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Fingolimod attenuates experimental autoimmune neuritis and contributes to Schwann cell-mediated axonal protection.

ABSTRACT: Fingolimod, a sphingosine-1-phosphate receptor modulator with well-described immunomodulatory properties involving peripheral immune cell trafficking, was the first oral agent approved for the treatment of relapsing remitting multiple sclerosis. Analogous immunomodulatory treatment options for chronic peripheral autoimmune neuropathies are lacking.We tested fingolimod in the animal model of experimental autoimmune neuritis in Lewis rat. Six to eight-week-old female rats were immunized with P2 peptide and from this day on treated with fingolimod. Histology of the sciatic nerve was done to analyze T cell and macrophage cell count, intercellular adhesion molecule (ICAM) and amyloid precursor protein (APP) expression, as well as apoptotic Schwann cell counts.Preventive oral treatment with 0.1 mg/kg up to 3 mg/kg fingolimod once daily dissolved in rapeseed oil completely ameliorated clinical neuritis signs. It reduced circulating peripheral blood T cells and infiltrating T cells and macrophages in the sciatic nerve, whereas at the same time, it preserved blood-nerve barrier impermeability. Most importantly, fingolimod showed beneficial properties on the pathogenic process as indicated by fewer apoptotic Schwann cells and a lower amount of amyloid precursor protein indicative of axonal damage at the peak of disease course.Taken together, orally administered low-dose fingolimod showed an impressive immunomodulatory effect in the rat model of experimental autoimmune neuritis. Our current observations introduce fingolimod as an attractive treatment option for neuritis patients.

SUBMITTER: Ambrosius B

PROVIDER: S-EPMC5406994 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Fingolimod attenuates experimental autoimmune neuritis and contributes to Schwann cell-mediated axonal protection.

Ambrosius Björn B Pitarokoili Kalliopi K Schrewe Lisa L Pedreiturria Xiomara X Motte Jeremias J Gold Ralf R

Journal of neuroinflammation 20170426 1

<h4>Background</h4>Fingolimod, a sphingosine-1-phosphate receptor modulator with well-described immunomodulatory properties involving peripheral immune cell trafficking, was the first oral agent approved for the treatment of relapsing remitting multiple sclerosis. Analogous immunomodulatory treatment options for chronic peripheral autoimmune neuropathies are lacking.<h4>Methods</h4>We tested fingolimod in the animal model of experimental autoimmune neuritis in Lewis rat. Six to eight-week-old fe ...[more]

PMID: 28446186

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Project description:BACKGROUND: Recent reports show that gene therapy may provide a long-term, safe and effective intervention for human diseases. In this study, we investigated the effectiveness of adeno-associated virus 2 (AAV2) based human interferon-alpha (hIFN-?) gene therapy in experimental autoimmune uveoretinitis (EAU), a classic model for human uveitis. METHODOLOGY/PRINCIPAL FINDINGS: An AAV2 vector harboring the hIFN-? gene (AAV2.hIFN-?) was subretinally injected into B10RIII mice at two doses (1.5×10(6) vg, 1.5×10(8) vg). AAV2 vector encoding green fluorescent protein (AAV2.GFP) was used as a control (5×10(8) vg). The expression of hIFN-? in homogenized eyes and serum was detected by ELISA three weeks after injection. The biodistribution of vector DNA in the injected eyes, contralateral eyes and distant organs was determined by PCR. EAU was induced by immunization with IRBP(161-180) three weeks following vector injections, and evaluated clinically and pathologically. IRBP-specific proliferation and IL-17 expression of lymphocytes from the spleen and lymph nodes were assayed to test the influence of the subretinal delivery of AAV2.hIFN-? on the systemic immune response. hIFN-? was effectively expressed in the eyes from three weeks to three months following subretinal injection of AAV2.hIFN-? vector. DNA of AAV2.GFP was observed only in the injected eyes, but not in the distant organs or contralateral eyes. Subretinal injection of both doses significantly attenuated EAU activity clinically and histologically. For the lower dose, there was no difference concerning lymphocyte proliferation and IL-17 production among the AAV2.hIFN-?, AAV2.GFP and PBS injected mice. However, the higher dose of AAV2.hIFN-? significantly suppressed lymphocyte proliferation and IL-17 production. CONCLUSIONS/SIGNIFICANCE: Subretinal delivery of AAV2.hIFN-? lead to an effective expression within the eye for at least three months and significantly attenuated EAU activity. AAV2.hIFN-? was shown to inhibit the systemic IRBP-specific immune response.

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Fingolimod attenuates experimental autoimmune neuritis and contributes to Schwann cell-mediated axonal protection.

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Fingolimod attenuates experimental autoimmune neuritis and contributes to Schwann cell-mediated axonal protection.

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