Altered CD4+/CD8+ T-Cell Ratios in Cerebrospinal Fluid of Natalizumab-Treated Patients With Multiple Sclerosis

Stüve, Olaf; Marra, Christina M.; Bar‐Or, Amit; Niino, Masaaki; Cravens, Petra D.; Cepok, Sabine; Frohman, Elliot M.; Phillips, J. Theodore; Arendt, Gabriele; Jerome, Keith R.; Cook, Linda; Grand’Maison, François; Hemmer, Bernhard; Monson, Nancy; Racke, Michael K.

doi:10.1001/archneur.63.10.1383

Cited by 260 publications

(219 citation statements)

References 30 publications

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“…Natalizumab treatment has been shown to reduce the migration of leukocytes into the CNS [1,6,11,16,17], to inhibit the retention of memory-and marginal zone-like B cells within the spleen [6] and to induce a sequestration of lymphocytes, in particular activated T cells [18], and of immature B cells [4] in the peripheral circulation of MS-treated patients. However, considering the scarcity of leukocytes in the CNS compared to the periphery and the slight contribution of memory-and marginal zone-like B cells on the composition of the lymphocyte pool, it is unlikely that the reduced migration of leukocytes into the CNS and the decreased retention of specific B-cell subsets in the spleen can quantitatively affect peripheral lymphocyte count or fully explain the increase of lymphocytes observed during natalizumab therapy.…”

Section: Discussionmentioning

confidence: 99%

Peripheral accumulation of newly produced T and B lymphocytes in natalizumab-treated multiple sclerosis patients

Zanotti

Chiarini

Serana

et al. 2012

Clinical Immunology

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The anti-α4 monoclonal antibody natalizumab inhibits lymphocyte extravasation into the central nervous system and increases peripheral T and B lymphocytes in multiple sclerosis patients. To investigate whether the lymphocyte accumulation was due to a higher lymphocyte production, an altered homeostasis, or a differential transmigration of lymphocyte subsets through endothelia, T-cell receptor excision circles and kappa-deleting recombination excision circles were quantified before and after treatment, T-cell receptor repertoire was analyzed by spectratyping, and T-and B-lymphocyte subset migration was studied using transwell coated with vascular and lymphatic endothelial cells. We found that the number of newly produced T and B lymphocytes is increased because of a high release and of a low propensity of naïve subsets to migrate across endothelial cells. In some patients this resulted in an enlargement of T-cell heterogeneity. Because new lymphocyte production ensures the integrity of immune surveillance, its quantification could be used to monitor natalizumab therapy safety.

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Section: Discussionmentioning

confidence: 99%

Peripheral accumulation of newly produced T and B lymphocytes in natalizumab-treated multiple sclerosis patients

Zanotti

Chiarini

Serana

et al. 2012

Clinical Immunology

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“…Thus, ␣ 4 integrins can mediate both the initial low-affinity interaction of circulating leukocytes with the CNS microvasculature and the subsequent G protein-dependent arrest requiring high-affinity binding of ␣ 4 integrins. In humans, predominant involvement of ␣ 4 integrins in leukocyte recruitment across the BBB has been supported by the observation that therapeutic targeting of leukocyte trafficking across the BBB by blocking ␣ 4 integrin with the humanized Ab natalizumab has proven beneficial for the treatment of MS (11,12) and reduces the number of inflammatory cells present in the cerebrospinal fluid of natalizumab-treated MS patients (13).…”

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confidence: 99%

E- and P-Selectin Are Not Required for the Development of Experimental Autoimmune Encephalomyelitis in C57BL/6 and SJL Mice

Döring

Wild

Vestweber

et al. 2007

The Journal of Immunology

102

106

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In multiple sclerosis and in its animal model experimental autoimmune encephalomyelitis (EAE), inflammatory cells migrate across the endothelial blood-brain barrier (BBB) and gain access to the CNS. It is well-established that α4 integrins are actively involved in leukocyte recruitment across the BBB during EAE. In contrast, the role of endothelial E- and P-selectin in this process has been a controversial issue. In this study, we demonstrate that P-selectin protein can be detected in meningeal blood vessel endothelial cells in healthy SJL and C57BL/6 mice and on rare parenchymal CNS blood vessels in C57BL/6, but not SJL, mice. During EAE, expression of P-selectin but not E-selectin was found up-regulated on inflamed CNS microvessels surrounded by inflammatory infiltrates irrespective of their meningeal or parenchymal localization with a more prominent immunostaining detected in C57BL/6 as compared with SJL mice. P-selectin immunostaining could be localized to CNS endothelial cells and to CD41-positive platelets adhering to the vessel wall. Despite the presence of P-selectin in wild-type mice, E/P-selectin-deficient SJL and C57BL/6 mice developed clinical EAE indistinguishable from wild-type mice. Absence of E- and P-selectin did neither influence the activation of myelin-specific T cells nor the composition of the cellular infiltrates in the CNS during EAE. Finally, endothelial-specific tetracycline-inducible expression of E-selectin at the BBB in transgenic C57BL/6 mice did not alter the development of EAE. Thus, E- and P-selectin are not required for leukocyte recruitment across the BBB and the development of EAE in C57BL/6 and in SJL mice.

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“…(3) Relatively small sample size . Based on previous CSF studies,19, 21 we estimated that 15 patients analyzed before and after therapy provide sufficient power to reproducibly identify 20–30% effect sizes. High statistical significance, reproducibility of results between STT, LTT, and LTT+1y time points and between Cohorts A and B support our conclusion that the study is powered to detect biologically meaningful effect sizes.…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamic effects of daclizumab in the intrathecal compartment

Komori

Kósa

Stein

et al. 2017

Ann Clin Transl Neurol

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ObjectiveIt was previously demonstrated that daclizumab therapy normalizes cellular cerebrospinal fluid (CSF) abnormalities typical of multiple sclerosis (MS) in the majority of treated patients. However, CSF cells represent only the mobile portion of intrathecal immune responses. Therefore, we asked whether daclizumab also reverses compartmentalized inflammation and if not, whether residual inflammation correlates with clinical response to the drug.MethodsForty MS patients treated with an intravenous or subcutaneous injection of daclizumab were followed for up to 16 years in two open‐label clinical trials. MRI contrast‐enhancing lesions (CELs), clinical scales, and CSF biomarkers quantified residual disease.ResultsRapid decreases in CELs, sustained throughout the observation period, were observed with daclizumab treatment. Daclizumab therapy induced modest but statistically significant (P < 0.0001) decreases in CSF levels of T‐cell activation marker CD27 and IgG index. Interleukin 2 (IL‐2) CSF levels increased from baseline levels during treatment, consistent with reduced IL‐2 consumption by T cells, as a consequence of daclizumab's saturation of high‐affinity IL‐2 receptors. CSF levels of IL‐12p40, chitinase‐3‐like protein‐1 (CHI3L1), chemokine C‐X‐C motif ligand 13, and neurofilament light chain (NFL) were also significantly reduced by daclizumab. Among them, inhibition of CHI3L1 correlated with inhibition of NFL and with lack of disease progression.InterpretationThese observations confirm daclizumab's direct pharmacodynamics effects on immune cells within central nervous system tissues and identify inhibition of CSF biomarkers of myeloid lineage as a stronger determinant of reduction in clinical MS activity than inhibition of biomarkers of adaptive immunity.

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Altered CD4+/CD8+ T-Cell Ratios in Cerebrospinal Fluid of Natalizumab-Treated Patients With Multiple Sclerosis

Cited by 260 publications

References 30 publications

Peripheral accumulation of newly produced T and B lymphocytes in natalizumab-treated multiple sclerosis patients

Peripheral accumulation of newly produced T and B lymphocytes in natalizumab-treated multiple sclerosis patients

E- and P-Selectin Are Not Required for the Development of Experimental Autoimmune Encephalomyelitis in C57BL/6 and SJL Mice

Pharmacodynamic effects of daclizumab in the intrathecal compartment

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