Recombinant interleukin-2 directly augments the cytotoxicity of human monocytes

Malkovský, M; Loveland, Bruce E.; North, M. E.; Asherson, G. L.; Gao, Liquan; Ward, Paul; Fiers, Walter

doi:10.1038/325262a0

Cited by 274 publications

(83 citation statements)

References 30 publications

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“…For tumor-infiltrating lymphocytes, addition of GM-CSF to IL-2 has been reported to result in faster proliferation and enhanced tumor cytotoxicity (13). In addition, GM-CSF and IL-2 have been shown to enhance monocyte activation and cytotoxicity against melanoma cells in vitro (14,15) and to prolong polymorphonuclear neutrophil survival (16,17). However, GM-CSF and IL-2 used in combination can sometimes induce paradoxical effects.…”

Section: Resultsmentioning

confidence: 99%

Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-2 Fusion cDNA for Cancer Gene Immunotherapy

Stagg¹,

Wu²,

Bouganim³

et al. 2004

Cancer Research

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Genetic engineering of tumor cells to express both granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-2 can induce synergistic immune antitumor effects. Paradoxically, the combination has also been reported to down-regulate certain immune functions, highlighting the unpredictability of dual cytokine use. We hypothesized that a GM-CSF and IL-2 fusion transgene (GIFT) could circumvent such limitations yet preserve synergistic features. We designed a fusion cDNA of murine GM-CSF and IL-2. Protein structure computer modeling of GIFT protein predicted for intact ligand binding domains for both cytokines. B16 mouse melanoma cells were gene modified to express GIFT (B16GIFT), and these cells were unable to form tumors in C57bl/6 mice. Irradiated B16GIFT whole-cell tumor vaccine could also induce absolute protective immunity against challenge by live B16 cells. In mice with established melanoma, B16GIFT therapeutic cellular vaccine significantly improved tumor-free survival when compared with B16 expressing both IL-2 and GM-CSF. We show that GIFT induced a significantly greater tumor site recruitment of macrophages than combined GM-CSF and IL-2 and that macrophage recruitment arises from novel chemotactic feature of GIFT. In contrast to suppression by GM-CSF of natural killer (NK) cell recruitment despite coexpression of IL-2, GIFT leads to significant functional NK cell infiltration as confirmed in NK-defective beige mice. In conclusion, we demonstrated that a fusion between GM-CSF and IL-2 can invoke greater antitumor effect than both cytokines in combination, and novel immunobiological properties can arise from such chimeric constructs.

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Section: Resultsmentioning

confidence: 99%

Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-2 Fusion cDNA for Cancer Gene Immunotherapy

Stagg¹,

Wu²,

Bouganim³

et al. 2004

Cancer Research

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“…Monocytes constitute an early cellular response in inflammation. The early assembly of the high-affinity IL-2R (␣/␤/␥) may allow for an early induction of monocyte proliferation and cytotoxic activity by IL-2 [21].…”

Section: Discussionmentioning

confidence: 99%

Surface and Intracellular Interleukin‐2 Receptor Expression on Various Resting and Activated Populations Involved in Cell‐Mediated Immunity in Human Peripheral Blood

Hodge

Flower

et al. 2000

Scand J Immunol

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The kinetics of assembly of the high-affinity interleukin-2 receptor (IL-2R)␣/␤/␥ were investigated by studying intracellular and surface expression of IL-2R␣, ␤ and ␥ by T cells, monocytes and natural killer (NK) cells. IL-2R␣ and IL-2R␥ were expressed by small numbers of resting T cells. These numbers increased following stimulation, to maximal expression at 48 h and 72 h, respectively. This observation was consistent with de novo synthesis of the receptor protein in response to the stimulus. The proportion of T cells producing IL-2R␤ was smaller and up-regulated later than the proportion of cells producing IL-2R␣ or IL-2R␥. IL-2R␤ may therefore slow the assembly of the high-affinity IL-2R on T cells. A small number of resting NK cells expressed IL-2R␣, both on the cell surface and intracellularly, but this increased over 72 h on stimulated NK cells. IL-2R␤ was constitutively expressed, both on the cell surface and intracellularly, by monocytes and NK cells. An increased proportion of NK cells and monocytes produced IL-2R␤, 24 h and 4 h post-stimulation, respectively. Maximal or plateau expression occurred at 72 h and 24 h post-stimulation, for NK cells and monocytes, respectively. The early up-regulation of intracellular IL-2R␤ for monocytes may facilitate the upregulation of surface IL-2R␤, and early assembly of the high-affinity IL-2R, accelerating monocyte activation and function. High constitutive intracellular IL-2R␥ expression (> 80%) in all types of leucocyte investigated, decreased over the 72 h following stimulation with a concurrent increase in surface expression. IL-2R␥ was expressed by increased proportions of T cells, monocytes and NK cells, 4 h following stimulation. The intracellular storage of IL-2R␥ may accelerate translocation to the cell surface after stimulation. The early translocation of IL-2R␥ may reflect its usage as a signal transduction molecule by other cytokine receptors ¹ IL-4, IL-7, IL-9 and IL-15. This study delineated the potential expression of the high-affinity IL-2R␣/␤/␥ on various stimulated leucocytes. The differential kinetics of assembly of the high-affinity IL-2R␣/␤/␥ on different leucocyte subsets suggests that IL-2 may regulate the inflammatory cellular responses in a sequential manner, paralleling the timed expression of IL-2R␣/␤/␥ on the monocytes, NK cells and T cells.

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“…IL-2 directly activates monocytes and also contributes to the induction of other macrophage functions. 38,39 In addition, the release of other secondary mediators, such as GM-CSF, is triggered by IL-2. This event also contributes to macrophage activation because GM-CSF activates the first critical steps of an immunoregulatory pathway which includes the generation of dendritic cells from CD34ϩ hematopoetic progenitors, 41 the activation of APCs, 42 the increased expression of MHC class II antigens in APCs, 43 and the augmentation of the primary antibody response.…”

Section: Discussionmentioning

confidence: 99%

Cytokine and hepatitis B virus DNA Co-immunizations enhance cellular and humoral immune responses to the middle but not to the large hepatitis B virus surface antigen in mice

et al. 1998

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Genetic immunization is a potentially useful strategy to prevent or treat hepatitis B virus (HBV) infection. We have previously shown that HBV envelope proteins are highly immunogenic using this technique. The large envelope protein (LHBs), however, induced significantly weaker humoral and cellular immune responses when compared with the middle envelope protein (MHBs). We studied the effect of co-immunizations with cytokine DNA expression constructs encoding for interleukin (IL)-2 and (GM-CSF) on the immunogenicity of LHBs at the B-and T-cell level. Co-immunizations of mice with plasmids encoding for MHBs and IL-2 or GM-CSF increased anti-HBs responses, helper T-cell proliferative activity, and cytotoxic T lymphocyte (CTL) killing. In contrast, co-immunizations of plasmids encoding for LHBs and IL-2 or GM-CSF had no effect on humoral and cellular immune responses. LHBs did not inhibit the production or secretion of IL-2 and GM-CSF. In addition, IL-2, tumor necrosis factor alfa (TNF-␣), and interferon gamma (IFN-␥) had no suppressive effect on HBV envelope protein expression in vitro. Based on these data, MHBs, but not LHBs, genetic immunization can be augmented by IL-2 or GM-CSF cytokines. (HEPATOLOGY 1998;28:202-210.)Hepatitis B virus (HBV) is a noncytopathic, hepatotropic virus infecting more than 350 million individuals worldwide. 1 Hepatitis B is a leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. 2 The cellular immune response to HBV is thought to be responsible for viral clearance and pathogenesis of liver disease. In acutely infected patients who successfully clear the virus the CD4ϩ and CD8ϩ T-cell response to HBV is vigorous, polyclonal, and multispecific. [3][4][5][6][7][8][9][10] The T cells typically secrete type-1 antiviral cytokines, such as interferon gamma (IFN-␥) and tumor necrosis factor alfa (TNF-␣), upon antigen stimulation. By contrast, in chronically infected patients, the T-cell response is relatively weak and is antigenetically more restricted, except during acute exacerbations of chronic disease or after spontaneous or IFN-␣ induced viral clearance. [11][12][13] The cytokine profile of the intrahepatic HBVspecific T cells is variable in chronically infected individuals. The observation of spontaneous HBV clearance in some chronically infected individuals implies that the suboptimal cellular immune response may be reversible; therefore, strategies designed to boost the HBV-specific T-cell immune response, to alter the balance between the cytopathic and the regulatory components of the response, or to mimic the regulatory functions of the T-cell response in the liver may be able to terminate persistent infection.In this regard, genetic immunization offers the potential advantage of inducing cellular and humoral immune responses against conserved viral epitopes because this approach uses DNA expression plasmids, instead of proteins, for vaccination. This technique involves the transfer of a viral gene into muscle cells and antigen presenting cells by a plasmid vec...

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Recombinant interleukin-2 directly augments the cytotoxicity of human monocytes

Cited by 274 publications

References 30 publications

Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-2 Fusion cDNA for Cancer Gene Immunotherapy

Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-2 Fusion cDNA for Cancer Gene Immunotherapy

Surface and Intracellular Interleukin‐2 Receptor Expression on Various Resting and Activated Populations Involved in Cell‐Mediated Immunity in Human Peripheral Blood

Cytokine and hepatitis B virus DNA Co-immunizations enhance cellular and humoral immune responses to the middle but not to the large hepatitis B virus surface antigen in mice

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