotransduction of tumors by multiple herpes simplex vectors: Implications for tumor vaccine production

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

Cytotoxicity and cytotoxic molecules in invertebrates

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