Anti-CD20 therapy corrects a CD8 regulatory T cell deficit in multiple sclerosis

Howlett-Prieto, Quentin; Feng, Xuan; Kramer, John F.; Kramer, Kevin J.; Houston, Timothy W; Reder, Anthony T.

doi:10.1177/13524585211003301

Cited by 12 publications

(17 citation statements)

References 38 publications

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“…Lymphocyte subset frequency, median fluorescence intensity (MFI), and multiparameter compensation values were calculated with FlowJo software. 28 Clinical laboratory testing quantitated total white blood cells and absolute lymphocyte count, which paralleled flow cytometry classified lymphocytes.…”

Section: Methodsmentioning

confidence: 99%

Increased Percentage of CD8 ⁺ CD28 ⁻ Regulatory T Cells With Fingolimod Therapy in Multiple Sclerosis

Houston

Howlett-Prieto

Regenauer

et al. 2023

Neurol Neuroimmunol Neuroinflamm

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Background and ObjectivesFingolimod, an oral therapy for MS, decreases expression of membrane S1P1 receptors on CD4+memory cells, causing their retention and deactivation in lymph nodes. We determined fingolimod effects on the number and proportion of potentially CNS-damaging CD8+CD28+cytolytic T lymphocyte cells (CTLs) and on MS-depleted and dysfunctional CD8+CD28−anti-inflammatory suppressor/regulatory T cells (Treg) and on CD8+T-cell expression of the CD69 activation/lymph node retention protein in MS.MethodsCD8, CD28, CD4, and CD69 expression on peripheral blood mononuclear cells was measured with flow cytometry. In vitro concanavalin A (ConA) activation of T cells, including CD8+CD28−cells, was used to mimic inflammation.ResultsFifty-nine patients with MS, 35 therapy-naive (16 clinically stable; 19 exacerbating) and 24 fingolimod-treated (19 clinically stable; 5 exacerbating), and 26 matched healthy controls (HCs) were compared. In therapy-naive patients, the CD8+Treg percent of total lymphocytes was only 1/4 of HC levels. In fingolimod-treated patients, however, CD8+Treg percentages rose to 2.5-fold higher than in HC and 10-fold higher than in therapy-naive MS. With fingolimod therapy, in contrast, CD8+CTL levels were less than half of levels in HCs and therapy-naive patients. In HCs and all MS, activation with ConA strongly induced CD69 expression on CD4+cells and induced 3-fold higher CD69 levels on CD8+CTL than on CD8+Treg. Fingolimod and analogs in vitro did not modify lymphocyte CD69 expression. Lower levels of CD69 on CD8+Treg than on CTL may allow easier Treg egress from lymph nodes and enhance control of peripheral inflammation. In vitro activation reduced the already low CD8+Treg population in therapy-naive MS, but only slightly altered Treg levels in fingolimod-treated MS.DiscussionFingolimod therapy markedly increases the percentage of CD8+Treg in MS, reversing the low CD8+Treg:CTL ratio seen in untreated MS. The increase in immune regulatory cells has potential therapeutic benefit in MS. Activation in vitro depletes CD8+CD28+CTL in patients with MS; the loss is more pronounced in older patients with MS. This suggests that inflammation can disrupt the tenuous immune regulation in MS, especially in older patients.

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Section: Methodsmentioning

confidence: 99%

Increased Percentage of CD8 ⁺ CD28 ⁻ Regulatory T Cells With Fingolimod Therapy in Multiple Sclerosis

Houston

Howlett-Prieto

Regenauer

et al. 2023

Neurol Neuroimmunol Neuroinflamm

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“…Onset of depletion can be as quick as 2 weeks and has been seen up to 6 months post administration [ 26 , 27 ], and CD8 + CD20 + T cells appear to somewhat more susceptible to CD20 depletion over CD4 + CD20 + T cells [ 12 ]. However, it is important to realise that a depletion in CD20 + T cells or B cells are not the only mechanisms for the efficacy of CD20-depleting agents, as an increase in PB regulatory T (T Reg ) cells after ocrelizumab administration was seen, which may assist with the dampening down of neuroinflammation [ 28 ].…”

Section: Role In Autoimmunitymentioning

confidence: 99%

CD20+ T cells: an emerging T cell subset in human pathology

Lee

2022

Inflamm. Res.

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Introduction Although CD20 is classically a B cell marker, in the last three decades, dim expression has been noted on a subset of T cells as well that has been independently verified by a number of groups. Our understanding of these cells and their function is not well established. Methods A thorough review of original articles on CD20+T cells was undertaken of Pubmed by using combination of phrases including “CD20+”, “CD20-positive” and “T cells”. Articles in English were considered, and there was no time restriction. Results CD20+T cells express the standard T cell markers and, in comparison to CD20¯ T cells, appear to express greater inflammatory cytokines and markers of effector function. Although the ontogeny of these cells is still being established, the current theory is that CD20 may be acquired by trogocytosis from B cells. CD20+T cells may be found in healthy controls and in a wide range of pathologies including autoimmune diseases, haematological and non-haematological malignancies and human immunodeficiency virus (HIV) infections. One of the best studied diseases where these cells are found is multiple sclerosis (MS) where a number of therapeutic interventions, including anti-CD20 depletion, have been shown to effectively deplete these cells. Conclusion This review summarises the latest understanding of CD20+T cells, their presence in various diseases, their putative function and how they may be an ongoing target of CD20-depleting agents. Unfortunately, our understanding of these cells is still at its infancy and ongoing study in a wider range of pathologies is required.

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“… 32 Moreover, beyond B-cell depletion, the involvement of T-cells is emerging specifically in ocrelizumab-treated patients. 33 , 34 …”

Section: B-cells In Ms: Implications For Clinical Use Of Anti-cd20 Mabsmentioning

confidence: 99%

“…32 Moreover, beyond B-cell depletion, the involvement of T-cells is emerging specifically in ocrelizumab-treated patients. 33,34 In summary, these findings may explain why B-celldepleting agents are so effective in controlling clinical relapses and focal inflammation in RMS, but the mechanisms underlying the benefits on PPMS are less clear and investigated. Of note, in the ORATORIO trial, a minority of patients with PPMS, especially younger and closer to disease onset, have signs of acute radiological activity before being enrolled, 13 suggesting an action of the drug on relapse biology that may have occurred subclinically in some of these patients.…”

Section: Dovepressmentioning

confidence: 99%

Ocrelizumab for the Treatment of Multiple Sclerosis: Safety, Efficacy, and Pharmacology

Mancinelli¹,

Rossi²,

Capra³

2021

TCRM

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The success of selective B-cells depleting therapies, as the anti-CD20 antibodies, in patients with multiple sclerosis (MS) has confirmed that B-cells are critical in the immune pathogenesis of the disease. Ocrelizumab, a humanized monoclonal antibody that selectively targets CD20+ B-cells, profoundly suppresses acute inflammatory disease activity, representing a highly effective therapy for relapsing-remitting multiple sclerosis (RRMS). It is also the first proven therapy able to slow disability progression in primary progressive multiple sclerosis (PPMS), particularly in patients with signs of acute radiological activity before being enrolled. Effectiveness has widely been demonstrated in randomized clinical trials (RCTs), and recently confirmed in open-label extension trials. Here, we review the role of B-cells in MS, the mechanism of action of ocrelizumab, its pharmacokinetics and pharmacodynamics, and the clinical data supporting its use, as well as safety data. We focus on issues related to the maintenance of immunocompetence, essential to ensure an immune response to either a primary infection or a vaccination. Lastly, we discuss about the possible role of ocrelizumab as an exit strategy from natalizumab-treated patients at risk of developing multifocal progressive leukoencephalopathy. In view of using ocrelizumab chronically, collecting long-term safety data and finding strategies to minimize adverse events will be extremely relevant.

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Anti-CD20 therapy corrects a CD8 regulatory T cell deficit in multiple sclerosis

Cited by 12 publications

References 38 publications

Increased Percentage of CD8 ⁺ CD28 ⁻ Regulatory T Cells With Fingolimod Therapy in Multiple Sclerosis

Increased Percentage of CD8 ⁺ CD28 ⁻ Regulatory T Cells With Fingolimod Therapy in Multiple Sclerosis

CD20+ T cells: an emerging T cell subset in human pathology

Ocrelizumab for the Treatment of Multiple Sclerosis: Safety, Efficacy, and Pharmacology

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Anti-CD20 therapy corrects a CD8 regulatory T cell deficit in multiple sclerosis

Cited by 12 publications

References 38 publications

Increased Percentage of CD8 + CD28 − Regulatory T Cells With Fingolimod Therapy in Multiple Sclerosis

Increased Percentage of CD8 + CD28 − Regulatory T Cells With Fingolimod Therapy in Multiple Sclerosis

CD20+ T cells: an emerging T cell subset in human pathology

Ocrelizumab for the Treatment of Multiple Sclerosis: Safety, Efficacy, and Pharmacology

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Increased Percentage of CD8 ⁺ CD28 ⁻ Regulatory T Cells With Fingolimod Therapy in Multiple Sclerosis

Increased Percentage of CD8 ⁺ CD28 ⁻ Regulatory T Cells With Fingolimod Therapy in Multiple Sclerosis