Immune deviation following pulse cyclophosphamide/methylprednisolone treatment of multiple sclerosis: Increased interleukin‐4 production and associated eosinophilia

Smith, Derek R.; Balashov, Konstantin; Hafler, David A.; Khoury, Samia J.; Weiner, Howard L.

doi:10.1002/ana.410420307

Cited by 81 publications

(30 citation statements)

References 33 publications

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“…Thus, CY/MP treatment was associated with a shift in cytokines from Th1 to Th2/Th3 pattern. These results agree with our recent report of increased anti-CD3-induced IL-4 secretion by T cells in patients treated with cyclophosphamide (27). The increase in percentage of IL-4, IL-5, and TGF-␤-producing cells in CY/MP treated patients was much less than the changes we observed for IL-12 and IFN-␥.…”

Section: Discussionsupporting

confidence: 92%

Elevated interleukin-12 in progressive multiple sclerosis correlates with disease activity and is normalized by pulse cyclophosphamide therapy.

et al. 1998

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Section: Discussionsupporting

confidence: 92%

Elevated interleukin-12 in progressive multiple sclerosis correlates with disease activity and is normalized by pulse cyclophosphamide therapy.

et al. 1998

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“…Indeed, CTX-treated patients showed increased eosinophil counts that were positively and significantly correlated with an upregulation of interleukin-4 (IL-4) production by peripheral blood mononuclear cells (PBMC) [21]. Moreover, pulse CTX therapy induced increased interleukin-10 (IL-10) and decreased interferon gamma (IFNγ) and interleukin-12 (IL-12) production by MS PBMC [21,22]. Furthermore, an increased frequency of both myelin basic protein-and proteolipid proteinspecific IL-4 secreting T cell lines was observed in CTX treated compared with untreated MS patients [23].…”

Section: Discussionmentioning

confidence: 99%

Cyclophosphamide is effective in stabilizing rapidly deteriorating secondary progressive multiple sclerosis

Perini

Gallo

2003

J Neurol

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The safety and efficacy of pulse cyclophosphamide (CTX) therapy was investigated in patients with very active secondary progressive multiple sclerosis, characterized by frequent relapses and rapid disability progression. For this purpose the clinical and MRI effects were assessed. Sixteen patients, 11 female and 5 male, were experiencing rapidly deteriorating disease, characterized by frequent and severe relapses as well as rapid progression (defined by an increase of more than 1 EDSS point in a period of 1 year). Mean relapse rate in the two years preceding CTX therapy was 3.0 +/-1.4. Mean EDSS was 4.0+/-1.4 one year before therapy and 5.6+/-1.0 at study entry. Treatment consisted in administration of high dose intravenous CTX every four weeks for one year and then every eight weeks for an additional twelve months. CTX dose was tailored to the patient's white blood cell response, and ranged from 800 to 1,200 mg/m(2) body surface. MRI was performed before therapy and then at 12 (Y1) and 24 (Y2) months. Eight patients with similar clinical features constituted a control group. CTX therapy was safe and well tolerated, and no severe side effects were observed. The EDSS decreased to 4.3+/-1.6 at Y1 (Y0 vs.Y1: p< 0.001) and to 4.1+/-1.6 at Y2 (Y0 vs.Y2: p< 0.001). Only four patients experienced relapses during the first year of therapy, while no relapses were observed during the second year of therapy. The mean relapse rate during therapy was 0.25 +/-0.45 (p< 0.0001). No increase in T2 lesion load was observed over the two years. A significant clinical and MRI deterioration was observed in the control group. Therapy with pulse CTX was able to stop disease activity and progression in patients with rapidly evolving secondary-progressive MS.

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“…Several agents have been used to induce immune deviation in MS and EAE, including retinoids, glatiramer acetate, and cyclophosphamide (24,32,33). PPAR␣ agonists would represent another class of drugs with a favorable safety profile that could potentially be used in the treatment of human autoimmune disorders such as MS.…”

Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor α Agonists as Therapy for Autoimmune Disease

Lovett-Racke¹,

Hussain²,

Northrop³

et al. 2004

The Journal of Immunology

200

170

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Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. PPARγ ligands, which include the naturally occurring PG metabolite 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2), as well as thiazolidinediones, have been shown to have anti-inflammatory activity. The PPARα agonists, gemfibrozil, ciprofibrate, and fenofibrate, have an excellent track history as oral agents used to treat hypertriglyceridemia. In the present study, we demonstrate that these PPARα agonists can increase the production of the Th2 cytokine, IL-4, and suppress proliferation by TCR transgenic T cells specific for the myelin basic protein Ac1–11, as well as reduce NO production by microglia. Oral administration of gemfibrozil and fenofibrate inhibited clinical signs of experimental autoimmune encephalomyelitis. More importantly, gemfibrozil was shown to shift the cytokine secretion of human T cell lines by inhibiting IFN-γ and promoting IL-4 secretion. These results suggest that PPARα agonists such as gemfibrozil and fenofibrate, may be attractive candidates for use in human inflammatory conditions such as multiple sclerosis.

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Immune deviation following pulse cyclophosphamide/methylprednisolone treatment of multiple sclerosis: Increased interleukin‐4 production and associated eosinophilia

Cited by 81 publications

References 33 publications

Elevated interleukin-12 in progressive multiple sclerosis correlates with disease activity and is normalized by pulse cyclophosphamide therapy.

Elevated interleukin-12 in progressive multiple sclerosis correlates with disease activity and is normalized by pulse cyclophosphamide therapy.

Cyclophosphamide is effective in stabilizing rapidly deteriorating secondary progressive multiple sclerosis

Peroxisome Proliferator-Activated Receptor α Agonists as Therapy for Autoimmune Disease

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