Update on FTY720: review of mechanisms and clinical results

Chueh, Shih-Chieh; Kahan, Barry D.

doi:10.1097/00075200-200312000-00006

Cited by 6 publications

(2 citation statements)

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“…51 FTY720 is phosphorylated by sphingosine kinase-2 in a similar manner to the modification of Sph to S1P. 51 In addition to anti-inflammatory properties via S1P binding, FTY720 has also been shown to inhibit ceramide synthase, the class of enzyme that regulates ceramide acyl chain length during synthesis. 52 Because of its anti-inflammatory effects, and potential decrease in ceramides, it is possible that treatment with FTY720 in conjunction with other antiinflammatory compounds may impede pathogenesis of FD.…”

Section: Visual Pathology In Farber Disease Micementioning

confidence: 99%

Acid Ceramidase Deficiency in Mice Leads to Severe Ocular Pathology and Visual Impairment

Sajdak

Sikora

et al. 2019

The American Journal of Pathology

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Farber disease (FD) is a debilitating lysosomal storage disorder characterized by severe inflammation and neurodegeneration. FD is caused by mutations in the ASAH1 gene, resulting in deficient acid ceramidase (ACDase) activity. Patients with ACDase deficiency exhibit a broad clinical spectrum. In classic cases, patients develop hepatosplenomegaly, nervous system involvement, and childhood mortality. Ocular manifestations include decreased vision, a grayish appearance to the retina with a cherry red spot, and nystagmus. That said, the full effect of ACDase deficiency on the visual system has not been studied in detail. We previously developed a mouse model that is orthologous for a known patient mutation in Asah1 that recapitulates human FD. Herein, we report evidence of a severe ocular pathology in Asah1 P361R/P361R mice. Asah1 P361R/P361R mice exhibit progressive retinal and optic nerve pathology. Through noninvasive ocular imaging and histopathological analyses of these Asah1 P361R/ P361R animals, we revealed progressive inflammation, the presence of retinal dysplasia, and significant storage pathology in various cell types in both the retina and optic nerves. Lipidomic analyses of retinal tissues revealed an abnormal accumulation of ceramides and other sphingolipids. Electroretinograms and behavioral tests showed decreased retinal and visual responses. Taken together, these data suggest that ACDase deficiency leads to sphingolipid imbalance, inflammation, dysmorphic retinal and optic nerve pathology, and severe visual impairment. (Am J Pathol 2019, 189: 320e338; https://doi.

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Section: Visual Pathology In Farber Disease Micementioning

confidence: 99%

Acid Ceramidase Deficiency in Mice Leads to Severe Ocular Pathology and Visual Impairment

Sajdak

Sikora

et al. 2019

The American Journal of Pathology

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“…It induces sequestration of T and B cells into peripheral lymph nodes, mesenteric lymph nodes and Peyer patches by a mechanism involving the sphyngosine‐1‐phosphate receptor on lymphocytes. The exact mechanism is still unclear, but is coupled to G protein Rho activation and results in altered patterns of lymphocyte homing [30]. In experimental models, FTY 720 has been shown to prolong the survival of solid organ transplants, including liver transplantation [31], and the only significant side effect in phase II trails is bradycardia, because of cross‐reactivity with heart spingosine‐1‐phosphate [32].…”

Section: Mechanism Of Action Of Immunosuppressantsmentioning

confidence: 99%

Immunosuppression: towards a logical approach in liver transplantation

Perry

Neuberger

2004

Clinical and Experimental Immunology

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SummaryOver the last two decades there has been a significant increase in the number and types of immunosuppressive agents that have been available to clinicians. The protocols for immunosuppression used in liver transplantation have been derived historically from those in renal transplantation. During the last decade there has been a shift in the use of immunosuppression, with the introduction of interleukin (IL)-2 receptor antagonists in place of anti-lymphocyte preparations, substitution of tacrolimus for cyclosporin and mycophenolate for azathioprine. The use of corticosteroids has been reduced. For a variety of reasons, these changes have not always been made on the basis of properly randomized studies. The place of newer agents, such as sirolimus and leflunomide derivatives and of the microbiological agents, is unclear. In this review, we outline briefly the mechanism of action of drugs and suggest possible approaches to the management of the liver allograft recipient, suggesting how treatment could be adjusted according to the indication for transplantation as well as the individual's comorbidities.

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