Oral Cenerimod Effective in Reducing Gland Inflammation in Mouse Models
“These encouraging data suggest that cenerimod may be a promising approach to treating Sjögren’s syndrome,” the scientists said.
The study, titled “Cenerimod, a selective S1P1 receptor modulator, improves organ-specific disease outcomes in animal models of Sjögren’s syndrome” and funded by Idorsia Pharmaceuticals, was published in the journal Arthritis Research & Therapy.
Sjögren’s syndrome is an autoimmune disease, characterized by an altered immune system, that primarily targets the glands producing tears and saliva, leading to dryness in the eyes and mouth.
A hallmark of Sjögren’s is the infiltration of immune cells, mainly T-cells and B-cells, into these glands. In up to 40% of patients, these infiltrating cells form clusters known as ectopic lymphoid structures or ELS that drive local inflammation and tissue damage.
Cenerimod is a selective modulator of the sphingosine-1-phosphate 1 receptor (S1P1) that works by preventing immune cells from leaving lymph nodes and reaching organs where they can cause inflammation and disease.
To determine if cenerimod would be an effective treatment for Sjögren’s, scientists based at Idorsia, collaborating with researchers at the University of Birmingham, investigated the therapy in two mouse models that share some biological and clinical features of Sjögren’s syndrome.
“These models offer a valuable possibility to dissect the cellular and molecular mechanisms regulating breach of [immune] tolerance, autoimmunity and ELS formation in the salivary glands,” the team wrote.
In the first model, the salivary gland inflammation — sialadenitis — was induced using a virus. Here, the mice developed several features of Sjögren’s syndrome, including the formation of ELS within the salivary glands, autoimmunity, and a decreased saliva flow.
The researchers treated these mice with cenerimod one day or seven days after disease induction, which mimicked the early or established phases of the disease, respectively.
In both treatment regimens, cenerimod significantly reduced immune cells in the blood, including both B- and T-cells, compared with control animals treated with a placebo. This decrease, however, did not affect the ability of cenerimod-treated mice to mount an immune response against other infectious agents, the researchers said.
Cenerimod treatment also significantly reduced the migration of immune cells into the salivary glands in both treatment regimens. In the late therapeutic mode, the reduction in T- and B-cells was less pronounced compared with the early therapeutic regimen, but still significant over controls.
The therapy also decreased both the size and number of ELS within the salivary glands, which was accompanied by an overall depletion of chemokines — small immune signaling proteins – required for the assembly and maintenance of ELS. Factors associated with the production of self-targeting antibodies within the salivary gland also were decreased, especially in the early treatment group.
Additional experiments showed that cenerimod treatment significantly reduced a number of pro-inflammatory immune signaling proteins (cytokines) that attract immune cells into the glands. This ultimately resulted in improved salivary gland function.
“Cenerimod treatment led to an improved saliva production as compared to vehicle controls in both therapeutic regimens but this was more pronounced in the early therapeutic regimen,” the researchers wrote.
In the second mouse model — a well-recognized model of chronic Sjögren’s syndrome — sialadenitis occurs spontaneously in an age-dependent manner. With increasing age, these mice also have increased immune cell migration into glands, develop autoimmune antibodies, and exhibit a reduced flow of both saliva and tears.
At seven weeks of age, when abnormalities in B-cells already were detected, these mice received treatment with cenerimod, which continued for 10 weeks. Similar to the viral sialadenitis model, the treatment led to a significant reduction of immune cells in both the bloodstream and in the salivary glands, compared with controls.
The use of cenerimod also led to a pronounced reduction of the inflammatory environment, with a decrease in chemokines required for ELS and pro-inflammatory cytokines.
Tissue analysis showed both the number and average area of the ELS were similar between cenerimod-treated animals and controls, but treatment significantly reduced the T-cell population.
In addition, there was a reduction in factors that promote the production of autoimmune antibodies.
“Our data provide evidence that cenerimod has the capacity of targeting multiple disease-associated mechanisms in animal models of Sjögren’s syndrome, providing encouraging evidence that cenerimod may also be effective in treating Sjögren’s syndrome in humans,” the researchers concluded.