Rituximab Efficiently Depletes Increased CD20-Expressing T Cells in Multiple Sclerosis Patients

Palanichamy, Arumugam; Jahn, Sarah; Nickles, Dorothee; Derstine, Mia; Abounasr, Aya; Hauser, Stephen L.; Baranzini, Sergio E.; Leppert, David; Büdingen, Hans‐Christian von

doi:10.4049/jimmunol.1400118

Cited by 240 publications

(324 citation statements)

References 36 publications

(42 reference statements)

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“…To address this issue, we have sorted CD3 + CD20 + T cells directly from blood and determined the transcription of CD20. We found that-in contrast to conventional T cells-this T cell subset transcribes CD20, consistent with recent data (11). We also found that these CD3 + CD20…”

Section: Discussionsupporting

confidence: 81%

“…CD3 + CD20 + T cells produce more readily the cytokines IL-4, IL-17, TNF-a, and IFN-g than CD3 + CD20 2 T cells and respond to immunomodulatory drugs. Our analysis demonstrates a CD3 + CD20 + population comprising 3-5% of all lymphocytes in human blood, corroborating previous reports (11,13). This cell population is a T cell subset because these cells transcribe CD3 at a similar level as conventional T cells and lack surface molecules found on B cells such as CD19, CD40, and HLA-DR. All this justifies to call this population CD20 expressing T cells.…”

Section: Discussionsupporting

confidence: 75%

“…The number of CD3 + CD20 + cells were determined as described previously (11). Briefly, we identified these T cells by gating on CD3 + CD19 2 cells and afterward determining the CD20 expression (Supplemental Fig.…”

Section: Cd20mentioning

confidence: 99%

“…The description of CD3 + CD20 + T cells in rheumatoid arthritis patients and controls (9) was disputed and has been regarded as an artifact of flow cytometry (10). Yet recently, a subset of CD3 + CD20 + T cells that is also targeted by rituximab has been described (11). The issue remains complicated, however, because CD3 + B cells have been described as a result from ex vivo storage of blood samples, leading to contactdependent Ag exchange between T and B lymphocytes (12).…”

mentioning

confidence: 99%

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Features of Human CD3+CD20+ T Cells

Schuh

Berer

Mulazzani³

et al. 2016

The Journal of Immunology

155

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Monoclonal Abs against CD20 reduce the number of relapses in multiple sclerosis (MS); commonly this effect is solely attributed to depletion of B cells. Recently, however, a subset of CD3+CD20+ T cells has been described that is also targeted by the anti-CD20 mAb rituximab. Because the existence of cells coexpressing CD3 and CD20 is controversial and features of this subpopulation are poorly understood, we studied this issue in detail. In this study, we confirm that 3–5% of circulating human T cells display CD20 on their surface and transcribe both CD3 and CD20. We report that these CD3+CD20+ T cells pervade thymus, bone marrow, and secondary lymphatic organs. They are found in the cerebrospinal fluid even in the absence of inflammation; in the cerebrospinal fluid of MS patients they occur at a frequency similar to B cells. Phenotypically, these T cells are enriched in CD8+ and CD45RO+ memory cells and in CCR7− cells. Functionally, they show a higher frequency of IL-4–, IL-17–, IFN-γ–, and TNF-α–producing cells compared with T cells lacking CD20. CD20-expressing T cells respond variably to immunomodulatory treatments given to MS patients: they are reduced by fingolimod, alemtuzumab, and dimethyl fumarate, whereas natalizumab disproportionally increases them in the blood. After depletion by rituximab, they show earlier and higher repopulation than CD20+ B cells. Taken together, human CD3+CD20+ T cells pervade lymphatic organs and the cerebrospinal fluid, have a strong ability to produce different cytokines, and respond to MS disease modifying drugs.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionsupporting

confidence: 75%

Section: Cd20mentioning

confidence: 99%

mentioning

confidence: 99%

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Features of Human CD3+CD20+ T Cells

Schuh

Berer

Mulazzani³

et al. 2016

The Journal of Immunology

155

200

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“…Depletion of a small subset of CD20+ T cells in patients with MS treated with rituximab has also been reported [104]. The effectiveness of rituximab therapy depends on efficient depletion of noncirculating B cells and is associated with qualitative immunological changes that indicate reconfiguration of B-cell memory through sustained reduction of autoreactive clonal expansions and Bcell repopulation characterized by the predominance of IL10-producing Bregs [51,79].…”

Section: Inflammatory Myopathiesmentioning

confidence: 97%

Anti-B-Cell Therapies in Autoimmune Neurological Diseases: Rationale and Efficacy Trials

2016

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B cells have an ever-increasing role in the etiopathology of a number of autoimmune neurological disorders, acting as antibody-producing cells and, most importantly, as sensors, coordinators, and regulators of the immune response. B cells, among other functions, regulate the T-cell activation process through their participation in antigen presentation and production of cytokines. The availability of monoclonal antibodies or fusion proteins against B-cell surface molecules or Bcell trophic factors bestows a rational approach for treating autoimmune neurological disorders, even when T cells are the main effector cells. This review summarizes basic aspects of B-cell biology, discusses the role(s) of B cells in neurological autoimmunity, and presents anti-B-cell drugs that are either currently on the market or are expected to be available in the near future for treating neurological autoimmune disorders.

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Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab

et al. 2017

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IMPORTANCE Alemtuzumab, a CD52-depleting monoclonal antibody, effectively inhibits relapsing multiple sclerosis (MS) but is associated with a high incidence of secondary B-cell autoimmunities that limit use. These effects may be avoided through control of B-cell hyperproliferation.OBJECTIVE To investigate whether the data describing the effect of alemtuzumab on lymphocyte subsets collected during the phase 3 trial program reveal mechanisms explaining efficacy and the risk for secondary autoimmunity with treatment of MS. DESIGN, SETTING, AND PARTICIPANTS Lymphocyte reconstitution data from regulatory submissions of the pivotal Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I and II (CARE-MS I and II) trials were obtained from the European Medicines Agency via Freedom of Information requests. Data used in this study were reported from June 22 to October 12, 2016. MAIN OUTCOMES AND MEASURES Tabulated data from T-and B-lymphocyte subset analysis and antidrug antibody responses were extracted from the supplied documents.RESULTS Alemtuzumab depleted CD4 + T cells by more than 95%, including regulatory cells (−80%) and CD8 + T cells (>80% depletion), which remained well below reference levels throughout the trials. However, although CD19 + B cells were initially also depleted (>85%), marked (180% increase) hyperrepopulation of immature B cells occurred with conversion to mature B cells over time. These lymphocyte kinetics were associated with rapid development of alemtuzumab-binding and -neutralizing antibodies and subsequent occurrence of secondary B-cell autoimmunity. Hyperrepopulation of B cells masked a marked, long-term depletion of CD19 + memory B cells that may underpin efficacy in MS.CONCLUSIONS AND RELEVANCE Although blockade of memory T and B cells may limit MS, rapid CD19 + B-cell subset repopulation in the absence of effective T-cell regulation has implications for the safety and efficacy of alemtuzumab. Controlling B-cell proliferation until T-cell regulation recovers may limit secondary autoimmunity, which does not occur with other B-cell-depleting agents.

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Rituximab Efficiently Depletes Increased CD20-Expressing T Cells in Multiple Sclerosis Patients

Cited by 240 publications

References 36 publications

Features of Human CD3+CD20+ T Cells

Features of Human CD3+CD20+ T Cells

Anti-B-Cell Therapies in Autoimmune Neurological Diseases: Rationale and Efficacy Trials

Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab

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