Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of activated peripheral T cells.

Genestier, Laurent; Paillot, Romain; Fournel, Sylvie; Ferraro, Carole; Miossec, Pierre; Revillard, J P

doi:10.1172/jci2676

Cited by 400 publications

(302 citation statements)

References 38 publications

Supporting

Mentioning

266

Contrasting

Unclassified

Order By: Relevance

“…Mice which were primed with minor antigen incompatible spleen cells and simultaneously treated with CP showed clonal deletion of activated allogeneic T cells in the periphery and the thymus [43,44]. Interestingly, we found that CP induced apoptosis in activated as well as in resting T cell populations, while MTX only mediated apoptosis of activated T cells, as described previously [22].…”

Section: Discussionsupporting

confidence: 83%

“…Glucocorticoids have been shown to induce apoptosis of murine thymocytes [17], T cell hybridomas [18] and human leukaemic T cells [19]. Although methotrexate (MTX) was found to trigger CD95L expression in leukaemic T cell lines [20] and hepatoma cell lines [21], MTX may also induce apoptosis by a CD95-independent pathway [22]. Induction of CD95-dependent apoptosis by cyclophosphamide has been described for in vivo treatment of rat thymocytes [23].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Strauß

Osen

Debatin

2002

Clinical and Experimental Immunology

149

View full text Add to dashboard Cite

SUMMARYImmunosuppressive drugs (ISD) are used for the prevention and treatment of graft rejection, graftversus-host-disease (GVHD) and autoimmune disorders. The precise mechanisms by which ISD interfere with T cell activation and effector function or delete antigen-specific T cells are defined only partially. We analysed commonly used ISD such as dexamethasone (DEX), mycophenolic acid (MPA), FK506, cyclosporin A (CsA), rapamycin (RAP), methotrexate (MTX) and cyclophosphamide (CP) for apoptosis-induction and modulation of activation and effector function in human peripheral T cells, cytotoxic T cell lines (CTL) and Jurkat T cells. Of all drugs tested only CP and MTX prevented antigenspecific proliferation of T cells and decreased cytotoxicity of alloantigen specific CTL lines by direct induction of apoptosis. MTX and CP also slightly increased activation-induced cell death (AICD) and CD95-sensitivity. In contrast, all other drugs tested did not induce T cell apoptosis, increase CD95-sensitivity or AICD. CsA and FK506 even prevented AICD by down-modulation of CD95L. DEX, MPA, CsA, FK506 and RAP inhibited activation of naive T cells, but were not able to block proliferation of activated T cells nor decrease cytotoxic capacity of CTL lines. These results show that ISD can be classified according to their action on apoptosis-induction and inhibition of proliferation and would favour a rational combination therapy to delete existing reactive T cells and prevent further T cell activation.

show abstract

Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

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

Strauß

Osen

Debatin

2002

Clinical and Experimental Immunology

149

View full text Add to dashboard Cite

show abstract

“…We have previously described that nucleotide restriction inhibits T cell proliferation and could induce apoptosis of cycling T cells in vitro (7,8,27). Therefore, we investigated the effects of nucleotide synthesis inhibitors on T cell proliferation in vivo.…”

Section: Nucleotide Synthesis Inhibitors Affect Peptide-induced Prolimentioning

confidence: 99%

Restriction of De Novo Nucleotide Biosynthesis Interferes with Clonal Expansion and Differentiation into Effector and Memory CD8 T Cells

Quéméneur

Beloeil

Michallet

et al. 2004

The Journal of Immunology

View full text Add to dashboard Cite

Nucleotide synthesis inhibitors are currently used in neoplastic diseases or as immunosuppressive agents for the prevention of acute rejection in organ transplantation and the treatment of autoimmune disorders. We have previously described that these inhibitors interfere with proliferation and survival of primary T cells in vitro. However, the precise effects of nucleotide restriction on effector and memory functions have not been elucidated. In this study, we investigated the impact of nucleotide synthesis inhibition on CD8 T cell differentiation by using TCR transgenic mice (F5) specific for the influenza virus nucleoprotein 68 peptide presented on the H-2Db molecule. Our results show that methotrexate and 5-fluorouracil prevent the acquisition of effector functions, such as IFN-γ, granzyme B expression, and cytotoxic function following antigenic stimulation of naive cells. Surprisingly, in the presence of mycophenolate mofetil, activated F5 cells are still able to produce granzyme B and to kill target cells but to a lesser extent compared with control. All three inhibitors interfere with the differentiation of naive cells into memory CD8 T cells. In contrast, the drugs are unable to inhibit the development of improved cytotoxic functions displayed by memory CD8 T cells.

show abstract

“…We and other investigators showed that the immunosuppressive effects of the Western antirheumatic drug (ARD), HCQ, and of Chinese ARDs, tetrandrine (Tet) and Tripterygium wilfordii hook F (TWHf), were mediated through both the inhibition of T cell activation and the induction of T cell apoptosis (12)(13)(14)(15). In addition, high concentrations (0.1-10 M) of MTX, another important DMARD, have been shown to induce apoptosis of activated PBLs (16).…”

mentioning

confidence: 99%

Western and Chinese Antirheumatic Drug-Induced T Cell Apoptotic DNA Damage Uses Different Caspase Cascades and Is Independent of Fas/Fas Ligand Interaction

Lai

Chang

et al. 2001

The Journal of Immunology

View full text Add to dashboard Cite

Spontaneous or therapeutic induction of T cell apoptosis plays a critical role in establishing transplantation tolerance and maintaining remission of autoimmune diseases. We investigated the mechanisms of apoptosis induced by Chinese and Western antirheumatic drugs (ARDs) in human T cells. We found that hydroxychloroquine, Tripterygium wilfordii hook F, and tetrandrine (Tet), but not methotrexate, at therapeutic concentrations can cause T cell death. In addition, Tet selectively killed T cells, especially activated T cells. Although ARD-induced cytotoxicity was mediated through apoptotic mechanisms, Fas/Fas ligand interaction was not required. We further demonstrated that the processes of phosphatidylserine externalization and DNA damage along the ARD-induced T cell apoptotic pathway could operate independently, and that selective inhibition of DNA damage by caspase inhibitors did not prevent T cells from undergoing cell death. Moreover, we found that Tet- and Tripterygium wilfordii hook F-induced T cell DNA damage required caspase-3 activity, and hydroxychloroquine-induced T cell DNA damage was mediated through a caspase-3- and caspase-8-independent, but Z-Asp-Glu-Val-Asp-fluomethyl ketone-sensitive, signaling pathway. Finally, the observation that ARD-induced activation of caspase-3 in both Fas-sensitive and Fas-resistant Jurkat T cells indicates that Fas/Fas ligand interaction plays no role in ARD-induced T cell apoptosis. Our observations provide new information about the complex apoptotic mechanisms of ARDs, and have implications for combining Western and Chinese ARDs that have different immunomodulatory mechanisms in the therapy of autoimmune diseases and transplantation rejection.

show abstract

Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of activated peripheral T cells.

Cited by 400 publications

References 38 publications

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

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

Restriction of De Novo Nucleotide Biosynthesis Interferes with Clonal Expansion and Differentiation into Effector and Memory CD8 T Cells

Western and Chinese Antirheumatic Drug-Induced T Cell Apoptotic DNA Damage Uses Different Caspase Cascades and Is Independent of Fas/Fas Ligand Interaction

Contact Info

Product

Resources

About