Disruption of the interaction of T cells with antigen‐presenting cells by the active leflunomide metabolite teriflunomide: Involvement of impaired integrin activation and immunologic synapse formation

Zeyda, Maximilian; Poglitsch, Marko; Geyeregger, René; Smolen, Josef S; Zlabinger, Gerhard J.; Hörl, Walter H.; Waldhäusl, W.; Stulnig, Thomas M.; Säemann, Marcus D.

doi:10.1002/art.21255

Cited by 104 publications

(62 citation statements)

References 48 publications

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“…2,3 Teriflunomide's oral bioavailability is 100%, with peak plasma levels achieved within 1-2 hours of intake. Leflunomide is converted almost entirely into teriflunomide in the intestinal mucosa or plasma, making the pharmacokinetics of these drugs nearly identical.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Teriflunomide

Oh¹,

O'Connor²

2013

Neur Clin Pract

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SummaryTeriflunomide is a novel disease-modifying agent that was recently approved for use in the treatment of multiple sclerosis (MS). Teriflunomide has demonstrated clinical efficacy and safety in a number of large, multicenter, phase III clinical trials and is an attractive agent to add to the growing repertoire of available treatments for MS, as it has the benefit of oral administration. Furthermore, existing clinical experience with its parent drug, leflunomide, provides indirect long-term safety data. This review summarizes teriflunomide's pharmacologic properties, pivotal clinical trials, and safety profile, and ends with a discussion of the role of teriflunomide in the context of current and emerging MS treatment options.T eriflunomide was recently approved for use in relapsing forms of multiple sclerosis (MS) in the United States. It is the second oral agent that has been approved for MS, and existing experience with its parent drug, leflunomide, gives teriflunomide the benefit of indirect long-term safety data. This review summarizes teriflunomide's pharmacologic properties, clinical efficacy, safety profile, and use in light of the expanding treatment options of relapsing-remitting MS (RRMS). Mechanism of actionTeriflunomide is primarily an inhibitor of dihydroorotate-dehydrogenase (DHODH), a key mitochondrial enzyme involved in the de novo synthesis of pyrimidines in rapidly proliferating cells. In MS, teriflunomide reduces the activity of proliferating T-lymphocytes and B-lymphocytes, thereby diminishing the overall inflammatory response. Pyrimidines are involved in other cellular functions in addition to DNA/RNA synthesis, including protein and lipid glycosylation, phospholipid synthesis, and DNA repair, which lead to a variety of downstream immunomodulatory effects. Importantly, teriflunomide is a cytostatic rather than cytotoxic drug, as homeostatic hematopoietic cell lines are not affected by DHODH inhibition due to a DHODH-independent "salvage pathway" that can generate necessary cellular pools of pyrimidine.

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Section: Mechanism Of Actionmentioning

confidence: 99%

Teriflunomide

Oh¹,

O'Connor²

2013

Neur Clin Pract

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“…42 Teriflunomide has also demonstrated efficiency in inhibiting T-cell-dependent antibody production, suggesting that it modulates the interaction between T cells and B cells. 43 Direct T-cell inhibitory effects include the alteration of integrin function (at different stages of T-cell activation) and interference with calcium signaling to T cells. These inhibitory actions of teriflunomide lead to several results which include a diminished interaction between T cells and antigen-presenting cells, an impaired migratory capability of T cells (in vitro and in vivo), and a diminished ability for exposed T cells to activate monocytes in vitro.…”

Section: Effects On B and T Cellsmentioning

confidence: 99%

“…47,48 The effects of DHODH inhibition also extend to myeloid cell lines via the suppression of growth factor-induced proliferation in myeloid progenitors and mast cell lines. 43 In vitro suppression of myeloid progenitors by teriflunomide occurs at very low concentrations. Certain effector functions of the innate immune system are also suppressed by teriflunomide.…”

Section: Other Effectsmentioning

confidence: 99%

Emerging oral immunomodulating agents – focus on teriflunomide for the treatment of multiple sclerosis

Nwankwo¹,

Allington²,

Rivey³

2012

DNND

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Treatment for multiple sclerosis (MS), a chronic disease of the central nervous system, has historically relied exclusively on the use of injectable therapies. As the disease requires lifelong therapy, the development of oral therapies that are safe and effective would provide a more convenient dosage form that may improve patient compliance. One oral medication (fingolimod) was recently approved for treatment of MS. Teriflunomide, an immunomodulator, is one of four oral therapies currently undergoing Phase III trials. Teriflunomide exerts its clinical effects via selective inhibition of de novo pyrimidine synthesis, primarily targeting proliferating T and B lymphocytes in the periphery. Teriflunomide was effective as monotherapy in reducing magnetic resonance imaging lesions and annual relapse rates in Phase II and Phase III trials. When teriflunomide was added to interferon or glatiramer acetate therapy in Phase II trials, teriflunomide reduced magnetic resonance imaging lesions significantly more than either interferon or glatiramer acetate alone. Treatment-emergent adverse events occurred at similar rates among all groups in teriflunomide studies, with a trend towards a higher treatment emergent adverse events rate in the higher dosage group of teriflunomide (14 mg daily). Treatment discontinuations in teriflunomide trials were relatively low, suggesting that teriflunomide monotherapy is well tolerated. This article reviews the mode of action of teriflunomide, its pharmacokinetic, clinical efficacy, and safety profiles.

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“…Engagement of T cell receptor (TCR) by peptide-MHC complexes without co-stimulatory molecules results in profoundly anergic T cells that are unable to respond to further activation. 8,[21][22][23][24][25][26][27][28][29][30][31][32] It is therefore necessary to evaluate the expression pattern of these immune related molecules in tumor cell for further understanding the mechanism of tumor immune evasion and tumor development, and for identification of immunotherapeutic targets.…”

mentioning

confidence: 99%

Expression of immune-related molecules in primary EBV positive chinese nasopharyngeal carcinoma: Associated with latent membrane protein 1 (LMP1) expression

Li¹,

Zhang²,

Xie³

et al. 2007

Cancer Biology & Therapy

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To understand the role of Epstein-Barr virus (EBV) and viral products in associated with immunophenotype and clinical outcome of primary nasopharyngeal carcinoma (NPC), the expression levels of chemokines IFN-g-induced protein 10 (IP-10, CXCL10), stromal-derived factor-1 (SDF-1, CXCL12) and its receptor CXCR4 was investigated in 56 primary NPC biopsy specimens from Chinese NPC patients in parallels with LMP1 antigen and EBER1 by immunohistochemisty (IHC) and in situ hybridization (ISH). Moreover, the expression levels of HLA class I (b-microglobulin) and II antigen (HLA-DR), and co-stimulatory molecule CD54 were also evaluated in 31 out of these 56 patients using immunohistochemisty (IHC). Our results showed that (a) the elevated expression levels of IP10, SDF-1, CXCR4, b-microglobulin, HLA-DR and CD54 in NPC lesions was 66%, 36%, 30%, 42%, 55% and 69%, respectively. The differentiated nonkeratinizing and undifferentiated types of nasopharyngeal carcinoma (NPC) are associated with Epstein-Barr virus (EBV) in South China, which has the highest incidence rate in the world. 1 The EBV latent type II antigens include nuclear antigen 1 (EBNA1), and latent membrane protein 1 (LMP1, in approximately 50%, seen in ref.2) and protein 2 (LMP2), in addition small non-polyadenylated viral RNAs non-coding nuclear RNAs (EBERs) and BamHI-A rightward transcripts (BARTs) expressed in NPC tumor cells. The expressions of EBV antigens in NPC tumor cells provide the targets for adoptive immunotherapy. [3][4][5][6] However, the poorly differentiated NPC is always characterized by the presence of a highly cellular lymphoid stroma admixed with tumor cells. 7 However, the role of local immunity surrounding NPC cells and the role EBV and viral products expressed in tumor cell remain unclear, which is associated with the expression of immune-related molecules including chemokines and receptors, HLA class I and II antigens, and co-stimulatory molecules and the role of EBV and viral products to alter the expression of immune-related molecules on tumor cells. It has been reported that the expression pattern of immune related-molecules on tumor cells will affect the outcome of T-cell-based adoptive immunotherapy for NPC. [8][9][10] In the tumor bed, chemokines and cytokines are secreted by both tumor-infiltrating immune cells and the tumor cells, and these chemokines and cytokines are capable of pleiotropic effects. 8 For example, IP-10 is a CXC chemokine produced by endothelial cells and macrophages post-stimulated by IFNg. IP-10 can induce rapid and transient adhesion of human IL-2-stimulated T lymphocytes to endothelial cells through its receptor CXCR3, which is selectively expressed on activated T cells. It is thought that expression of IP-10 in tumor cells induces potent anti-tumor functions, such as induction of the Th1 immune response and inhibition of angiogenesis. 11-13 SDF-1 is a a-chemokine, and bind to the only receptor CXCR4. Recent studies suggested that the SDF-1/CXCR4 axis play an important and unique role not only in th...

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Disruption of the interaction of T cells with antigen‐presenting cells by the active leflunomide metabolite teriflunomide: Involvement of impaired integrin activation and immunologic synapse formation

Cited by 104 publications

References 48 publications

Teriflunomide

Teriflunomide

Emerging oral immunomodulating agents – focus on teriflunomide for the treatment of multiple sclerosis

Expression of immune-related molecules in primary EBV positive chinese nasopharyngeal carcinoma: Associated with latent membrane protein 1 (LMP1) expression

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Disruption of the interaction of T cells with antigen‐presenting cells by the active leflunomide metabolite teriflunomide: Involvement of impaired integrin activation and immunologic synapse formation

Cited by 104 publications

References 48 publications

Teriflunomide

Teriflunomide

Emerging oral immunomodulating agents &ndash; focus on teriflunomide for the treatment of multiple sclerosis

Expression of immune-related molecules in primary EBV positive chinese nasopharyngeal carcinoma: Associated with latent membrane protein 1 (LMP1) expression

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Emerging oral immunomodulating agents – focus on teriflunomide for the treatment of multiple sclerosis