Ofatumumab’s Hidden Power: How a B Cell Drug Also Tames Rogue T Cells in Multiple Sclerosis
Multiple sclerosis (MS) has long been understood as an immune-mediated disease driven by the immune system’s misguided attack on the central nervous system (CNS). For years, scientists focused primarily on B cells—a type of white blood cell that produces antibodies—as key culprits in fueling inflammation and tissue damage. This focus led to the development of anti-CD20 therapies, such as rituximab, ocrelizumab, and ofatumumab, which effectively deplete B cells and have revolutionized MS treatment.
But the immune system is more than just B cells. T cells—particularly subsets that are pro-inflammatory—also play a pivotal role in MS, from disrupting the blood-brain barrier to triggering demyelination. What if anti-CD20 therapies were doing more than just wiping out B cells?
That’s exactly the question explored in a 2022 study by Marina Rode von Essen and colleagues, who investigated how ofatumumab affects T cells in people with relapsing-remitting MS (RRMS). Their findings shed light on a deeper mechanism: ofatumumab may work not only by targeting B cells but also by reshaping the behavior and migration of inflammatory T cells.
A Dual Role for Ofatumumab
Ofatumumab is designed to target CD20, a protein on the surface of B cells. But a smaller subset of T cells—called CD20+ T cells—also express this marker. These T cells are highly inflammatory, produce large amounts of cytokines (such as IFN-γ, TNFα, and GM-CSF), and are enriched in the brains of MS patients.
The study showed that ofatumumab does indeed deplete these CD20+ T cells. This matters because:
CD20+ T cells migrate easily into the CNS. By reducing them, ofatumumab lowers the number of T cells capable of crossing the blood-brain barrier.
They are highly autoreactive. Depleting them reduces harmful immune responses against myelin.
They are “cytokine factories.” Their depletion helps tone down the inflammatory storm in MS.
In essence, ofatumumab seems to act as both a B cell therapy and a CD20+ T cell therapy.
Restoring Balance in the T Cell Compartment
A healthy immune system relies on a balance between “fighters” (effector T cells) and “peacekeepers” (regulatory T cells, or Tregs). In MS, this balance is skewed toward inflammation, with too many effector T cells and not enough regulation.
The researchers found that after ofatumumab treatment:
Regulatory T cells increased in frequency.
The ratios of inflammatory cells (like Th17.1 and T follicular helper cells) to their regulatory counterparts shifted toward control.
Effector T cells produced fewer pro-inflammatory cytokines when stimulated.
This suggests that ofatumumab doesn’t just deplete harmful cells—it also helps restore immune equilibrium.
Blocking the Invasion: Reduced T Cell Migration
One of the most damaging features of MS is the ability of immune cells to infiltrate the CNS. The study used a sophisticated in vitro blood-brain barrier (BBB) model to test how well T cells from treated patients could cross into the CNS environment.
The results were striking:
General T cell migration remained unchanged.
Migration of CD20+ T cells across the BBB was severely reduced.
This finding highlights a targeted effect: ofatumumab doesn’t indiscriminately suppress all T cell activity but specifically hampers the ability of pathogenic CD20+ T cells to enter the brain.
A Technical Note: The “Hidden” CD20+ T Cells
An interesting methodological challenge the team addressed was how to detect CD20+ T cells accurately. Since therapeutic antibodies like ofatumumab bind CD20 tightly, they can block the laboratory antibodies used for flow cytometry, leading to false negatives.
To overcome this, the researchers used antibodies targeting intracellular CD20. This confirmed that the reduction in CD20+ T cells was real, not just an artifact of measurement.
What This Means for MS Therapy
The study reframes our understanding of how ofatumumab works. It’s not simply a “B cell depleter.” Instead, it reshapes the broader immune environment by:
Eliminating pathogenic CD20+ T cells.
Enhancing regulatory control.
Dampening inflammatory cytokine production.
Limiting CNS infiltration by harmful T cells.
These effects together may explain why anti-CD20 therapies are so effective in reducing relapses and MRI lesion activity in MS.
Final Thoughts
For patients and clinicians, the takeaway is powerful: therapies like ofatumumab may be working on more fronts than previously realized. By targeting both B cells and a critical subset of T cells, these treatments help restore immune balance and block the destructive immune traffic into the brain.
As research continues, future therapies may be refined to more precisely target these dual mechanisms—ushering in a new era of personalized, mechanism-based MS treatment.
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:
von Essen, M. R., Hansen, R. H., Højgaard, C., Ammitzbøll, C., Wiendl, H., & Sellebjerg, F. (2022). Ofatumumab modulates inflammatory T cell responses and migratory potential in patients with multiple sclerosis. Neurology: Neuroimmunology & Neuroinflammation, 9(4), e200004.
