IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H)

Abstract

Phase II clinical trials revealed that the lymphocyte-depleting humanized monoclonal antibody alemtuzumab (Campath-1H) is highly effective in the treatment of early relapsing-remitting multiple sclerosis. However, 30% of patients develop autoimmunity months to years after pulsed exposure to alemtuzumab, usually targeting the thyroid gland and, more rarely, blood components. In this study, we show that autoimmunity arose in those patients with greater T cell apoptosis and cell cycling in response to alemtuzumab-induced lymphocyte depletion, a phenomenon that is driven by higher levels of IL-21. Before treatment, patients who went on to develop secondary autoimmunity had more than 2-fold greater levels of serum IL-21 than the nonautoimmune group. We suggest that serum IL-21 may, therefore, serve as a biomarker for the risk of developing autoimmunity months to years after alemtuzumab treatment. This has implications for counseling those patients with multiple sclerosis who are considering lymphocyte-depleting therapy with alemtuzumab. Finally, we demonstrate through genotyping that IL-21 expression is genetically predetermined. We propose that, by driving cycles of T cell expansion and apoptosis to excess, IL-21 increases the stochastic opportunities for T cells to encounter self antigen and, hence, for autoimmunity. IntroductionAutoimmunity arising in the context of lymphopenia is well recognized experimentally but rarely encountered and, hence, difficult to study in humans. We have identified an example of predictable autoimmunity in humans, arising after treatment of multiple sclerosis with the lymphocyte-depleting monoclonal antibody alemtuzumab. This human "model" provides a unique opportunity to explore the immunological mechanisms underlying the development of lymphopenia-associated autoimmunity in humans.Alemtuzumab, licensed for the treatment of B cell chronic lymphocytic leukemia, is a humanized monoclonal antibody directed against CD52, a protein widely distributed on the surface of lymphocytes and monocytes but with unknown function. A single pulse of treatment leads to a rapid, profound, and prolonged lymphopenia. Cell numbers recover but at varying rates; CD4 + T cells are particularly slow to recover, remaining depleted for at least 5 years (1). A recently published phase II trial has shown that alemtuzumab reduces the risk of disease activity and accumulation of disability by over 70% compared with interferon beta in patients with early relapsing-remitting multiple sclerosis (2). The principal adverse effect is autoimmunity, arising in the setting of T cell

Genetics of Multiple Sclerosis

“…The results of a phase II clinical trial with the lymphocyte-depleting humanized monoclonal antibody alemtuzumab (Campath-1H) show that it is highly effective in the treatment of early relapsing-remitting MS (87). A single pulse of treatment results in rapid, profound and prolonged lymphopenia.…”

Alemtuzumab Therapy for Multiple Sclerosis

“…We have shown that pre-treatment serum interleukin-21 may serve as a biomarker for the risk of developing autoimmunity for months to years [28].…”

Immune Mechanisms Underlying the Beneficial Effects of Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis

“…Changes in T-cell properties are also seen at the individual cell level after alemtuzumab administration [33]. In vitro Tcell proliferative potential is substantially increased 3 months after therapy compared to pretreatment.…”