Ocrelizumab and the Role of NK Cells in Multiple Sclerosis

Multiple Sclerosis (MS) is a complex immune-mediated disease where the immune system mistakenly attacks the central nervous system, leading to inflammation and neurodegeneration. Over the past few years, B cell–depleting therapies have dramatically reshaped the treatment landscape, with ocrelizumab—a humanized anti-CD20 monoclonal antibody—standing out as one of the most effective options for reducing relapse rates and slowing disease progression.

Most discussions around ocrelizumab focus on its ability to eliminate circulating CD20+ B cells, a major driver of disease activity in MS. But what about other immune cells that interact with B cells and play key roles in immune regulation? A recent longitudinal study explored just that, with a spotlight on natural killer (NK) cells, the innate immune players often described as the "first responders" of the immune system.

Why Look at NK Cells in MS?
NK cells are best known for their ability to kill virally infected and tumor cells, but they also carry regulatory roles that can shape autoimmune responses. Several receptors are central to their cytotoxic activity and regulation, including CD94/NKG2C, NKG2D, NKp46, and DNAM-1.

Previous in vitro work suggested that anti-CD20 therapies might enhance NK cell activity, selectively expanding CD94/NKG2C+ memory NK cells and boosting their cytotoxic potential. However, little was known about how these effects play out in vivo in MS patients receiving ocrelizumab.

The Study Design
Researchers conducted a prospective longitudinal study involving 30 RMS patients who started ocrelizumab treatment and were followed for 12 months. Using flow cytometry, the team examined both:

T cell subsets (to monitor the broader lymphocyte compartment)

NK cell phenotypes, with a focus on activating receptors

Samples were collected before treatment, and then again at 6 months and 12 months.

Key Findings
Overall lymphocyte reduction

At both 6 and 12 months, patients showed a decline in total lymphocyte counts—consistent with ocrelizumab’s known systemic immune effects.

T cell remodeling

The T cell compartment shifted toward a naïve phenotype (increased CD4+CD45RA+ and CD8+CD45RA+ cells).

Meanwhile, the proportion of activated/memory T cells (CD4+CD45RO+ and CD8+CD45RO+ cells) decreased.

This suggests that ocrelizumab doesn’t just deplete B cells—it also indirectly shapes T cell dynamics, dampening the activated/memory pool often linked to chronic inflammation.

NK cell activation profile Perhaps the most striking finding: NK cells displayed a higher expression of activating receptors (CD94/NKG2C, NKG2D, NKp46, DNAM) after treatment.

This shift indicates a tilt toward a more cytotoxic and potentially regulatory NK cell phenotype.

What Does This Mean?
The study suggests that ocrelizumab’s impact extends beyond B cell depletion. By reducing the pool of activated/memory T cells, it may help dampen autoimmune responses at large. At the same time, the upregulation of activating receptors on NK cells could enhance their ability to regulate immune activity or target residual pathogenic cells.

In other words, ocrelizumab may reprogram the immune landscape, not only suppressing inflammation but also promoting a more controlled, regulatory immune profile.

Looking Ahead
While these findings are promising, important questions remain:

Do the NK cell changes directly contribute to clinical improvements in RMS, or are they secondary effects?

Could NK cell profiling serve as a biomarker for treatment response to ocrelizumab?

How durable are these NK cell changes over long-term treatment?

Future studies with larger cohorts and mechanistic insights will be critical to unravel these links.

Takeaway
This study adds an important piece to the puzzle of how ocrelizumab works in RMS. Beyond its hallmark role in B cell depletion, it also drives shifts in T cell balance and enhances NK cell activation, potentially reinforcing its therapeutic effects.

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:
Abbadessa, G., Bruzzaniti, S., Miele, G., Piemonte, E., Lepore, M. T., Signoriello, E., ... & Bonavita, S. (2023). Effects of ocrelizumab on NK cell activation in Relapsing Multiple Sclerosis (P2-3.004). Neurology, 100(17_supplement_2), 3163.