Rituximab-induced B cell depletion in autoimmune diseases: Potential effects on T cells (original) (raw)
Related papers
Arthritis & Rheumatology, 2015
Objective. Rituximab, a type I anti-CD20 monoclonal antibody (mAb), induces incomplete B cell depletion in some patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), thus contributing to a poor clinical response. The mechanisms of this resistance remain elusive. The purpose of this study was to determine whether type II mAb are more efficient than type I mAb at depleting B cells from RA and SLE patients, whether internalization influences the efficiency of depletion, and whether Fcg receptor type IIb (FcgRIIb) and the B cell receptor regulate this internalization process. Methods. We used an in vitro whole blood B celldepletion assay to assess the efficiency of depletion, flow cytometry to study cell surface protein expression, and surface fluorescence-quenching assays to assess rituximab internalization, in samples from patients with RA and patients with SLE. Paired t-test or Mann-Whitney U test was used to compare groups, and Spearman's rank correlation test was used to assess correlation. Results. We found that type II mAb internalized significantly less rituximab than type I mAb and depleted B cells from patients with RA and SLE at least 2-fold more efficiently than type I mAb. Internalization of rituximab was highly variable between patients, was regulated by FcgRIIb, and inversely correlated with cytotoxicity in whole blood B cell-depletion assays. The lowest levels of internalization were seen in IgD-B cells, including postswitched (IgD-CD271) memory cells. Internalization of type I anti-CD20 mAb was also partially inhibited by anti-IgM stimulation. Conclusion. Variability in internalization of rituximab was observed and was correlated with impaired B cell depletion. Therefore, slower-internalizing type II mAb should be considered as alternative B cell-depleting agents for the treatment of RA and SLE. B cell-targeted monoclonal antibodies (mAb) are increasingly being explored for use in the treatment of autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Rituximab (RTX), a chimeric anti-CD20 mAb, is licensed for the treatment of RA and is used extensively off-label for the treatment of refractory SLE. However, RTX induces incomplete B cell depletion in some individuals with RA (1) and SLE (2), which may at least partly explain the poor clinical response noted in some individuals (3,4). A long duration of B cell depletion in RA (using an extra dose of RTX) (5) and SLE patients is associated with better clinical response (6). Hence, enhancing B cell depletion may improve treatment efficacy, and understanding the mechanisms of resistance in RA and SLE is of clear clinical importance. B cell-depletion Supported by Arthritis Research UK
B-cell depletion with rituximab in the treatment of autoimmune diseases
Expert Opinion on Biological Therapy, 2007
Learning points for clinicians • Hepatic autoimmune overlap syndromes should be considered in patients with evidence of more than one autoimmune hepatic disease. • Disease resistant to standard immunosuppression and treatment of cholestasis can progress rapidly to cirrhosis and associated complications. • Specialist input and treatment with novel therapies, such as B-cell depleting agents, present an opportunity to achieve disease remission in refractory cases.
The Journal of Rheumatology, 2010
Objective.Rituximab has recently emerged as a novel treatment strategy for systemic lupus erythematosus (SLE). We investigated longitudinally the differentiation and phenotypic changes of peripheral B cells and T cells in patients with SLE after rituximab treatment.Methods.Phenotypic changes on B cells and T cells in 10 patients with SLE treated with rituximab were analyzed before, 28 days after, and 2 years after rituximab treatment, and at relapse.Results.Rituximab rapidly depleted naive and memory B cells from the peripheral blood. In the patients with prolonged remission, the memory B cells remained depleted while naive B cells recovered within 3–9 months, and the expression levels of CD40 and CD80 remained downregulated for 2 years. There was also a decrease of memory T cells relative to naive T cells, and the expression of CD40L and inducible costimulator (ICOS) on CD4-positive T cells rapidly decreased and remained downregulated for 2 years. In 1 patient, an increase in the n...
BioMed research international, 2014
Autoimmunity remains a complex physiologic deviation, enabled and perpetuated by a variety of interplayers and pathways. Simplistic approaches, targeting either isolated end-effectors of more centrally placed interactors of these mechanisms, are continuously tried in an effort to comprehend and halt cascades with potential disabling and deleterious effects in the affected individuals. This review focuses on theoretical and clinically proved effects of rituximab-induced CD20+ B cell depletion on different systemic autoimmune diseases and extrapolates on pathogenetic mechanisms that may account for different interindividual or interdisease responses.
Rituximab Therapy and Autoimmune Disease
Current Immunology Reviews, 2012
In recent years, advances in our understanding of the regulation of the immune system have enabled the identification of cellular and molecular targets that could affect the pathogenesis of many autoimmune diseases. B-cells play pivotal role in autoantigen presentation and in autoantibody production. Thus, rituximab (RTX), a chimeric monoclonal antibody specific for human CD20, which targets B lymphocytes, could be a potential new biological treatment for autoimmune diseases. The aim of this mini review is to discuss the potential use of RTX in the management of autoimmune disorders. Results from early phase clinical trials indicates that RTX therapy may provide clinical benefit in systemic lupus erythematosus, Sjogren' syndrome, thrombocytopenic purpura, hemolytic anemia, rheumatoid arthritis and myasthenia gravis. So, it is concluded that RTX therapy alone/or in combinations with corticosteroids, is likely to provide an important new treatment option for a number of difficult to treat autoimmune diseases.
B cells as a therapeutic target in autoimmune diseases other than rheumatoid arthritis
Rheumatology
Selective B-cell depletion with anti-CD20 therapy is a promising novel treatment option for patients with refractory autoimmune disease. The anti-CD20 antibody, rituximab, is the first therapeutic monoclonal antibody to have been approved by the European Medical Agency (EMEA) and the US Food and Drug Administration (FDA) for the treatment of relapsed, low-grade, follicular non-Hodgkin's lymphoma. Rituximab is now being studied in a range of autoimmune diseases, most notably rheumatoid arthritis, but also chronic immune thrombocytopenic purpura and systemic lupus erythematosus. Current data obtained from studies of rituximab single-agent therapy for autoimmune disease show good tolerability and sustained improvement in disease symptoms, although the precise mechanisms of action in autoimmunity remain to be fully clarified. Future research is likely to be focused on the optimization of responses with rituximab-based therapy. However, early observations suggest that this approach is likely to yield significant clinical benefits in a wide range of organ-specific and systemic autoimmune diseases.
B-Cell Depletion and Repopulation in Autoimmune Diseases
Clinical Reviews in Allergy & Immunology, 2008
Although T-lymphocytes have long been regarded as the prime effector of autoimmune diseases, numerous studies have since highlighted a key role for Blymphocytes. For example, disturbances in the distribution of circulating B-cell subsets were reported in primary Sjögren's syndrome (pSS) and systemic lupus erythematosus (SLE). Consequently, this was the rationale to treat such patients for B-cell depletion with anti-CD20 monoclonal antibody (rituximab). The aim of this review is to describe and analyze the B-cell subset distribution at baseline and after rituximab therapy in patients with SLE, rheumatoid arthritis, and pSS. Finally, we will compare factors that may interfere with anti-CD20-mediated B-cell depletion in these autoimmune diseases.