Natalizumab, a powerful medication used to treat multiple sclerosis (MS), has been a game-changer for many patients. Known for its ability to dramatically reduce disease relapses, it’s often hailed as one of the most effective therapies for relapsing-remitting MS. But a recent study suggests that this drug might come with a catch—it could be quietly disrupting the immune system’s balance in a way we didn’t fully appreciate until now.

A team of researchers from Japan, led by Dr. Kimitoshi Kimura, took a closer look at what happens to different types of T cells—the immune system’s orchestrators—when patients are treated with natalizumab. What they found could have implications for how we monitor and manage MS in the clinic.

A Quick Refresher: What Does Natalizumab Do?
Natalizumab is a monoclonal antibody—a lab-made protein that binds specifically to a molecule on immune cells called α4-integrin (CD49d). This protein helps immune cells latch onto blood vessel walls and move into the brain and spinal cord—critical steps in triggering inflammation during MS relapses.

By blocking CD49d, natalizumab prevents immune cells from crossing into the central nervous system (CNS), keeping inflammation at bay. Sounds great, right?

Mostly, it is. But the story gets more complicated when you realize that not all T cells are created equal—some are inflammatory, while others keep the immune system in check.

The Study: Unpacking the Balance Between Inflammatory and Regulatory T Cells
Kimura and colleagues studied 27 MS patients who hadn’t received natalizumab, 8 who were actively being treated, 7 patients with neuromyelitis optica (NMO) (a similar condition), and 8 healthy controls. They wanted to know: how does natalizumab affect the balance between inflammatory T cells (Th1 and Th17) and regulatory T cells (Tregs)?

They focused on CD49d-positive cells, since these are the ones capable of entering the CNS and driving inflammation.

Here’s what they found:

Natalizumab reduced CD49d expression across the board, but it hit regulatory T cells harder than it did inflammatory ones.

This skewed the ratio—more inflammatory cells remained CD49d-positive, meaning they might still slip into the CNS and stir up trouble.

In fact, in two patients who experienced disease relapses while on natalizumab, the imbalance was especially pronounced.

Proinflammatory Genes Cranked Up
The researchers didn’t stop at counting cells. They also measured gene expression in CD49d-positive memory T cells. The results were striking:

Proinflammatory genes like TBX21 (T-bet), RORC, IFN-γ, and IL-17A were significantly increased.

At the same time, FOXP3, the key gene for Treg development and function, was decreased.

This suggests that the immune cells that retained CD49d—those still capable of CNS migration—were skewed toward inflammation.

And when these cells were stimulated in the lab, they produced more inflammatory cytokines like IFN-γ and IL-17A—especially in natalizumab-treated patients.

Why This Matters
This research challenges the idea that natalizumab simply “locks the gate” to the CNS for all immune cells. It turns out the gate might not be equally closed to everyone.

Inflammatory T cells may retain more migratory capacity than we thought.

Regulatory cells, which suppress inflammation, are disproportionately excluded—potentially tilting the immune system toward a more aggressive state in some patients.

The CD49d ratios (Th1/Treg and Th17/Treg) could serve as biomarkers to monitor relapse risk, as seen in the two patients who relapsed.

Could future MS drugs target CD49d more selectively?
Only more research will tell. But one thing is clear: the immune system is never simple, and even our most sophisticated tools can have unintended consequences.

Final Thoughts
The immune system walks a fine line between protecting us and harming us. Treatments like natalizumab are powerful tools—but as this study shows, they may shift that balance in ways we need to understand better.

Disclaimer: This blog post is based on the information provided in the cited scientific article. It aims to provide an accessible summary of the research findings and should not be considered as definitive medical advice. For any health concerns, please consult with a qualified healthcare professional.

Reference:
Kimura K. et al. Disrupted Balance of T Cells Under Natalizumab Treatment in Multiple Sclerosis. Neurol Neuroimmunol Neuroinflamm. 2016;3:e210. doi:10.1212/NXI.0000000000000210.