Effect of Fk506 Versus Cyclosporine on Human Natural and Antibody-Dependent Cytotoxicity Reactions in Vitro

Wasik, M; Górski, A; Stepień-Sopniewska, B; Lagodzinski, Z

doi:10.1097/00007890-199101000-00045

Cited by 26 publications

(16 citation statements)

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“…Our data are consistent with a previous report by Wasik et al [13], where no significant effect on human natural cytotoxicity and ADCC was observed by PBMCs incubated with FK506 for 24 -48 h in culture. Our studies using purified NK cells also demonstrate no dramatic changes of NK cytotoxicity and proliferation in response to IL-2 by FK506 within 48 h (data not shown).…”

Section: Discussionsupporting

confidence: 94%

“…Therefore, they are likely to be a target for FK506 action. However, earlier studies by Wasik et al [13] demonstrated little or no significant inhibition of human NK cell function by FK506 in natural cytotoxicity and ADCC in a 48-h culture in vitro. As immunosuppressive action of FK506 requires continuous maintenance of serum concentration for days or longer, the effect of FK506 on NK cells might have been underestimated in the previous studies.…”

Section: Introductionmentioning

confidence: 92%

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FK506 causes cellular and functional defects in human natural killer cells

Kim

Kim²,

Kang

et al. 2010

Journal of Leukocyte Biology

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The role of NK cells in allogeneic HCT has been increasingly appreciated, particularly in the GVL effect. Although FK506 has been used widely to prevent GVHD, its action was considered to be primarily through activated T cells. In this study, we provide direct evidence for the first time that human NK cells are immediate targets of FK506. Our in vivo data from patients undergoing peripheral blood stem cell transplantation or BMT showed a reduced number of NK cells with down-regulated CD25 expression in their peripheral blood compartment. Likewise, FK506 caused profound inhibition of NK cell proliferation in vitro and suppressed NK cytotoxicity and cytokine secretion in response to IL-2. These defects were accompanied by impaired cell clustering and selective down-regulation of adhesion molecules, ICAM-1, CD2, CD49d, and CD58. Furthermore, FK506 specifically inhibited expression of NKG2D, CD48, and DNAM1 receptors without affecting that of 2B4, NKp30, NKp44, and NKp46. As a result, natural cytotoxicity against K562 tumor targets was impaired, while leaving redirected ADCC via 2B4 intact. Finally, FK506-treated NK cells showed impaired IL-2R signaling and inhibition of STAT3. Collectively, these signaling impairments and selective down-regulation of NK receptors by FK506 may underlie the proliferative and functional defects of NK cells. Thus, our data provide a new insight into the mechanism of immunosuppression by FK506, which should be considered to interpret the outcome of graft transplantation.

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Section: Discussionsupporting

confidence: 94%

Section: Introductionmentioning

confidence: 92%

FK506 causes cellular and functional defects in human natural killer cells

Kim

Kim²,

Kang

et al. 2010

Journal of Leukocyte Biology

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“…Both the cyclosporine-based and FK506-based regimens of immunosuppressants used affect interleukin-2 production, on which T and NK lymphocytes depend for clonal expansion [39,40]. However, it was demonstrated that NK cells and Antibody-dependent cell-mediated cytotoxicity (ADCC) activity are resistant to FK506 [41], and Vampa et al [42] demonstrated in a direct ex vivo setting that recipient NK antidonor cytotoxicity was increased 3 days after transplantation despite quadruple immunosuppression therapy. Recipients exhibiting increased NK cytotoxicity against their donors after transplantation were found to possess more activating KIR genes specific for donor class I MHC than those in whom killing activity did not increase.…”

Section: Discussionmentioning

confidence: 99%

Impact of HLA-C and Bw Epitopes Disparity on Liver Transplantation Outcome

et al. 2005

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“…Therefore, it is important to investigate the mechanism of the antitumoral effect in individual experiments. Especially, in our experiments using a widely used immunosuppressant, FK506, which has a biological action not only on T cells, but also on NK cells, macrophages, and fibroblasts (47)(48)(49), it is very interesting to see whether the mechanism of the antitumoral effect of electroporation mediated IL-12 gene therapy is dependent on immunological components or not. We previously reported that electroporation-mediated IL-12 gene therapies for HCC were found to have an antitumor effect against mIL-12-tranferred HCC, distant HCC, and spontaneous lung metastasis (19).…”

Section: Discussionmentioning

confidence: 99%

IL-12 Gene Therapy Is an Effective Therapeutic Strategy for Hepatocellular Carcinoma in Immunosuppressed Mice

Harada¹,

Shimada²,

Okano

et al. 2004

The Journal of Immunology

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Immunosuppressive therapy for organ transplantation is essential for controlling rejection. When liver transplantation is performed as a therapy for hepatocellular carcinoma (HCC), recurrent HCC is one of the most fatal complications. In this study, we show that intratumoral murine IL-12 (mIL-12) gene therapy has the potential to be an effective treatment for malignancies under immunosuppression. C3H mice (H-2k), injected with FK506 (3 mg/kg) i.p., were s.c. implanted with 2.5 × 106 MH134 cells (H-2k) and we treated the established HCC with electroporation-mediated gene therapy using mIL-12 plasmid DNA. Intratumoral gene transfer of mIL-12 elevated intratumoral mIL-12, IFN-γ, and IFN-γ-inducible protein-10, significantly reduced the number of microvessels and inhibited the growth of HCC, compared with HCC-transferred control pCAGGS plasmid. The inhibition of tumor growth in immunosuppressed mice was comparable with that of mIL-12 gene therapy in immunocompetent mice. Intratumoral mIL-12 gene therapy enhanced lymphocytic infiltration into the tumor and elicited the MH134-specific CTL response even under FK506. The dose of FK506 was sufficient to prevent the rejection of distant allogenic skin grafts (BALB/c mice, H-2d) and tumors, B7-p815 (H-2d) used as transplants, during mIL-12 gene therapy against MH134. Ab-mediated depletion studies suggested that the inhibition of tumor growth, neovascularization, and spontaneous lung metastasis by mIL-12 was dependent almost entirely on NK cells and partially on T cells. These results suggest that intratumoral mIL-12 gene therapy is a potent effective strategy not only to treat recurrences of HCC in liver transplantation, but also to treat solid malignant tumors in immunosuppressed patients with transplanted organ.

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Effect of Fk506 Versus Cyclosporine on Human Natural and Antibody-Dependent Cytotoxicity Reactions in Vitro

Cited by 26 publications

References 0 publications

FK506 causes cellular and functional defects in human natural killer cells

FK506 causes cellular and functional defects in human natural killer cells

Impact of HLA-C and Bw Epitopes Disparity on Liver Transplantation Outcome

IL-12 Gene Therapy Is an Effective Therapeutic Strategy for Hepatocellular Carcinoma in Immunosuppressed Mice

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