High interindividual variability in the CD4/CD8 T cell ratio and natalizumab concentration levels in the cerebrospinal fluid of patients with multiple sclerosis

Harrer, Andrea; Pilz, Georg; Wipfler, Peter; Oppermann, Katrin; Sellner, Johann; Hitzl, Wolfgang; Haschke-Becher, Elisabeth; Afazel, Shahrzad; Rispens, Theo; Kleij, Desirée van der; Trinka, Eugen; Kraus, Jörg

doi:10.1111/cei.12590

Cited by 21 publications

(18 citation statements)

References 30 publications

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“…Although a role of alpha4 integrins in peripheral lymphoid tissue compartmentalization has been established in animal models [20], a similar effect of natalizumab on germinal center reactions in the CSF is unlikely. The transit of natalizumab across the blood-brain-barrier as an antibody is limited and CSF concentration levels of natalizumab are 350 times less than in serum [8]. In contrast, natalizumab is more likely to affect B cell trafficking across the blood-brain-barrier in agreement with recent studies in EAE models [18].…”

Section: Discussionsupporting

confidence: 85%

Fingolimod alters intrathecal B cell maturation in multiple sclerosis patients

Kowarik

Astling

Lepennetier

et al. 2020

Preprint

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Background: B cells are postulated to play multiple roles in the pathogenesis of multiple sclerosis (MS) including pathogenic antibody production, antigen-presentation and pro-inflammatory cytokine secretion. Natalizumab and fingolimod are effective MS therapies that disrupt lymphocyte migration but exert differential effects on B cell maturation and trafficking. Herein, we investigated their effects on peripheral blood and cerebrospinal fluid (CSF) B cell repertoires.Methods: Paired CSF and peripheral blood (PB) lymphocytes were collected from MS patients at baseline and after 6 months of treatment with fingolimod (n = 4) or natalizumab (n = 4). B cell subsets including naïve, CD27+ memory, CD27-IgD- double-negative B cells and plasmablasts were collected by FACS and their respective heavy-chain variable region (VH) repertoires assessed by next generation deep sequencing (Illumina MiSeq).Results: Treatment with fingolimod lead to a distinct contraction of the PB B cell pool whereas natalizumab resulted in an expansion of circulating PB B cells. In contrast, CSF B cell numbers remained stable under treatment with fingolimod but decreased following natalizumab therapy. Clonal overlap between CSF and peripheral blood B cells was reduced following natalizumab treatment (-24% reduction of clonal groups) but remained stable with fingolimod therapy. Lineage analyses of CSF B cell repertoires at baseline and following therapy revealed large, clonally expanded B cell clusters in natalizumab-treated MS patients but no intrathecal clonal expansion following fingolimod therapy. Conclusions: Our findings suggest that natalizumab treatment diminishes the exchange of peripheral and intrathecal B cells but does not impact intrathecal clonal expansion. In contrast, fingolimod treatment fails to alter B cell exchange across the blood-brain-barrier but affects intrathecal clonal expansion. Sphingosine-1 phosphate receptor inhibition may impact MS disease progression by inhibiting intrathecal germinal center activity.

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Section: Discussionsupporting

confidence: 85%

Fingolimod alters intrathecal B cell maturation in multiple sclerosis patients

Kowarik

Astling

Lepennetier

et al. 2020

Preprint

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“…The magnitude and timing of the changes observed in natalizumab-treated patients were similar to those published in smaller observational studies. 11 , 22 – 29 CD34+ hematopoietic progenitor cells were previously found to increase above the normal reference levels in natalizumab-treated patients. 11 We observed similarly increased levels of CD34+ cells (mean of 7.7 cells/mm 3 ); however, clonality (evaluated by the excess immunoglobulin light chain kappa or lambda proteins on cells) was not observed (data not shown), and counts returned to the normal range approximately 16 weeks after treatment interruption.…”

Section: Discussionmentioning

confidence: 92%

Reversibility of the effects of natalizumab on peripheral immune cell dynamics in MS patients

et al. 2017

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Objective:To characterize the reversibility of natalizumab-mediated changes in pharmacokinetics/pharmacodynamics in patients with multiple sclerosis (MS) following therapy interruption.Methods:Pharmacokinetic/pharmacodynamic data were collected in the Safety and Efficacy of Natalizumab in the Treatment of Multiple Sclerosis (AFFIRM) (every 12 weeks for 116 weeks) and Randomized Treatment Interruption of Natalizumab (RESTORE) (every 4 weeks for 28 weeks) studies. Serum natalizumab and soluble vascular cell adhesion molecule–1 (sVCAM-1) were measured using immunoassays. Lymphocyte subsets, α4-integrin expression/saturation, and vascular cell adhesion molecule–1 (VCAM-1) binding were assessed using flow cytometry.Results:Blood lymphocyte counts (cells/L) in natalizumab-treated patients increased from 2.1 × 109 to 3.5 × 109. Starting 8 weeks post last natalizumab dose, lymphocyte counts became significantly lower in patients interrupting treatment than in those continuing treatment (3.1 × 109 vs 3.5 × 109; p = 0.031), plateauing at prenatalizumab levels from week 16 onward. All measured cell subpopulation, α4-integrin expression/saturation, and sVCAM changes demonstrated similar reversibility. Lymphocyte counts remained within the normal range. Ex vivo VCAM-1 binding to lymphocytes increased until ≈16 weeks after the last natalizumab dose, then plateaued, suggesting reversibility of immune cell functionality. The temporal appearance of gadolinium-enhancing lesions was consistent with pharmacodynamic marker reversal.Conclusions:Natalizumab's effects on peripheral immune cells and pharmacodynamic markers were reversible, with changes starting 8 weeks post last natalizumab dose; levels returned to those observed/expected in untreated patients ≈16 weeks post last dose. This reversibility differentiates natalizumab from MS treatments that require longer reconstitution times. Characterization of the time course of natalizumab's biological effects may help clinicians make treatment sequencing decisions.Classification of evidence:This study provides Class III evidence that the pharmacodynamic markers of natalizumab are reversed ≈16 weeks after stopping natalizumab.

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“…The CD4 + /CD8 + ratio has been recognized as an important indicator for evaluating the state of immunomodulation and response to homeostasis of the intrinsic immune system (23). Previous studies have shown that the increased CD4 + /CD8 + ratio has been observed in many autoimmune diseases such as SLE (24), inflammatory bowel disease (25) and multiple sclerosis (26). A low CD4 + /CD8 + ratio was considered as a marker of decreased immune function (27), which could result in increasing the risk of HIV-infected, pulmonary tuberculosis and even some tumors (28,29).…”

Section: Discussionmentioning

confidence: 99%

Vitamin D improves immune function in immunosuppressant mice induced by glucocorticoid

Wang¹,

Wang²,

Xu³

et al. 2016

Biomedical Reports

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Vitamin D is an essential fat-soluble vitamin with multiple functions. Vitamin D receptor has been shown to be expressed in several types of immune cells suggesting vitamin D may have immune regulatory roles. Vitamin D insufficiency has been suggested to increase the risk of autoimmune diseases. However, little is known regarding its immunomodulatory effects in the condition of immune suppression. The aim of the present study was to investigate the regulatory effects of vitamin D on immune function in immunosuppressant mice. An immunosuppressant mouse model was induced by intraperitoneal injection with glucocorticiod for 3 days. Immunosuppressant mice were intragastrically administered with 1,25-dihydroxy-vitamin D3 [1,25(OH)D; 0,4, 6 or 10 IU/g body weight] for 7 days. On day 8, the mice were decapitated. The body weight and the weights of thymus and spleen were measured. Thymus and spleen indexes were calculated. The ratio of CD4/CD8 T lymphocytes in the peripheral blood, proliferation and interleukin-2 (IL-2) production of spleen T lymphocytes was detected. Compared with the mice in the control group, the body weight, thymus and spleen indexes, the ratios of CD4/CD8 in peripheral blood and IL-2 production and proliferation of spleen T lymphocytes were decreased in immunosuppressant mice induced by glucocorticiod. However, in vitamin D-treated mice, the thymus indexes, the ratios of CD4/CD8, secretion of IL-2 and the proliferation index of spleen T lymphocytes were significantly increased (P<0.05). Among the three doses of 1,25(OH)D, 6 IU/g was most effective in improving the immune function. These results indicate that vitamin D supplementation can improve immune recovery in immunosuppressant mice by stimulating T-cell proliferation and elevating IL-2 production.

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High interindividual variability in the CD4/CD8 T cell ratio and natalizumab concentration levels in the cerebrospinal fluid of patients with multiple sclerosis

Cited by 21 publications

References 30 publications

Fingolimod alters intrathecal B cell maturation in multiple sclerosis patients

Fingolimod alters intrathecal B cell maturation in multiple sclerosis patients

Reversibility of the effects of natalizumab on peripheral immune cell dynamics in MS patients

Vitamin D improves immune function in immunosuppressant mice induced by glucocorticoid

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