Treatment Response in MS: Unlocking the Power of Natural Killer Cells

Over the past 20 years, therapies for multiple sclerosis (MS) have evolved dramatically. At the heart of this progress is a deeper understanding of the immune system’s role in driving inflammation, demyelination, and neurodegeneration in MS. Monoclonal antibodies (mAbs), engineered to act as “guided missiles” against specific immune targets, have opened entirely new therapeutic pathways.

One particularly fascinating example is daclizumab, a humanized monoclonal antibody initially designed to block activation of T cells. Its story illustrates how science often takes unexpected turns.

What Is Daclizumab?
Daclizumab is an IgG1 monoclonal antibody that binds to CD25, the alpha subunit of the interleukin-2 (IL-2) receptor. Because IL-2 is a critical growth factor for T cells, early researchers believed that blocking IL-2 signaling with daclizumab would suppress autoreactive T cells central to MS pathology.

And indeed, early trials showed daclizumab could reduce inflammatory disease activity in MS patients. But the real surprise came when scientists dug deeper. The Unexpected Discovery: Natural Killer Cells
Instead of primarily suppressing T cells, daclizumab’s most striking biological effect was the dramatic expansion of CD56^bright natural killer (NK) cells—a subset known for their immunoregulatory roles.

These NK cells could infiltrate the central nervous system (CNS).

They directly killed activated autoreactive T cells.

Their expansion strongly correlated with reduced disease activity in patients.

In other words, daclizumab was not just blocking harmful immune responses; it was actively enhancing the body’s natural brakes on inflammation.

This finding reshaped the drug’s perceived mechanism of action, highlighting a unique interplay between innate and adaptive immunity in MS.

Clinical Evidence: From Proof-of-Concept to Phase II
Early open-label trials gave a promising signal: patients with relapsing–remitting MS (RRMS) and even some with secondary progressive MS (SPMS) showed significant reductions in MRI-detected lesions and relapse rates.

Larger, controlled studies soon followed:

CHOICE Trial – As an add-on to interferon beta, high-dose daclizumab reduced new MRI lesions by 72%.

SELECT Trial – As monotherapy, daclizumab reduced annual relapse rates by about 50–54%, cut new lesion formation by nearly 70–80%, and slowed disability progression.

SELECTION Extension – Sustained benefits were observed over two years, with no rebound after treatment withdrawal.

Across studies, the expansion of CD56^bright NK cells consistently emerged as a biomarker of treatment response.

Safety: The Double-Edged Sword
Like other potent immunotherapies, daclizumab is not without risks. While generally well tolerated, several safety concerns emerged:

Infections – Slightly increased rates, though no opportunistic infections like PML were reported.

Skin reactions – Rashes and dermatitis were fairly common, sometimes severe.

Liver toxicity – Elevated liver enzymes, and in rare cases, serious autoimmune hepatitis.

Autoimmune phenomena – Inflammation of organs such as thyroid or kidney, likely linked to effects on regulatory T cells.

Because of these risks, researchers concluded that if approved, daclizumab would likely serve as a second-line therapy—reserved for patients with active disease not adequately controlled by safer drugs.

Why Daclizumab Mattered
Even beyond its clinical outcomes, daclizumab’s story is scientifically remarkable. It challenged the simple view that blocking T cells is enough to treat MS, and instead spotlighted the regulatory potential of NK cells. This discovery opened new avenues for understanding how the innate immune system can shape autoimmune disease.

The Road Ahead
At the time of this review (2013), ongoing phase III trials such as DECIDE were expected to clarify daclizumab’s long-term safety and efficacy compared to established treatments. Although daclizumab was later approved and then withdrawn due to rare but severe adverse events, its legacy remains:

It expanded our understanding of immune regulation in MS.

It showed the importance of monitoring unexpected mechanisms of action in immunotherapy.

It reinforced the delicate balance between efficacy and safety in treating chronic autoimmune diseases.

Final Thoughts
The story of daclizumab illustrates both the promise and peril of modern immunotherapy. It delivered robust reductions in disease activity and taught us about the surprising protective role of NK cells in MS. At the same time, it underscored the need for rigorous long-term safety monitoring when introducing powerful new biologics.

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:
Milo, R. (2014). The efficacy and safety of daclizumab and its potential role in the treatment of multiple sclerosis. Therapeutic advances in neurological disorders, 7(1), 7-21.