In JoVE (1)

Other Publications (21)

Articles by Tilman Schneider-Hohendorf in JoVE

Other articles by Tilman Schneider-Hohendorf on PubMed

Regulatory T Cells Exhibit Enhanced Migratory Characteristics, a Feature Impaired in Patients with Multiple Sclerosis

European Journal of Immunology. Dec, 2010  |  Pubmed ID: 21108477

Migration of immune cells characterizes inflammation and plays a key role in autoimmune diseases such as MS. CD4(+)Foxp3(+) regulatory T cells (Treg) have the potential to dampen immune responses but show functional impairment in patients with MS. We here show that murine Treg exhibit higher constitutive cell motility in horizontal migration on laminin, surpass non-Treg in transwell assays through microporous membranes as well as across primary brain endothelium and are present in the naïve CNS to a significantly higher extent compared to spleen, lymph nodes and blood. Likewise, human Treg from healthy donors significantly exceed non-Treg in migratory rates across primary human brain endothelium. Finally, we investigated whether the propensity to migrate is impaired as a feature of autoimmunity and therefore tested patients with MS. Treg from patients with stable relapsing-remitting MS show significantly impaired migratory capacity under non-inflammatory conditions compared to healthy donors. We hypothesize that the enhanced propensity to migrate is a feature of Treg that allows for an equilibrium in parenchymal immune surveillance, e.g. of the CNS. Impaired Treg migration across the intact blood-brain barrier, as observed for Treg from patients with MS, indicates a broader functional deficiency hypothetically contributing to early CNS lesion development or phases of MS remissions.

Temporal Pattern of ICAM-I Mediated Regulatory T Cell Recruitment to Sites of Inflammation in Adoptive Transfer Model of Multiple Sclerosis

PloS One. 2010  |  Pubmed ID: 21085578

Migration of immune cells to the target organ plays a key role in autoimmune disorders like multiple sclerosis (MS). However, the exact underlying mechanisms of this active process during autoimmune lesion pathogenesis remain elusive. To test if pro-inflammatory and regulatory T cells migrate via a similar molecular mechanism, we analyzed the expression of different adhesion molecules, as well as the composition of infiltrating T cells in an in vivo model of MS, adoptive transfer experimental autoimmune encephalomyelitis in rats. We found that the upregulation of ICAM-I and VCAM-I parallels the development of clinical disease onset, but persists on elevated levels also in the phase of clinical remission. However, the composition of infiltrating T cells found in the developing versus resolving lesion phase changed over time, containing increased numbers of regulatory T cells (FoxP3) only in the phase of clinical remission. In order to test the relevance of the expression of cell adhesion molecules, animals were treated with purified antibodies to ICAM-I and VCAM-I either in the phase of active disease or in early remission. Treatment with a blocking ICAM-I antibody in the phase of disease progression led to a milder disease course. However, administration during early clinical remission aggravates clinical symptoms. Treatment with anti-VCAM-I at different timepoints had no significant effect on the disease course. In summary, our results indicate that adhesion molecules are not only important for capture and migration of pro-inflammatory T cells into the central nervous system, but also permit access of anti-inflammatory cells, such as regulatory T cells. Therefore it is likely to assume that intervention at the blood brain barrier is time dependent and could result in different therapeutic outcomes depending on the phase of CNS lesion development.

Volume Regulation of Murine T Lymphocytes Relies on Voltage-dependent and Two-pore Domain Potassium Channels

Biochimica Et Biophysica Acta. Aug, 2011  |  Pubmed ID: 21575593

A variety of ion channels are supposed to orchestrate the homoeostatic volume regulation in T lymphocytes. However, the relative contribution of different potassium channels to the osmotic volume regulation and in particular to the regulatory volume decrease (RVD) in T cells is far from clear. This study explores a putative role of the newly identified K(2P) channels (TASK1, TASK2, TASK3 and TRESK) along with the voltage-gated potassium channel K(V)1.3 and the calcium-activated potassium channel K(Ca)3.1 in the RVD of murine T lymphocytes, using genetic and pharmacological approaches. K(2P) channel knockouts exerted profound effects on the osmotic properties of murine T lymphocytes, as revealed by reduced water and RVD-related solute permeabilities. Moreover, both genetic and pharmacological data proved a key role of K(V)1.3 and TASK2 channels in the RVD of murine T cells exposed to hypotonic saline. Our experiments demonstrate a leading role of potassium channels in the osmoregulation of T lymphocytes under different conditions. In summary, the present study sheds new light on the complex and partially redundant network of potassium channels involved in the basic physiological process of the cellular volume homeostasis and extends the repertoire of potassium channels by the family of K(2P) channels.

Blockade of the Kinin Receptor B1 Protects from Autoimmune CNS Disease by Reducing Leukocyte Trafficking

Journal of Autoimmunity. Mar, 2011  |  Pubmed ID: 21216565

Disruption of the blood brain barrier (BBB) and transendothelial trafficking of immune cells into the central nervous system (CNS) are pathophysiological hallmarks of Multiple Sclerosis (MS) and its animal model, Experimental Autoimmune Encephalomyelitis (EAE). Kinins are proinflammatory peptides which are released during tissue injury including EAE. They increase vascular permeability and enhance inflammation by acting on distinct bradykinin receptors, B1R and B2R. We studied the expression of B1R and B2R and the effect of their inhibition on the disease course, BBB integrity and T cell migration following myelin oligodendrocyte glycoprotein (MOG(35-55))-induced EAE. B1R, but not B2R expression was markedly enhanced in inflammatory CNS lesions in mice and humans. Brain endothelial cells could be identified as major source of B1R protein. The severity of EAE was significantly alleviated in B1R(-/-) mice compared with wild-type (WT) controls (P<0.05). Treatment of WT mice with the B1R antagonist R715 before and after disease onset was equally effective (P<0.05) while B1R activation by R838 promoted EAE (P<0.05). B1R inhibition was accompanied by a remarkable reduction of BBB disruption and tissue inflammation. In vitro analyses revealed that B1R suppression reverses the upregulation of ICAM-I and VCAM-I at the inflamed BBB thereby limiting T cell transmigration. In contrast, blocking B2R had no significant impact on EAE. We conclude that B1R inhibition can reduce BBB damage and cell invasion during autoimmune CNS disease and may offer a novel anti-inflammatory strategy for the treatment of MS.

Immunological and Clinical Consequences of Treating a Patient with Natalizumab

Multiple Sclerosis (Houndmills, Basingstoke, England). Mar, 2012  |  Pubmed ID: 21908480

Long-term therapy with natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML).

L-Selectin is a Possible Biomarker for Individual PML Risk in Natalizumab-treated MS Patients

Neurology. Aug, 2013  |  Pubmed ID: 23925765

To find biomarkers identifying patients at risk for the development of progressive multifocal leukoencephalopathy (PML) during natalizumab treatment.

VLA-4 Blockade Promotes Differential Routes into Human CNS Involving PSGL-1 Rolling of T Cells and MCAM-adhesion of TH17 Cells

The Journal of Experimental Medicine. Aug, 2014  |  Pubmed ID: 25135296

The focus of this study is the characterization of human T cell blood-brain barrier migration and corresponding molecular trafficking signatures. We examined peripheral blood and cerebrospinal fluid immune cells from patients under long-term anti-very late antigen-4 (VLA-4)/natalizumab therapy (LTNT) and from CNS specimens. LTNT patients' cerebrospinal fluid T cells exhibited healthy central-/effector-memory ratios, but lacked CD49d and showed enhanced myeloma cell adhesion molecule (MCAM) expression. LTNT led to an increase of PSGL-1 expression on peripheral T cells. Although vascular cell adhesion molecule-1 (VLA-4 receptor) was expressed at all CNS barriers, P-selectin (PSGL-1-receptor) was mainly detected at the choroid plexus. Accordingly, in vitro experiments under physiological flow conditions using primary human endothelial cells and LTNT patients' T cells showed increased PSGL-1-mediated rolling and residual adhesion, even under VLA-4 blockade. Adhesion of MCAM(+)/TH17 cells was not affected by VLA-4 blocking alone, but was abrogated when both VLA-4 and MCAM were inhibited. Consistent with these data, MCAM(+) cells were detected in white matter lesions, and in gray matter of multiple sclerosis patients. Our data indicate that lymphocyte trafficking into the CNS under VLA-4 blockade can occur by using the alternative adhesion molecules, PSGL-1 and MCAM, the latter representing an exclusive pathway for TH17 cells to migrate over the blood-brain barrier.

Ultraviolet B Light Attenuates the Systemic Immune Response in Central Nervous System Autoimmunity

Annals of Neurology. May, 2014  |  Pubmed ID: 24771567

Environmental conditions (eg, latitude) play a critical role in the susceptibility and severity of many autoimmune disorders, including multiple sclerosis (MS). Here, we investigated the mechanisms underlying the beneficial effects of immune regulatory processes induced in the skin by moderate ultraviolet B (UVB) radiation on central nervous system (CNS) autoimmunity.

Specific Loss of Cellular L-selectin on CD4+ T Cells is Associated with PML Development During HIV Infection

AIDS (London, England). Jan, 2014  |  Pubmed ID: 24445368

HIV progressive multifocal leukoencephalopathy (PML) patients had a significantly lower expression of CD62L on CD4 T cells (P < 0.001) when compared with HIV patients who did not develop PML. CD62L expression on CD4 T cells did not correlate with parameters such as CDC stage, CD4 cell percentage (of total CD3 T cells), CD4 cell counts, virus count, or clinical parameters. Measurement of CD62L might provide a biomarker for PML risk and could prompt a treatment change and/or close monitoring.

Neurocognitive Decline in HIV Patients is Associated with Ongoing T-cell Activation in the Cerebrospinal Fluid

Annals of Clinical and Translational Neurology. Sep, 2015  |  Pubmed ID: 26401512

HIV-associated neurocognitive disorders (HAND) remain a challenge despite combination antiretroviral therapy (cART). Immune cell activation has been implicated to play a major role in the development of HAND.

Trafficking of Lymphocytes into the CNS

Oncotarget. Jul, 2015  |  Pubmed ID: 26255669

Assessment of Immune Functions and MRI Disease Activity in Relapsing-remitting Multiple Sclerosis Patients Switching from Natalizumab to Fingolimod (ToFingo-Successor)

BMC Neurology. Jun, 2015  |  Pubmed ID: 26099927

In light of the increased risk of progressive multifocal encephalopathy (PML) development under long-term treatment with the monoclonal antibody natalizumab which is approved for treatment of active relapsing remitting multiple sclerosis (RRMS), there is a clear need for alternative treatment options with comparable efficacy and reduced PML risk. One such option is fingolimod, a functional sphingosin-1-receptor antagonist that has been approved as first oral drug for treatment of active RRMS. However, the optimal switching design in terms of prevention of disease reoccurrence is still unknown. Moreover, potential additive effects of both drugs on immune functions, especially with regard to migration, have not yet been evaluated.

Therapeutic Uses of Anti-α4-integrin (anti-VLA-4) Antibodies in Multiple Sclerosis

International Immunology. Jan, 2015  |  Pubmed ID: 25326459

Multiple sclerosis (MS) is a disorder of putative autoimmune origin, where immune cells invade the central nervous system and cause damage by attacking the myelin sheath of nerve cells. The blockade of the integrin very late antigen-4 (VLA-4) with the monoclonal antibody natalizumab has become the most effective therapy against MS since its approval in 2004. It is assumed that the inhibition of VLA-4-mediated immune cell adhesion to the endothelium of the blood-brain barrier (BBB) alleviates pathogenic processes of MS and, therefore, reduces disease severity and burden. Not all approaches to treat additional immune-mediated disorders (e.g. Rasmussen encephalitis and neuromyelitis optica) with natalizumab have been successful, but allowed researchers to gain additional insight into mechanisms of specific immune cell subsets' migration through the BBB in the human system. While the long-term efficacy and general tolerability of natalizumab in MS are clear, the over 400 cases of natalizumab-associated progressive multifocal leukoencephalopathy (PML) have been of great concern and methods of risk stratification in patients have become a major area of research. Modern risk stratification includes established factors such as treatment duration, previous immune-suppressive therapy, and anti-John Cunningham virus (JCV) antibody seropositivity, but also experimental factors such as anti-JCV antibody titers and levels of L-selectin. Today, anti-VLA-4 therapy is reserved for patients with highly active relapsing-remitting MS and patients are monitored closely for early signs of potential PML.

CD62L Test at 2 Years of Natalizumab Predicts Progressive Multifocal Leukoencephalopathy

Neurology. Nov, 2016  |  Pubmed ID: 27815407

CD62L is Not a Reliable Biomarker for Predicting PML Risk in Natalizumab-treated R-MS Patients

Neurology. Aug, 2016  |  Pubmed ID: 27572431

Impaired NK-mediated Regulation of T-cell Activity in Multiple Sclerosis is Reconstituted by IL-2 Receptor Modulation

Proceedings of the National Academy of Sciences of the United States of America. May, 2016  |  Pubmed ID: 27162345

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(bright) NK cells represent the major intrathecal NK-cell subset in both MS patients and healthy individuals. Investigating the peripheral blood and cerebrospinal fluid of MS patients treated with natalizumab revealed that transmigration of this subset depends on the α4β1 integrin very late antigen (VLA)-4. Although no MS-related changes in the migratory capacity of NK cells were observed, NK cells derived from patients with MS exhibit a reduced cytolytic activity in response to antigen-activated CD4(+) T cells. Defective NK-mediated immune regulation in MS is mainly attributable to a CD4(+) T-cell evasion caused by an impaired DNAX accessory molecule (DNAM)-1/CD155 interaction. Both the expression of the activating NK-cell receptor DNAM-1, a genetic alteration consistently found in MS-association studies, and up-regulation of the receptor's ligand CD155 on CD4(+) T cells are reduced in MS. Therapeutic immune modulation of IL-2 receptor restores impaired immune regulation in MS by increasing the proportion of CD155-expressing CD4(+) T cells and the cytolytic activity of NK cells.

CD8(+) T-cell Pathogenicity in Rasmussen Encephalitis Elucidated by Large-scale T-cell Receptor Sequencing

Nature Communications. Apr, 2016  |  Pubmed ID: 27040081

Rasmussen encephalitis (RE) is a rare paediatric epilepsy with uni-hemispheric inflammation and progressive neurological deficits. To elucidate RE immunopathology, we applied T-cell receptor (TCR) sequencing to blood (n=23), cerebrospinal fluid (n=2) and brain biopsies (n=5) of RE patients, and paediatric controls. RE patients present with peripheral CD8(+) T-cell expansion and its strength correlates with disease severity. In addition, RE is the only paediatric epilepsy with prominent T-cell expansions in the CNS. Consistently, common clones are shared between RE patients, who also share MHC-I alleles. Public RE clones share Vβ genes and length of the CDR3. Rituximab/natalizumab/basiliximab treatment does not change TCR diversity, stem cell transplantation replaces the TCR repertoire with minimal overlap between donor and recipient, as observed in individual cases. Our study supports the hypothesis of an antigen-specific attack of peripherally expanded CD8(+) lymphocytes against CNS structures in RE, which might be ameliorated by restricting access to the CNS.

Therapy with Natalizumab is Associated with High JCV Seroconversion and Rising JCV Index Values

Neurology(R) Neuroimmunology & Neuroinflammation. Feb, 2016  |  Pubmed ID: 26848486

The aim of the study was to analyze John Cunningham virus (JCV) serology in natalizumab-treated patients over time and assess whether they are influenced by natalizumab treatment.

CD4+ T Effector Memory Cell Dysfunction is Associated with the Accumulation of Granulocytic Myeloid-derived Suppressor Cells in Glioblastoma Patients

Neuro-oncology. Jun, 2016  |  Pubmed ID: 26578623

Myeloid-derived suppressor cells (MDSCs) comprise a heterogeneous population of myeloid cells that are significantly expanded in cancer patients and are associated with tumor progression.

PML Risk Stratification Using Anti-JCV Antibody Index and L-selectin

Multiple Sclerosis (Houndmills, Basingstoke, England). Jul, 2016  |  Pubmed ID: 26432858

Natalizumab treatment is associated with progressive multifocal leukoencephalopathy (PML) development. Treatment duration, prior immunosuppressant use, and JCV serostatus are currently used for risk stratification, but PML incidence stays high. Anti-JCV antibody index and L-selectin (CD62L) have been proposed as additional risk stratification parameters.

Natalizumab-associated PML: Challenges with Incidence, Resulting Risk, and Risk Stratification

Neurology. Mar, 2017  |  Pubmed ID: 28228564

Progressive multifocal leukoencephalopathy (PML) associated with natalizumab treatment continues to be a severe problem of clinically successful therapy. This is an update of risk stratification developments and discusses the current approach to depict and calculate PML incidence and PML risk. (1) PML incidence and resulting risk used in today's clinical practice are potentially outdated and the risk for patients with prior immunosuppression might have been underestimated. (2) Risk stratification according to treatment duration epochs likely suggests lower risk due to patients stopping treatment within a given epoch. PML incidence within the complete treatment epoch is statistically lowered due to the fact that patients at the beginning of an epoch presumably have a lower PML risk than the patients at the end. Periodic risk is not accurate in assessing risk for long treatment durations. (3) The JC virus (JCV) serostatus risk factor has low specificity concerning PML prediction and anti-JCV seroconversion during treatment with natalizumab further lowers its specificity over time. Specificity of the risk factor treatment duration varies depending on the average treatment duration and the number of short-term patients. These short-term patients reduce overall average treatment duration and thus enhance the specificity of the risk factor and reduce overall PML incidence. It is also suggested that short-term natalizumab patients are exclusively non-PML, even though they might still develop PML. Clinicians have to consider the cumulative risk of patients to stratify efficiently.

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