How Natalizumab Calms Inflammation and Sparks Repair in Multiple Sclerosis

Multiple sclerosis (MS) is often described as the body’s immune system mistakenly turning against itself, attacking the protective myelin sheath that insulates nerve fibers in the brain and spinal cord. This damage disrupts communication between neurons and leads to symptoms ranging from fatigue and numbness to vision problems and paralysis. Among the different types of MS, relapsing-remitting MS (RRMS) is the most common, characterized by flare-ups of symptoms followed by partial recovery.

Over the past two decades, disease-modifying therapies (DMTs) have transformed the outlook for people with RRMS. One of the most powerful is natalizumab (Tysabri™), a monoclonal antibody that blocks immune cells from crossing the blood-brain barrier and fueling inflammation. While natalizumab is known to reduce relapses, scientists are still unraveling exactly how it reshapes the biology of the central nervous system.

A study by researchers in Norway and the Czech Republic provides some of the clearest answers yet—by looking directly at the proteins in cerebrospinal fluid (CSF), the liquid that bathes the brain and spinal cord. Their work paints a picture of natalizumab not only dampening harmful immune activity but also nudging the brain toward repair.

The Study: Tracking Proteins Before and After Treatment
The researchers analyzed CSF samples from 76 patients with RRMS who began natalizumab therapy. Samples were collected before treatment and again after about two years on the drug. Using advanced mass spectrometry, they catalogued over a thousand different proteins.

Out of these, 287 proteins showed significant changes after treatment. To ensure reliability, a second, smaller patient group was studied using a targeted technique called parallel reaction monitoring, which confirmed most of the findings.

This approach provided a molecular “before-and-after snapshot” of how natalizumab alters the brain’s biochemical environment.

Key Findings: From Inflammation to Repair
1. Dampening the Immune Fire
As expected, natalizumab reduced immune-related proteins in the CSF:

Immunoglobulins (antibodies, especially IgM and IgG subclasses) dropped significantly.

Proteins like chitinase-3-like protein 1 (CHI3L1), chitotriosidase (CHIT1), and VCAM1—all linked to inflammation in MS—also decreased.

These reductions confirm natalizumab’s ability to silence the immune system’s attack inside the brain.

2. Boosting Metabolism and Repair
Intriguingly, the study found increases in proteins tied to energy metabolism and neuronal function:

Lactate dehydrogenase A and B (LDHA, LDHB) and malate dehydrogenase (MDH1), enzymes central to cellular energy cycles, rose in abundance.

Lactadherin (MFGE8), involved in neuron development and clearing damaged cells, also increased.

Proteins linked to synaptic activity and nerve growth, like glutamate receptor 4 (GRIA4) and LRRC4B, were more abundant.

These shifts suggest that once inflammation is under control, the brain may pivot toward regeneration and repair.

3. Mixed Picture for Biomarkers
Some proteins long considered biomarkers of MS activity were clearly affected by natalizumab, such as CHI3L1 and CD163. Others, like vitamin D-binding protein and apolipoproteins A-I and A-II, remained unchanged.

This distinction is important: it means not all proposed biomarkers are equally useful for tracking treatment response, and some may reflect ongoing disease processes unaffected by natalizumab.

Why This Matters
This study highlights that natalizumab’s impact goes beyond halting immune attacks. By shifting the CSF protein landscape, it appears to foster a biochemical environment more supportive of neural stability and recovery.

For patients, this raises hope that treatments might not only slow progression but also enable the brain to heal itself, at least partially.

For researchers, the work underscores the potential of proteomics—the large-scale study of proteins—to uncover hidden mechanisms of drug action and identify new biomarkers that predict treatment success.

Looking Ahead
While these findings are promising, they also raise new questions. For example:

Do the increases in metabolic enzymes translate to measurable improvements in brain energy use?

Can the rise in neuronal proteins be linked to clinical recovery or remyelination?

Which of the unchanged biomarkers might signal disease activity beyond inflammation, such as chronic neurodegeneration?

Future studies could help tailor treatments by distinguishing which patients benefit most from natalizumab and which may need combination therapies targeting other pathways. Takeaway
Natalizumab is more than just an anti-inflammatory shield in MS—it actively reshapes the brain’s protein environment, dialing down immune chaos while boosting signals of repair. This dual action could explain why it remains one of the most effective therapies for RRMS, despite its risks.

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:
Lereim, R. R., Nytrova, P., Guldbrandsen, A., Havrdova, E. K., Myhr, K. M., Barsnes, H., & Berven, F. S. (2024). Natalizumab promotes anti-inflammatory and repair effects in multiple sclerosis. Plos one, 19(3), e0300914.