Exit Strategies: S1P Signaling and T Cell Migration

Baeyens, Audrey; Fang, Victoria; Chen, Cynthia; Schwab, Susan R.

doi:10.1016/j.it.2015.10.005

Cited by 134 publications

(102 citation statements)

References 91 publications

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“…LCL351 elevated circulating S1P levels basally; however, this was not significant and LCL351 prevented DSS-induced increases in S1P (Table S1). While we know that the S1P gradient is important for egress of WBCs from secondary lymph tissues and other vascular and immunological biologies (reviewed in [41]), we know relatively little about the role of S1P in WBC infiltration into inflamed tissues [42]. However, we hypothesize that the number of circulating WBCs are increased in response to LCL351, partly due to the inability of LCL351 to inhibit SK1 in circulation (half-life 30–45 minutes; slight basal increase in S1P).…”

Section: Discussionmentioning

confidence: 99%

Novel sphingosine kinase-1 inhibitor, LCL351, reduces immune responses in murine DSS-induced colitis

Pulkoski-Gross

Uys

Orr-Gandy

et al. 2017

Prostaglandins & Other Lipid Mediators

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Sphingosine-1-phosphate (S1P) is a biologically active sphingolipid metabolite which has been implicated in many diseases including cancer and inflammatory diseases. Recently, sphingosine kinase 1 (SK1), one of the isozymes which generates S1P, has been implicated in the development and progression of inflammatory bowel disease (IBD). Based on our previous work, we set out to determine the efficacy of a novel SK1 selective inhibitor, LCL351, in a murine model of IBD. LCL351 selectively inhibits SK1 both in vitro and in cells. LCL351, which accumulates in relevant tissues such as colon, did not have any adverse side effects in vivo. In mice challenged with dextran sodium sulfate (DSS), a murine model for IBD, LCL351 treatment protected from blood loss and splenomegaly. Additionally, LCL351 treatment reduced the expression of pro-inflammatory markers, and reduced neutrophil infiltration in colon tissue. Our results suggest inflammation associated with IBD can be targeted pharmacologically through the inhibition and degradation of SK1. Furthermore, our data also identifies desirable properties of SK1 inhibitors.

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Section: Discussionmentioning

confidence: 99%

Novel sphingosine kinase-1 inhibitor, LCL351, reduces immune responses in murine DSS-induced colitis

Pulkoski-Gross

Uys

Orr-Gandy

et al. 2017

Prostaglandins & Other Lipid Mediators

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“…Researchers have recently investigated strategies to target the sphingosine-1-phosphate pathway, which reduces circulating lymphocytes by sequestering them in secondary lymphoid organs. 127 In a phase 2 trial of patients with UC, once daily ozanimod (1 mg) resulted in statistically significant increases in clinical remission and mucosal healing at week 8 compared with placebo. 128 An important observation from this trial was that the rates of histologic remission (22%) were lower than the rates of mucosal healing at week 8 (34%) with ozanimod, but by week 32 these rates were more comparable (31% vs 33%).…”

Section: Inhibiting Additional Cytokine Pathwaysmentioning

confidence: 99%

Lessons Learned From Trials Targeting Cytokine Pathways in Patients With Inflammatory Bowel Diseases

et al. 2017

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Insights into the pathogenesis of inflammatory bowel diseases (IBD) have provided important information for the development of therapeutics. Levels of interleukin 23 (IL23) and T-helper (Th) 17 cell pathway molecules are elevated in inflamed intestinal tissues of patients with IBD. Loss of function variants of the interleukin 23 receptor gene (IL23R) protect against IBD, and in animals, blocking IL23 reduces severity of colitis. These findings indicated that the IL23 and Th17 cell pathways might be promising targets for treatment of IBD. Clinical trials have investigated the effects of agents designed to target distinct levels of the IL23 and Th17 cell pathways, and the results are providing insights into IBD pathogenesis and additional strategies for modulating these pathways. Strategies to reduce levels of proinflammatory cytokines more broadly and increase anti-inflammatory mechanisms are also emerging for treatment of IBD. The results from trials targeting these immune system pathways have provided important lessons for future trials. Findings indicate the importance of improving approaches to integrate patient features and biomarkers of response with selection of therapeutics.

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“…CD8-Trm remain in tissues despite the lack of persistent antigen6, an attribute associated with the expression of CD69 and CD10378. CD69, the classical early activation marker, also has a reciprocal relationship with sphingosine-1-phosphate receptor-1 (S1PR1)9; CD69 upregulation leads to S1PR1 downregulation, which prevents cell egress from both lymphoid and non-lymphoid organs following sphingosine-1-phosphate (S1P) gradients1011. CD103 is the ligand for e-cadherin12, which is highly expressed on epithelial cells in mucosal tissues13.…”

mentioning

confidence: 99%

An altered endometrial CD8 tissue resident memory T cell population in recurrent miscarriage

Southcombe

Mounce

McGee

et al. 2017

Sci Rep

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When trying to conceive 1% of couples have recurrent miscarriages, defined as three or more consecutive pregnancy losses. This is not accounted for by the known incidence of chromosomal aneuploidy in miscarriage, and it has been suggested that there is an immunological aetiology. The endometrial mucosa is populated by a variety of immune cells which in addition to providing host pathogen immunity must facilitate pregnancy. Here we characterise the endometrial CD8-T cell population during the embryonic window of implantation and find that the majority of cells are tissue resident memory T cells with high levels of CD69 and CD103 expression, proteins that prevent cells egress. We demonstrate that unexplained recurrent miscarriage is associated with significantly decreased expression of the T-cell co-receptor CD8 and tissue residency marker CD69. These cells differ from those found in control women, with less expression of CD127 indicating a lack of homeostatic cell control through IL-7 signalling. Nevertheless this population is resident in the endometrium of women who have RM, more than three months after the last miscarriage, indicating that the memory CD8-T cell population is altered in RM patients. This is the first evidence of a differing pre-pregnancy phenotype in endometrial immune cells in RM.

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Exit Strategies: S1P Signaling and T Cell Migration

Cited by 134 publications

References 91 publications

Novel sphingosine kinase-1 inhibitor, LCL351, reduces immune responses in murine DSS-induced colitis

Novel sphingosine kinase-1 inhibitor, LCL351, reduces immune responses in murine DSS-induced colitis

Lessons Learned From Trials Targeting Cytokine Pathways in Patients With Inflammatory Bowel Diseases

An altered endometrial CD8 tissue resident memory T cell population in recurrent miscarriage

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