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Exploring a Novel Therapeutic Target in a Murine Model of Systemic Lupus Erythematosus: Targeting Sphingosine-1-Phosphate Receptors

Conference Correspondent - Conference Correspondent

The pathogenesis of systemic lupus erythematosus (SLE) is characterized by complex immune dysfunction, including aberrant T-cell responses that result in tissue damage and terminal organ failure. FTY720 (fingolimod) is a US Food and Drug Administration–approved therapy for multiple sclerosis, and is believed to act as an immune modulator, curtailing T-cell proliferation through the downregulation of sphingosine-1-phosphate (S1P) receptors. Tracy and colleagues (Abstract 540) examined the effect of FTY720 in attenuating tissue injury and sought to define a subset of S1P receptors that may be altered in an autoimmune-prone ischemic reperfusion injury mouse model.

Immune competent mice (C57BL/6) and autoimmune-prone mice (B6.MRL/lpr) were treated with FTY720 or a control, and were then subjected to superior mesenteric artery ischemic reperfusion injury. Tissue injury was assessed by histologic analysis of tissue samples, which also served to identify the degree to which inflammatory cells infiltrated the injured tissues. Specific S1P receptor expression patterns were defined by immunofluorescence staining of tissue samples.

Autoimmune-prone mice receiving FTY720 demonstrated an approximately 50% attenuation in tissue injury compared with immunocompetent controls, with decreased T-cell infiltration and an 86% reduction in levels of interleukin (IL)-6 and IL-1B. Moreover, tissue samples evaluated by immunofluorescence staining of specific S1P receptors revealed increased S1P1, S1P2, and S1P3 expression patterns in the autoimmune-prone mice compared with in the immunocompetent controls after the ischemic reperfusion injury. Immune competent mice did not demonstrate these marked changes in attenuated tissue injury or in reductions in IL-6 or IL-1B levels.

These results support the hypothesis that S1P receptor interaction is a key regulator of T-cell–mediated tissue damage, and could represent a novel therapeutic target in patients with SLE. Further studies are needed to define S1P receptor expression in human SLE and how this expression influences immune cell responsiveness during states of active inflammation in this disease.

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Last modified: August 30, 2021