How Natalizumab Shapes the Immune Response in MS: More Than Just a Barrier Blocker
Multiple sclerosis (MS) is a complex, immune-mediated disease where the body’s own immune system turns against the brain and spinal cord. Scientists have long known that immune cells—especially T-cells—play a key role in this misguided attack, but unraveling exactly how is still an ongoing mystery.
One of the most effective therapies for relapsing-remitting MS is natalizumab, a monoclonal antibody that blocks a molecule called VLA-4 on immune cells. This molecule acts like a key that helps immune cells unlock the blood-brain barrier and sneak into the central nervous system (CNS). Natalizumab effectively locks the door, preventing immune cells from entering the brain and causing inflammation.
But what happens to all those blocked T-cells that can’t get in? A team of Danish researchers set out to answer this in a 2012 study published in PLoS ONE. Their findings reveal new insights into how natalizumab shapes the immune system of MS patients—insights that may inform future treatments or help fine-tune the use of existing ones.
The Big Questions
The researchers wanted to know:
Does natalizumab change the makeup of circulating T-cells in the blood?
Do these T-cells become more inflammatory or activated?
Are myelin-reactive (autoimmune) T-cells more common or more aggressive after treatment?
Study Design at a Glance
21 untreated and 25 natalizumab-treated MS patients were compared.
Blood samples were analyzed for T-cell types, activation markers, and gene expression.
The researchers also stimulated immune cells in the lab with myelin basic protein (MBP), a key component of the brain’s myelin sheath, to see how they reacted.
Key Findings
1. T-Cells Pile Up in the Blood
As expected, patients treated with natalizumab had more circulating T-cells in their blood—especially effector memory T-cells, a type of T-cell known for rapid response and cytokine release.
These are the immune system’s "foot soldiers" who are ready for action but now stuck in the bloodstream due to blocked access to the brain.
2. VLA-4 Expression Drops, But Not From the Gene Level
The surface expression of VLA-4 was lower on T-cells in treated patients. But this wasn’t because the cells made less VLA-4; instead, it may be due to internalization or shedding of the molecule, possibly triggered by the drug itself.
It’s like the door key (VLA-4) is still made, but hidden from the cell’s surface—possibly an adaptation to being constantly blocked.
3. A Subtle Boost in Inflammatory Tone
Treated patients showed higher levels of TNF-α mRNA, a pro-inflammatory signal, and lower levels of IL-10, an anti-inflammatory cytokine, in both CD4+ and CD8+ T-cells.
However, most other inflammatory markers and transcription factors (like IFN-γ, IL-17, or FOXP3) were unchanged, suggesting only a mild tilt toward inflammation.
The immune system isn’t going haywire—but it’s not entirely calm either.
4. No Surge in Myelin-Reactive T-Cells
T-cells from treated and untreated patients responded similarly to MBP stimulation in the lab. There was no evidence that natalizumab causes a buildup of particularly aggressive, myelin-targeting T-cells.
This helps reassure that the drug isn’t inadvertently stockpiling dangerous autoimmune cells in the bloodstream.
5. CD134: A Marker of Subtle Immunomodulation
One of the more intriguing findings was the reduction in CD134 expression on a specific subset of CD4+ T-cells (those with high CD26 expression) in treated patients.
Even more interesting: when natalizumab was added to cell cultures in the lab, it directly reduced CD134 expression on these MBP-reactive cells.
CD134 is like a volume knob for T-cell activation. Its reduction hints that natalizumab may do more than just block movement—it might soften the immune response at a cellular level.
What Does This Mean?
This study underscores that natalizumab doesn’t just trap immune cells in the bloodstream—it may also reshape the immune landscape, favoring less activated or less co-stimulatory T-cells.
The increased numbers of effector memory T-cells could seem concerning, as these cells are primed for quick inflammatory action. However, their behavior doesn’t appear drastically more aggressive.
Also, importantly, no increase in harmful, myelin-targeting T-cells was observed, which is good news in terms of safety.
A Balanced Take
While the findings suggest some immunological shifts with natalizumab—like more effector memory cells and more TNF-α—there’s no clear evidence of dangerous immune activation or increased autoimmunity.
Still, these immune shifts may help explain why stopping natalizumab can sometimes trigger rebound disease activity, as the body is suddenly flooded with previously trapped immune cells.
Final Thoughts
Natalizumab is a powerful tool in the MS treatment arsenal. This study adds to our understanding of how it works—not just at the level of brain inflammation, but at the level of cellular mechanics and immune signaling.
By highlighting that natalizumab affects both the traffic and temperament of immune cells, this research offers a more complete picture of its impact—and opens doors for improving or combining therapies in the future.
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:
Börnsen, L., Christensen, J. R., Ratzer, R., Oturai, A. B., Sørensen, P. S., Søndergaard, H. B., & Sellebjerg, F. (2012). Effect of natalizumab on circulating CD4+ T-cells in multiple sclerosis. PloS one, 7(11), e47578.
