S1P receptor antagonists fingolimod and siponimod do not improve the outcome of experimental autoimmune myasthenia gravis mice after disease onset. Issue 3 (19th December 2017)

• Record Type: Journal Article
• Authors: Pelz, Andreas; Schaffert, Hanne; Diallo, Radharani; Hiepe, Falk; Meisel, Andreas; Kohler, Siegfried
• Is Part Of: European journal of immunology. Volume 48:Issue 3(2018)
• Page Start: 498
• Page End: 508
• Publication Date: 2017-12-19
• Subjects: Acetylcholine receptor -- BAF312 -- EAMG -- FTY720 -- T cells; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201747187
• Languages: English
• ISSNs: 0014-2980

Abstract

Abstract: Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness and fatigue in the presence of circulating antibodies against components of the neuromuscular junction. Most patients have a good prognosis, but some are refractory to standard‐of‐care immunosuppressive treatment and suffer from recurrent myasthenic crises. Functional sphingosine‐1‐phosphate (S1P) antagonists like fingolimod and siponimod (BAF312) are successfully used for the treatment of multiple sclerosis, and fingolimod was shown to prevent the development of myasthenic symptoms in experimental autoimmune myasthenia gravis (EAMG), the standard model of MG. Here, we investigated whether fingolimod or siponimod improves outcome in EAMG mice when administered after disease onset, modeling the clinical setting in human MG. Both S1P antagonists inhibited lymphocyte egress, resulting in peripheral lymphopenia. After stimulation, there were differences in T‐cell responses, but no change in either antibody titers or total or antigen‐specific plasma cell populations after treatment. Most importantly, disease incidence and severity were not influenced by fingolimod or siponimod therapy. Although fingolimod and siponimod did lead to subtle changes in T‐cell responses, they had no significant effect on antibody titers and disease severity. In conclusion, our data show no evidence of a therapeutic potential for S1P receptor antagonists in MG treatment. Abstract : Prophylactic administration of S1P receptor functional antagonist has been shown to prevent the development of EAMG. Here we observed that the more relevant treatment after disease onset does not improve outcome of EAMG mice. We conclude that S1P receptor antagonists do not provide a new treatment option for myasthenia gravis.