The Bigger Picture
The autoimmune phenomenon is not unique to alemtuzumab or MS. “This turns out to be one of a family of clinical situations where the reconstitution of the depleted lymphocyte repertoire leads to autoimmunity,” Dr. Coles said. A similar effect was seen years ago when very lymphopenic patients with HIV were given antiviral therapy. About 10% of treated patients had this effect. Furthermore, about 10% of patients who undergo bone marrow transplant may experience similar autoimmune concerns.
“What we do think is true is that we have tapped into a classical expression of autoimmunity,” Dr. Coles said. “Alemtuzumab is a fantastic opportunity to study the mechanisms underlying lymphopenia-associated autoimmunity.”
A Tantalizing Prospect
“It is a tantalizing prospect that susceptible individuals might be identified in the future prior to treatment,” Dr. Coles said. “We looked at IL-21. We showed that after treatment, and perhaps more interestingly, before treatment with alemtuzumab, serum levels of IL-21 are greater in those who subsequently develop autoimmune disease. This [finding] suggests [that] some individuals are prone to developing autoimmune disease and could be identified potentially prior to treatment with alemtuzumab.”
More research is needed, including the development of more sensitive IL-21 assays for use in this population, Dr. Coles said. “Please do not attempt to predict the risk of autoimmunity after alemtuzumab using the current commercial assays. This is a source of some frustration for me.” A potential route of lymphocyte repertoire reconstitution after alemtuzumab is thymic reconstitution, which could lead to a more diverse immune repertoire, Dr. Coles said. “If we can direct reconstitution through the thymic reconstitution, we should be able to prevent autoimmunity.”
Dr. Coles receives honoraria for travel and speaking from Sanofi Genzyme, which markets alemtuzumab.
—Damian McNamara