Induction of apoptosis and modulation of activation and effector function in T cells by immunosuppressive drugs

Strauß, Gudrun; Osen, Wolfram; Debatin, Klaus‐Michael

doi:10.1046/j.1365-2249.2002.01777.x

Cited by 145 publications

(109 citation statements)

References 55 publications

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“…However, although HOA does not induce apoptosis of A549 cells, it does promote the death of Jurkat cells, as witnessed by the degradation of PARP and the presence of a subG 1 flow cytometry peak. In this regard, the induction of apoptosis by a number of antifolate drugs in T cells is a well-characterized phenomenon (20). These results suggest that the HOA-induced impairment of DNA synthesis drives Jurkat cells into an apoptotic program.…”

Section: Discussionmentioning

confidence: 92%

Pivotal role of dihydrofolate reductase knockdown in the anticancer activity of 2-hydroxyoleic acid

Lladó¹,

Terés

Higuera

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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␣-Hydroxy-9-cis-octadecenoic acid, a synthetic fatty acid that modifies the composition and structure of lipid membranes. 2-Hydroxyoleic acid (HOA) generated interest due to its potent, yet nontoxic, anticancer activity. It induces cell cycle arrest in human lung cancer (A549) cells and apoptosis in human leukemia (Jurkat) cells. These two pathways may explain how HOA induces regression of a variety of cancers. We showed that HOA repressed the expression of dihydrofolate reductase (DHFR), the enzyme responsible for tetrahydrofolate (THF) synthesis. Folinic acid, which readily produces THF without the participation of DHFR, reverses the antitumor effects of HOA in A549 and Jurkat cells, as well as the inhibitory influence on cyclin D and cdk2 in A549 cells, and on DNA and PARP degradation in Jurkat cells. This effect was very specific, because either elaidic acid (an analog of HOA) or other lipids, failed to alter A549 or Jurkat cell growth. THF is a cofactor necessary for DNA synthesis. Thus, impairment of DNA synthesis appears to be a common mechanism involved in the different responses elicited by cancer cells following treatment with HOA, namely cell cycle arrest or apoptosis. Compared with other antifolates, such as methotrexate, HOA did not directly inhibit DHFR but rather, it repressed its expression, a mode of action that offers certain therapeutic advantages. These results not only demonstrate the effect of a fatty acid on the expression of DHFR, but also emphasize the potential of HOA to be used as a wide-spectrum drug against cancer.anticancer ͉ DNA ͉ membrane-lipid therapy ͉ neoplasia ͉ nutrigenetics 2 -Hydroxyoleic acid (HOA) is a potent anticancer drug whose molecular mechanism of action is still not fully understood. Although HOA induces cell cycle exit in human lung cancer (A549) cells (1), it induces apoptosis in human leukemia cells (2). The IC 50 of this drug for most cancer cells studied is in the range of 30-150 M, whereas its IC 50 in normal cells is over 5,000 M (2). Thus, this drug does not produce toxicity at therapeutic doses despite acting efficiently in cell and animal models of human cancers (2, 3). Hence, it is important to define the mode of action of this compound and whether common molecular events underlie its therapeutic effects and the regression of different types of cancer.HOA was developed on the basis that the lipid composition and structure of the plasma membrane can be altered by certain antitumor drugs and that these modifications are involved in their action against cancer (4, 5). In this context, anthracyclines that are unable to enter cancer cells or bind to DNA still have strong antitumor activity (6). Indeed, those used in human therapy regulate plasma membrane structure, and they induce changes in the localization and activity of important peripheral signaling proteins, such as G proteins and PKC (4,7,8). This mode of action also appears to be responsible for the activity of hexamethylene bisacetamide against cancers (9, 10).In the search for molecules capable of i...

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Section: Discussionmentioning

confidence: 92%

Pivotal role of dihydrofolate reductase knockdown in the anticancer activity of 2-hydroxyoleic acid

Lladó¹,

Terés

Higuera

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…22 In brief, PBMC from HLA-A1 À donors were stimulated weekly with the mitomycin C-treated HLA-A1 þ lymphoblastoid cell line (LCL) 721 or the HLA-A1-transfected LCL C1R.A1. 37 CTL were used for apoptosis induction after they achieved specific cytotoxicity toward HLA-A1 expressing target cells (tested by standard chromium release assay). CD4 þ and CD8 þ T cells were isolated from CTL culture after the 4th round of stimulation.…”

Section: Methodsmentioning

confidence: 99%

4-hydroperoxy-cyclophosphamide mediates caspase-independent T-cell apoptosis involving oxidative stress-induced nuclear relocation of mitochondrial apoptogenic factors AIF and EndoG

et al. 2007

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Apoptosis is a major mechanism of treatment-induced T-cell depletion in leukemia and autoimmune diseases. While 'classical' apoptosis is considered to depend on caspase activation, caspase-independent death is increasingly recognized as an alternative pathway. Although the DNA-damaging drug cyclophosphamide (CY) is widely used for therapy of hematological malignancies and autoimmune disorders, the molecular mechanism of apoptosis induction remains largely unknown. Here, we report that treatment of Jurkat, cytotoxic, and primary leukemic T cells with an activated analog of CY, 4-hydroperoxycyclophosphamide (4-OOH-CY), induces caspase activation and typical features of apoptosis, although cell death was not prevented by caspase inhibition. Also depletion of murine thymocytes and splenocytes after CY treatment in vivo was not inhibited by Z-Val-Ala-DL-Asp-fluoromethylketone (Z-VAD.fmk). Caspase-8 and receptor-induced protein (RIP) were dispensable for 4-OOH-CY-mediated apoptosis, while overexpression of Bcl-2 was partially protective. 4-OOH-CY treatment induced reactive oxygen species production, upregulation of Bax, and nuclear relocation of the mitochondrial factors apoptosis-inducing factor (AIF) and endonuclease G (EndoG). The antioxidant N-acetyl-L-cysteine substantially inhibited conformational changes of Bax, loss of mitochondrial membrane potential, nuclear relocation of mitochondrial factors, and apoptosis induction in 4-OOH-CYtreated T cells. These results strongly indicate that oxidative damage-induced nuclear translocation of AIF and EndoG in 4-OOH-CY-treated T cells might represent an alternative death pathway in the absence of caspase activity.

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“…As stimulation with HLA-A1 expressing C1R.A1.CD95L cells prevent the activation of CD8 þ T cells (see Figure 2), we examined whether the presence of m-CD95L expressing APC could prevent the development of HLA-A1-specific CTL. Standard chromium release assays using T cells from C1R.A1.puro or C1R.A1.CD95L-stimulated cultures after different rounds of stimulation were used to test cytotoxicity towards the HLA-A1 expressing mouse mastocytoma cell line P1.A1 23 and the parental line P1.HTR (P1) (Figure 5a). C1R.A1.puro stimulated T cells started to exhibit HLA-A1-specific cytotoxicity after three rounds of stimulation and the lytic capacity of T cells increased with further stimulation.…”

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confidence: 99%

Membrane-bound CD95 ligand expressed on human antigen-presenting cells prevents alloantigen-specific T cell response without impairment of viral and third-party T cell immunity

et al. 2006

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Genetically modified antigen-presenting cells (APC) represent an attractive strategy for in vitro immunomodulation. In the human system, APC expressing HLA-A1 and a membrane-bound form of CD95L (m-CD95L) were used for selective depletion of HLA-A1-specific T cells. In short-term assays, m-CD95L-expressing APC-induced apoptosis in activated T cells and the constitutive presence of m-CD95L and HLA-A1 expressing APC in long-term T cell cultures prevented the expansion of CD4 þ and CD8 þ HLA-A1-specifc T cells and the development of HLA-A1-specific cytotoxicity. However, immunity towards third party, viral and bacterial antigens was maintained and T cells spared from depletion could be induced to develop cytotoxicity towards unrelated antigens. Interestingly, inhibition of HLA-A1-specific T cell response absolutely requires the coexpression of m-CD95L and HLA-A1 antigen on the same APC. Thus, m-CD95L expressing APC might be used in clinical settings to obtain tolerance induction in allogeneic transplantation systems or autoimmune diseases. Apoptosis mediated by the CD95 system plays a pivotal regulatory role in the maintenance of immune homeostasis. Deficiency in CD95 or CD95L expression in T cells mediates lymphoproliferative disorders due to the lack of apoptosis induction. 1 Paradoxically, several molecules of the CD95 signaling pathway are also required for T cell activation and proliferation. 2 In addition to T cells, live and death of antigenpresenting cells, which initiate T cell responses has to be tightly controlled to avoid the establishment of autoimmunity. 3 Activation-induced cell death (AICD) represents an apoptosis mechanism mediated via the interaction of CD95 with its ligand CD95L, to mediate T cell death and initiate the termination of an immune response to maintain tolerance to self antigens and to prevent autoimmunity. 4 Owing to the constitutive expression of CD95L in immune privileged organs such as testis or eye, 5,6 CD95L was considered as an immunoprotective agent able to counterattack activated T cells in vivo. However, the role of CD95L in transplantation tolerance is still controversial. While allogeneic pancreatic islands transplanted together with syngeneic CD95L expressing myoblasts were tolerated, 7 allogeneic CD95L expressing pancreatic b cells were rejected due to increased neutrophil infiltration. 8 Lack of immunogenicity of tumors and resistance towards T cell attacks were also correlated with the expression of CD95L on tumor tissues. Such tumors were shown to kill CD95-positive cells in vitro. 9 However, transfection of CD95L into murine tumor cells did not enhance tumor growth, but instead induced accelerated tumor rejection by neutrophils in vivo. [10][11][12] Systemic immunomodulation by CD95L was successfully achieved by antigen-presenting cells modified to express CD95L. 13 In mice antigen-specific elimination of activated T cells by engagement of CD95L on APC and CD95 on the activated T cells has been demonstrated in several models. 14,15 This approach benefits from the hig...

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Induction of apoptosis and modulation of activation and effector function in T cells by immunosuppressive drugs

Cited by 145 publications

References 55 publications

Pivotal role of dihydrofolate reductase knockdown in the anticancer activity of 2-hydroxyoleic acid

Pivotal role of dihydrofolate reductase knockdown in the anticancer activity of 2-hydroxyoleic acid

4-hydroperoxy-cyclophosphamide mediates caspase-independent T-cell apoptosis involving oxidative stress-induced nuclear relocation of mitochondrial apoptogenic factors AIF and EndoG

Membrane-bound CD95 ligand expressed on human antigen-presenting cells prevents alloantigen-specific T cell response without impairment of viral and third-party T cell immunity

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