VLA-4 blockade promotes differential routes into human CNS involving PSGL-1 rolling of T cells and MCAM-adhesion of TH17 cells

Schneider‐Hohendorf, Tilman; Rossaint, Jan; Mohan, Hema; Böning, Daniel; Breuer, Johanna; Groß, Catharina C.; Flanagan, Ken; Sorokin, Lydia; Vestweber, Dietmar; Zarbock, Alexander; Schwab, Nicholas; Wiendl, Heinz

doi:10.1016/j.jneuroim.2014.08.080

Cited by 10 publications

(13 citation statements)

References 32 publications

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“…2D, Lower) suggest that transmigration of NK cells into the CNS is VLA-4-dependent. Of note, NK cells were negative for melanoma cell adhesion molecule (MCAM, CD146) ( Table 1), which has recently been identified to be involved in an alternative migratory pathway of Th17 cells across the BBB (38). Finally, a higher proportion of intrathecal CD56 dim NK cells expressed GrK in comparison with those of the PB (Fig.…”

Section: Resultsmentioning

confidence: 91%

“…Finally, reduction of intrathecal CD56 bright NK-cell frequencies to levels of healthy individuals in MS patients treated with the α 4 β 1 integrin blocker (44) natalizumab indicates that transmigration of NK cells into the CNS depends on VLA-4. The alternative MCAM-dependent pathway that has been recently described for Th17 (38) MS is associated with alterations of the peripheral NK-cell compartment. We found reduced cell surface expression of the activating NK-cell receptor DNAM-1 (CD226), a genetic alteration consistently found in MS-association studies (16)(17)(18), and 2B4.…”

Section: Discussionmentioning

confidence: 95%

“…Static imaging of CD56 bright and CD56 dim NK-cell subsets was performed as previously described (38).…”

Section: Methodsmentioning

confidence: 99%

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Impaired NK-mediated regulation of T-cell activity in multiple sclerosis is reconstituted by IL-2 receptor modulation

Groß

Schulte‐Mecklenbeck

Rünzi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) resulting from a breakdown in peripheral immune tolerance. Although a beneficial role of natural killer (NK)-cell immune-regulatory function has been proposed, it still needs to be elucidated whether NK cells are functionally impaired as part of the disease. We observed NK cells in active MS lesions in close proximity to T cells. In accordance with a higher migratory capacity across the blood-brain barrier, CD56

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Section: Resultsmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 95%

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Impaired NK-mediated regulation of T-cell activity in multiple sclerosis is reconstituted by IL-2 receptor modulation

Groß

Schulte‐Mecklenbeck

Rünzi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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153

206

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“…In this context, it was shown that long-term treatment with natalizumab leads to an upregulation of P-selectin glycoprotein ligand-1 on T cells, enhancing their rolling capacity over endothelial cells. Under these circumstances, a subpopulation of T cells expressing melanoma cell adhesion molecule is able to adhere to endothelial cells independently of the VLA-4 pathway [48]. In vivo, this results in high quantities of melanoma cell adhesion molecule-expressing T cells (mainly Th17 cells) in the cerebrospinal fluid (CSF) of patients treated with natalizumab.…”

Section: Natalizumabmentioning

confidence: 99%

Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications

Bittner

Wiendl

2016

Neurotherapeutics

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Therapeutic options for multiple sclerosis (MS) have significantly increased over the last few years. T lymphocytes are considered to play a central role in initiating and perpetuating the pathological immune response. Currently approved therapies for MS target T lymphocytes, either in an unspecific manner or directly by interference with specific Tcell pathways. While the concept of BT-cell-specific therapyî mplies specificity and selectivity, currently approved approaches come from a general shaping of the immune system towards anti-inflammatory immune responses by non-T-cellselective immune suppression or immune modulation (e.g., interferons-immune modulation approach) to a depletion of immune cell populations involving T cells (e.g., anti-CD52, alemtuzumab-immune selective depletion approach), or a selective inhibition of distinct molecular pathways in order to sequester leucocytes (e.g., natalizumab-leukocyte sequestration approach). This review will highlight the rationale and results of different T-cell-directed therapeutic approaches coming from basic animal experiments to clinical trials. We will first discuss the pathophysiological rationale for targeting T lymphocytes in MS leading to currently approved treatments acting on T lymphocytes. Furthermore, we will disuss previous promising concepts that have failed to show efficacy in clinical trials or were halted as a result of unexpected adverse events. Learning from the discrepancies between expectations and failures in practical outcomes helps to optimize future research approaches and clinical study designs. As our current view of MS pathogenesis and patient needs is rapidly evolving, novel therapeutic approaches targeting T lymphocytes will also be discussed, including specific molecular interventions such as cytokine-directed treatments or strategies enhancing immunoregulatory mechanisms. Based on clinical experience and novel pathophysiological approaches, T-cell-based strategies will remain a pillarstone of MS therapy.

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“…For example, recent findings suggest that lymphocyte trafficking into the central nervous system of patients with multiple sclerosis receiving natalizumab can occur by using the alternative adhesion molecules, P-selectin glycoprotein ligand-1 (PSGL-1) and melanoma cell adhesion molecule (MCAM), the latter representing an exclusive pathway for T helper 17 (TH17) cells to migrate over the blood-brain barrier. 6 Taken together, any effort to substantially improve current stroke treatment is greatly appreciated. Clinician scientist should team up with partners from the industries to identify the most promising drug targets.…”

mentioning

confidence: 99%

Response to Letter Regarding Article, “Blocking of α4 Integrin Does Not Protect From Acute Ischemic Stroke in Mice”

Kleinschnitz

Langhauser

Wiendl

2014

Stroke

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VLA-4 blockade promotes differential routes into human CNS involving PSGL-1 rolling of T cells and MCAM-adhesion of TH17 cells

Cited by 10 publications

References 32 publications

Impaired NK-mediated regulation of T-cell activity in multiple sclerosis is reconstituted by IL-2 receptor modulation

Impaired NK-mediated regulation of T-cell activity in multiple sclerosis is reconstituted by IL-2 receptor modulation

Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications

Response to Letter Regarding Article, “Blocking of α4 Integrin Does Not Protect From Acute Ischemic Stroke in Mice”

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