Clinical trials have shown that ocrelizumab — an antibody targeting B-cells — is effective in multiple sclerosis (MS). As a result, some researchers and clinicians claim that B-cell depletion is a sufficient therapy in MS, and that drugs targeting other immune cells are obsolete. Not everyone agrees.
A debate at the 10th World Congress on Controversies in Neurology (CONy) in Lisbon, Portugal (March 17-20, 2016), set out to get a clearer picture of this controversy, and explore if targeting multiple cellular targets in MS can provide additional benefits.
Hans-Peter Hartung from the Heinrich Heine University of Düsseldorf, Germany, is among the scientists who believe that new research has clearly shown that MS primarily has a B-cell-related pathology. He argued that theories dating back more than a decade about a primary role for T-cells in the disease are outdated.
Dr. Hartung cited research highlighting the involvement of B-cells from numerous angles to support his argument. Analyses of MS patients’ brains post-mortem revealed B-cell related immune factors, B-cells in MS lesions, and antibodies against myelin and B-cells in the blood and cerebrospinal fluid. As B-cells are believed to be an upstream regulator of T-cells, his arguments make intuitive sense.
Bruno Gran, at the University of Nottingham, U.K., however, maintained that there is still plenty of evidence in favor of a T-cell contribution to MS. T-cells are known to control other immune cells by either activating or blocking their actions. In addition to B-cells, T-cells are also found in brain lesions in MS patients. Moreover, he drew the audience’s attention to the fact that T-cells could potentially also directly attack myelin-producing oligodendrocytes and neurons.
The B-cell component in MS is tightly linked to an immune signature, which might be related to viral infections, he added. Evidence that most MS patients have had an Epstein-Barr virus infection has been published. Researchers have also shown that a B-cell derived antibody response produces more myelin damage when T-cells signal to other immune cells, such as macrophages — providing further evidence that T-cells cannot be excluded as disease contributors.
One of Dr. Hartung’s main arguments was what he called the convincing evidence of rituximab’s effectivity in relapsing-remitting MS, suppressing inflammatory disease activity. This activity is likely not dependent on B-cell-mediated antibody production — a claim both Drs. Gran and Hartung agreed with. The drug’s effects are too fast to involve antibodies, and B-cell derived plasma cells are not depleted by the treatment, Dr. Gran said. Dr. Hartung added that the mechanism is rather reliant on the process of antigen presentation by B-cells to T-cells; an observation to which Dr. Gran agreed, adding that other pro-inflammatory B-cell processes might also contribute.
Dr. Hartung also mentioned the success of the two OPERA clinical trials on ocrelizumab in relapsing-remitting MS, and the recently completed Phase 3 trial in primary progressive MS as evidence of a primary role of B-cells in MS.
Dr. Gran, however, countered by stating that rituximab, while mainly targeting B-cells, also have effects on T-cells; for example, it depletes a type of T-cell called CD20dim . He also reminded the audience of studies showing that treatments primarily targeting T-cells have B-cell targeting effects. Natalizumab affects the levels of circulating B-cells, he said, and fingolimod has been shown to promote a regulatory function of B-cells.
He added that numerous studies have shown that the most potent disease-modifying treatments, both licensed and experimental — such as hematopoietic stem-cell transplantation — deplete both B- and T-cells. Also, genome-wide association studies have shown that risk genes for MS are expressed in both cell types.
Dr. Gran concluded, “it would be unwise to exclusively target B-cells in MS at this stage,” and added that, in fact, we’re not currently able to do so. Until scientists uncover more crucial mechanisms leading to the disease, treatments should not be narrowed to B-cell therapies only, he said.
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