Mitoxantrone induces cell death in peripheral blood leucocytes of multiple sclerosis patients

Chan, Andrew; Weilbach, F. X.; Toyka, Klaus V.; Gold, Ralf

doi:10.1111/j.1365-2249.2005.02653.x

Cited by 91 publications

(47 citation statements)

References 23 publications

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“…These results extend recent reports that higher concentrations of mitoxantrone (as achieved soon after i.v. infusion) can mediate immune cell necrosis, whereas at lower concentrations mitoxantrone can trigger immune cell apoptosis (20,21). Together, these findings support the notion that mitoxantrone induces the preferential death of CD19 ϩ CD27 ϩ memory B cells, resulting in a relatively higher proportion of circulating CD19 ϩ CD27 Ϫ naive B cells.…”

Section: Treatment With Mitoxantrone Results In Reciprocal Modulationsupporting

confidence: 76%

“…Mitoxantrone, recently approved for the therapy of MS, is a relatively nonselective anti-metabolite chemotherapeutic drug thought to impact both T cell and B cell responses (20,21). We applied our ex vivo assay to B cells freshly isolated from a sequential cohort of MS patients before and during standard mitoxantrone treatment (23).…”

Section: Treatment With Mitoxantrone Results In Reciprocal Modulationmentioning

confidence: 99%

“…We next show that this cytokine network is dysregulated in patients with the autoimmune disease multiple sclerosis (MS), 3 whose B cells exhibit a significantly diminished capacity to secrete the immune regulatory cytokine IL-10. Treatment with mitoxantrone, an approved chemotherapy for aggressive MS (20,21), resulted in increased B cell production of IL-10 and decreased production of the proinflammatory cytokines TNF-␣ and lymphotoxin (LT). Prospective studies of reconstituting human B cells following selective and nonselective depletion allowed us to further probe the in vivo regulation of B cell effector cytokines.…”

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confidence: 99%

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Distinct Effector Cytokine Profiles of Memory and Naive Human B Cell Subsets and Implication in Multiple Sclerosis

Duddy

Niino

Adatia

et al. 2007

The Journal of Immunology

583

594

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Although recent animal studies have fuelled growing interest in Ab-independent functions of B cells, relatively little is known about how human B cells and their subsets may contribute to the regulation of immune responses in either health or disease. In this study, we first confirm that effector cytokine production by normal human B cells is context dependent and demonstrate that this involves the reciprocal regulation of proinflammatory and anti-inflammatory cytokines. We further report that this cytokine network is dysregulated in patients with the autoimmune disease multiple sclerosis, whose B cells exhibit a decreased average production of the down-regulatory cytokine IL-10. Treatment with the approved chemotherapeutic agent mitoxantrone reciprocally modulated B cell proinflammatory and anti-inflammatory cytokines, establishing that the B cell cytokine network can be targeted in vivo. Prospective studies of human B cells reconstituting following in vivo depletion suggested that different B cell subsets produced distinct effector cytokines. We confirmed in normal human B cell subsets that IL-10 is produced almost exclusively by naive B cells while the proinflammatory cytokines lymphotoxin and TNF-α are largely produced by memory B cells. These results point to an in vivo switch in the cytokine “program” of human B cells transitioning from the naive pool to the memory pool. We propose a model that ascribes distinct and proactive roles to memory and naive human B cell subsets in the regulation of memory immune responses and in autoimmunity. Our findings are of particular relevance at a time when B cell directed therapies are being applied to clinical trials of several autoimmune diseases.

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Section: Treatment With Mitoxantrone Results In Reciprocal Modulationsupporting

confidence: 76%

Section: Treatment With Mitoxantrone Results In Reciprocal Modulationmentioning

confidence: 99%

mentioning

confidence: 99%

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Distinct Effector Cytokine Profiles of Memory and Naive Human B Cell Subsets and Implication in Multiple Sclerosis

Duddy

Niino

Adatia

et al. 2007

The Journal of Immunology

583

594

View full text Add to dashboard Cite

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“…26 Comparison of peripheral blood mononuclear cells obtained from MS patients, before and immediately after application of mitoxantrone, exhibited a decreased proliferation of peripheral blood mononuclear cells based on necrotic cell death, predominantly in B cells. 27 Fidler et al 21 reported a decreased secretion of the pro-inflammatory cytokines interferon-␥, tumor necrosis factor-␣ and interleukin (IL)-2. In contrast, recent ex vivo analysis of the cytokine profile of immune cells obtained from patients before and during treatment with mitoxantrone revealed a decrease of IL-10 (an anti-inflammatory cytokine) expressing monocytes and a decrease of IL-2R-␤1 expressing T cells after six months of treatment.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Immunosuppressive Agents in Multiple Sclerosis

2007

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Summary:Immunosuppressive agents have been used in multiple sclerosis (MS) for decades. The approval of several immunomodulatory agents against MS beginning in the 1990s, whose putative mechanisms of action appeared "more MSspecific," curtailed the importance of immunosuppressants, which made them treatment options of second choice. However, with the recent approval of mitoxantrone for treatment of patients with active forms of relapsing-remitting or secondary progressive MS and with a number of oral immunosuppressive agents being assessed in phase II and III clinical trials, a "renaissance" of this type of agents is currently occurring. This review provides an outline of the most important clinical studies and discusses relevant side effects of the major immunosuppressants (i.e., mitoxantrone, azathioprine, cyclophosphamide, methotrexate, mycophenolate mofetil, cladribine, and sirolimus/temsirolimus). The current knowledge of the putative mechanisms of action of these compounds is discussed.

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“…They are strictly contraindicated for long term use as they are associated with a number of side effects (Merck,). Chemotherapeutics with a potential of suppressing the immune system like mitoxantrone inducing the apoptosis of lymphocytes and cyclophosphamide acting against both the T & B-cell activities, were also tried against RR and secondary progressive MS (Chan et al, 2005;Fauci et al, 1971; Multiple Sclerosis Treatments). The drugs in development for MS are Fingolimod and BG00012 that are in phase II clinical trials.…”

Section: Multiple Sclerosis (Ms)mentioning

confidence: 99%

Recent Advances in the Treatment of Neurological Autoimmune Disorders

Kanwar¹,

Sriramoju²,

Kanwar³

2011

Autoimmune Disorders - Current Concepts and Advances From Bedside to Mechanistic Insights

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Mitoxantrone induces cell death in peripheral blood leucocytes of multiple sclerosis patients

Abstract: Summary Mitoxantrone (MX) is a cytotoxic drug with proven clinical efficacy in active multiple sclerosis (MS). In this ex vivo

Cited by 91 publications

References 23 publications

Distinct Effector Cytokine Profiles of Memory and Naive Human B Cell Subsets and Implication in Multiple Sclerosis

Distinct Effector Cytokine Profiles of Memory and Naive Human B Cell Subsets and Implication in Multiple Sclerosis

Immunosuppressive Agents in Multiple Sclerosis

Recent Advances in the Treatment of Neurological Autoimmune Disorders

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