Fingolimod’s Hidden Talent: Calming the Immune Cells That Fuel MS

Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) that blends inflammation, demyelination, and neurodegeneration into a debilitating clinical picture. Over the past two decades, therapies have largely focused on limiting the damaging activity of lymphocytes—immune cells that mistakenly attack the body’s own nervous tissue. One of the landmark drugs in this arena is fingolimod, an oral therapy that has become a cornerstone in treating relapsing-remitting MS.

Fingolimod is best known for “trapping” lymphocytes in lymph nodes by targeting sphingosine-1-phosphate (S1P) receptors, thereby preventing their migration into the CNS where they could do harm. But a fascinating 2015 study by Di Dario et al. turns the spotlight on another class of immune cells—myeloid cells—revealing that fingolimod’s effects may extend much further than previously thought.

Beyond Lymphocytes: Why Myeloid Cells Matter
Myeloid cells—including monocytes, macrophages, and microglia—play an essential role in immune defense. In MS, however, they become a double-edged sword. Instead of protecting neurons, they can fuel inflammation, release toxic molecules, and devour myelin, the protective sheath around nerve fibers.

Importantly, myeloid cells also express S1P receptors, making them potential direct targets of fingolimod. The question the researchers asked was simple but profound: Does fingolimod dampen the inflammatory activity of these cells, both in the periphery and inside the CNS?

The Study at a Glance
The team combined in vitro, in vivo, and ex vivo experiments:

In vitro (human monocytes): Peripheral blood mononuclear cells (PBMCs) from healthy individuals and MS patients were exposed to fingolimod and stimulated with lipopolysaccharide (LPS), a strong immune activator.

In vivo (mouse model of MS, EAE): Mice induced with experimental autoimmune encephalomyelitis (EAE) were treated with fingolimod after disease onset, and their immune cells from spleen and CNS were analyzed.

Ex vivo (MS patients): Blood from MS patients on fingolimod therapy was tested for responsiveness to LPS compared to untreated patients and healthy controls.

Key Findings
Fingolimod reduces monocyte reactivity in vitro

When exposed to LPS, monocytes normally ramp up activation markers like CD25 and CD150 and secrete inflammatory cytokines such as TNF-α.

Fingolimod significantly dampened this activation without killing the cells—suggesting a targeted immunomodulatory effect rather than broad toxicity.

In EAE mice, fingolimod tames inflammation at its source

Treated mice had a milder disease course.

Their splenic macrophages and CNS-resident microglia produced less TNF-α, a cytokine heavily implicated in MS pathology.

Patients on fingolimod show “resistant” monocytes

In people with MS taking fingolimod, monocytes needed a much stronger stimulus to become activated compared to those from untreated patients or healthy individuals.

At lower levels of stimulation, their monocytes essentially stayed “quiet.”

Why This Matters
These results expand the scope of fingolimod’s known mechanism of action. Instead of working only by sequestering lymphocytes, fingolimod also appears to recalibrate the inflammatory threshold of myeloid cells.

This dual action could explain its effectiveness in reducing relapses and slowing MS progression. By making myeloid cells less eager to spark inflammation, fingolimod may provide a layer of neuroprotection beyond its role in lymphocyte trafficking.

But there’s a trade-off. Suppressing myeloid activity might also blunt protective immune responses against infections. Indeed, fingolimod-treated patients sometimes show weaker vaccine responses and have an elevated risk of infections like varicella-zoster virus. This underlines the delicate balance in MS therapy between taming harmful immunity and preserving protective defenses.

Looking Ahead
The work by Di Dario and colleagues opens the door to several exciting questions:

Could targeting myeloid cell activation be a new therapeutic avenue in MS?

How do these changes in monocyte behavior affect long-term CNS repair and neurodegeneration?

Can we harness fingolimod’s myeloid-modulating effects while minimizing risks to antiviral immunity?

As MS therapies evolve, this study reminds us that the immune system is more than lymphocytes alone. Myeloid cells—once thought to be just “bystanders” or “clean-up crews”—are active participants in MS pathology and valuable targets for treatment.

Take-Home Message
Fingolimod doesn’t just keep lymphocytes locked away; it also raises the activation threshold of myeloid cells, dialing down inflammation in both the periphery and the CNS. This broader mechanism of action may be key to its effectiveness in MS—while also highlighting the importance of vigilance against infections during therapy.

Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

References:
Di Dario, M., Colombo, E., Govi, C., De Feo, D., Messina, M. J., Romeo, M., ... & Farina, C. (2015). Myeloid cells as target of fingolimod action in multiple sclerosis. Neuroimmunology & Neuroinflammation, 2(6), e157.