Conference Coverage

What Is the Mechanism of Alemtuzumab-Induced Autoimmunity?

Investigators examine whether reduced thymic function and depletion of B and T cells explain increased autoimmune risk after treatment.


 

SAN DIEGO—The monoclonal antibody alemtuzumab can be an effective treatment for people living with multiple sclerosis (MS), but the agent is also associated with an increased risk for developing other autoimmune diseases, leaving clinicians with a conundrum.

Alemtuzumab is an efficacious treatment in MS that can slow the rate of brain atrophy over the long term, said Alasdair Coles, MD, Professor of Neuroimmunology at the University of Cambridge, United Kingdom, at ACTRIMS 2018 Forum. “But one or two years after each cycle of alemtuzumab, patients are at high risk of autoimmune diseases. This is the not-too-worrying thyroid disease, but there are some troubling and potentially serious complications at lower frequency.”

Alasdair Coles, MD

Autoimmune thyroid disease can affect as much as 40% of patients treated with alemtuzumab, but immune thrombocytopenia (3%) and autoimmune renal disease (0.1%) are also reported. About one in 10 people treated with the monoclonal antibody for MS can also develop de novo asymptomatic autoantibodies.

“People ask, ‘Why doesn’t MS come back as part of this generic mechanism?’ I don’t know the answer to that question,” said Dr. Coles.

In the United States, alemtuzumab is indicated for treatment of relapsing-remitting MS in adults who have failed to respond adequately to two or more previous therapies. In contrast, “this has become a first-line treatment in the UK,” said Dr. Coles. “Unfortunately, we can offer no proven treatment to prevent this autoimmunity.”

Considering Proposed Mechanisms

Dr. Coles and other researchers are investigating the cellular mechanism underlying the paradoxical autoimmunity associated with alemtuzumab. Some have suggested that faulty immune B cells could be the culprit, but “there is no difference in B cell reconstitution between those who do and do not get autoimmunity,” said Dr. Coles. “So, we do not think that autoimmunity after alemtuzumab is primarily a B cell problem.” Other investigators have suggested that the mechanism is the depletion of a key immune regulatory cell associated with alemtuzumab. One such example is depletion in T cells as part of an autoimmune cascade that involve CD52-high expressing cells and sialic acid-binding immunoglobulin-like lectin 10. “We do not believe this,” said Dr. Coles. “We cannot replicate the finding of reduced CD52 high cells in type 1 diabetes or MS, nor the binding of SIGLEC-10 to CD52.”

Along with his colleague Joanne Jones, MD, PhD, also at the University of Cambridge, Dr. Coles and his team instead propose that autoimmunity after alemtuzumab therapy is associated with a homeostatic proliferation of T cells in the context of a defective thymus. “We see thymic function reduced after alemtuzumab for a few months. We do not know if alemtuzumab is having a direct impact on the thymus or if it is an indirect effect through a cytokine storm at the time of administering alemtuzumab.”

In addition, in contrast with B cells, both CD4-positive and CD8-positive T cells are clonally restricted after alemtuzumab treatment, said Dr. Coles. “These are the only changes that distinguish patients who do and do not develop autoimmunity,” he said. “Those who develop autoimmunity have reduced clonality and impaired thymic function, compared with those who do not.”

The theory is that the reconstitution of T cells after alemtuzumab comes preferentially from expansion of peripheral T cells, rather than naïve T cells from the thymus, which leads to a higher representation of autoreactive T cells and thus leads to B-cell- and antibody-mediated autoimmunity.

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