Max-Philipp Stenner

Publications of Max-Philipp Stenner

• Immunological and clinical consequences of treating a patient with natalizumab.

  Authors: Nicholas Schwab, Karin G Höhn, Tilman Schneider-Hohendorf, Imke Metz, Max-Philipp Stenner, Samantha Jilek, Renaud A Du Pasquier, Ralf Gold, Sven G Meuth, Richard M Ransohoff, Wolfgang Brück, Heinz Wiendl

  Multiple sclerosis (Houndmills, Basingstoke, England). 09/2011; 18(3):335-44.

  Background: Long-term therapy with natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML). Objectives: We present a patient study through therapy, the diagnosis of PMLBackground: Long-term therapy with natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML). Objectives: We present a patient study through therapy, the diagnosis of PML (after 29 infusions), plasma exchange (PE) and development of immune reconstitution inflammatory syndrome (IRIS). Methods: Routine diagnostics, magnetic resonance imaging (MRI), immunological status (flow cytometry, T-cell migration assays and T-cell repertoire analysis), and brain biopsy with immunohistological analysis. Results: CD49d decreased after 12 months of treatment. At PML diagnosis, CD49d expression and migratory capacity of T cells was low and peripheral T-cell receptor (TCR) complexity showed severe perturbations. The distribution of peripheral monocytes changed from CCR5+ to CCR7+. After PE some changes reverted: CD49d increased and overshot earliest levels, migratory capacities of T cells recovered and peripheral TCR complexity increased. With no clinical, routine laboratory or cerebrospinal fluid (CSF) changes, MRI 2 months after PE demonstrated progressive lesion development. Brain histopathology confirmed the presence of infiltrates indicative of IRIS without clinical signs, immunologically accompanied by CCR7/CCR5 recovery of peripheral monocytes. Conclusion: Natalizumab-associated immunological changes accompanying PML were reversible after PE; IRIS can occur very late, remain asymptomatic and be elusive to CSF analysis. Our study may provide insights into the changes under treatment with natalizumab associated with JC virus control.

• Regulatory T cells exhibit enhanced migratory characteristics, a feature impaired in patients with multiple sclerosis.

  Authors: Tilman Schneider-Hohendorf, Max-Philipp Stenner, Christian Weidenfeller, Alla L Zozulya, Ole J Simon, Nicholas Schwab, Heinz Wiendl

  European journal of immunology. 12/2010; 40(12):3581-90.

  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 butMigration 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.

• Glatiramer acetate attenuates pro-inflammatory T cell responses but does not directly protect neurons from inflammatory cell death.

  Authors: Alexander M Herrmann, Kerstin Göbel, Ole J Simon, Nico Melzer, Michael K Schuhmann, Max-Philipp Stenner, Andreas Weishaupt, Christoph Kleinschnitz, Stefan Bittner, Patrick Meuth, Olaf Stuve, Thomas Budde, Bernd C Kieseier, Heinz Wiendl, Sven G Meuth

  The American journal of pathology. 10/2010; 177(6):3051-60.

  Glatiramer acetate (GA) is a synthetic, random, basic copolymer capable of modulating adaptive T cell responses. In animal models of various inflammatory and degenerative central nervous systemGlatiramer acetate (GA) is a synthetic, random, basic copolymer capable of modulating adaptive T cell responses. In animal models of various inflammatory and degenerative central nervous system disorders, GA-induced T cells cross the blood-brain barrier, secrete high levels of anti-inflammatory cytokines and neurotrophins, and thus both reduce neuronal damage and promote neurogenesis. Recently, it has been suggested that GA itself may permeate the (impaired) blood-brain-barrier and directly protect neurons under conditions of inflammation-mediated neurodegeneration. To test this hypothesis, we examined the direct effects of GA on neuronal functionality and T cell-mediated neuronal apoptosis in culture, acute brain slices, and focal experimental autoimmune encephalomyelitis. GA caused a depolarization of the resting membrane potential and led to an immediate impairment of action potential generation in neurons. Moreover, GA-incubated neurons underwent dose-dependent apoptosis. Apoptosis of ovalbumin peptide-loaded major histocompatibility complex class I-expressing neurons induced by ovalbumin-specific effector T cells could be reduced by pre-incubation of T cells, but not neurons with GA. Similar results could be found using acute brain slices. In focal experimental autoimmune encephalomyelitis, lesion size and neuronal apoptosis could be limited by pretreating rats with GA, whereas intracerebral GA application into the inflammatory lesion had no effect on neuronal survival. Our data suggest that GA attenuates adaptive pro-inflammatory T cell responses, but does not exert direct neuroprotective effects.

• FOXP3+ T regulatory cells in idiopathic inflammatory myopathies.

  Authors: Anne Waschbisch, Nicholas Schwab, Tobias Ruck, Max-Philipp Stenner, Heinz Wiendl

  Journal of neuroimmunology. 08/2010; 225(1-2):137-42.

  FOXP3+ T regulatory cells (Tregs) are considered key players in the maintenance of immune homeostasis. Here we studied the presence and potential role of FOXP3+ Tregs in myositis. CD3 and FOXP3FOXP3+ T regulatory cells (Tregs) are considered key players in the maintenance of immune homeostasis. Here we studied the presence and potential role of FOXP3+ Tregs in myositis. CD3 and FOXP3 expression in dermatomyositis, polymyositis and inclusion body myositis was assessed by immunohistochemistry and real-time PCR. FOXP3+ Tregs were found in close proximity to effector cells and their numbers correlated with the degree of inflammation. Despite divergent pathogenetic concepts, we observed no differences in the frequency of FOXP3 immunoreactive cells or FOXP3 mRNA expression between different myositis entities. Functional assays using human myoblasts as targets of CD8+ cells demonstrate that Tregs are capable to inhibit the lytic activity of cytotoxic cells. Our data suggest that FOXP3 Tregs serve to counterbalance muscle destruction by cytotoxic T cells in myositis.

• Upregulation of K2P5.1 potassium channels in multiple sclerosis.

  Authors: Stefan Bittner, Nicole Bobak, Alexander M Herrmann, Kerstin Göbel, Patrick Meuth, Karin G Höhn, Max-Philipp Stenner, Thomas Budde, Heinz Wiendl, Sven G Meuth

  Annals of neurology. 07/2010; 68(1):58-69.

  Activation of T cells critically depends on potassium channels. We here characterize the impact of K(2P)5.1 (KCNK5; TASK2), a member of the 2-pore domain family of potassium channels, on T-cellActivation of T cells critically depends on potassium channels. We here characterize the impact of K(2P)5.1 (KCNK5; TASK2), a member of the 2-pore domain family of potassium channels, on T-cell function and demonstrate its putative relevance in a T-cell-mediated autoimmune disorder, multiple sclerosis (MS). Expression of K(2P)5.1 was investigated on RNA and protein level in different immune cells and in MS patients' biospecimens (peripheral blood mononuclear cells, cerebrospinal fluid cells, brain tissue specimen). Functional consequences of K(2P)5.1 expression were analyzed using pharmacological modulation, small interfering RNA (siRNA), overexpression, electrophysiological recordings, and computer modeling. Human T cells constitutively express K(2P)5.1. After T-cell activation, a significant and time-dependent upregulation of K(2P)5.1 channel expression was observed. Pharmacological blockade of K(2P)5.1 or knockdown with siRNA resulted in reduced T-cell functions, whereas overexpression of K(2P)5.1 had the opposite effect. Electrophysiological recordings of T cells clearly dissected K(2P)5.1-mediated effects from other potassium channels. The pathophysiological relevance of these findings was demonstrated by a significant K(2P)5.1 upregulation in CD4(+) and CD8(+) T cells in relapsing/remitting MS (RRMS) patients during acute relapses as well as higher levels on CD8(+) T cells of clinically isolated syndrome, RRMS, and secondary progressive multiple sclerosis patients during clinically stable disease. T cells in the cerebrospinal fluid from MS patients exhibit significantly elevated K(2P)5.1 levels. Furthermore, K(2P)5.1-positive T cells can be found in inflammatory lesions in MS tissue specimens. Selective targeting of K(2P)5.1 may hold therapeutic promise for MS and putatively other T-cell-mediated disorders.

• Natalizumab treatment in a patient with chronic inflammatory demyelinating polyneuropathy.

  Authors: Christian Wolf, Til Menge, Max-Philipp Stenner, Gerd Meyer zu Hörste, Andreas Saleh, Hans-Peter Hartung, Heinz Wiendl, Bernd C Kieseier

  Archives of neurology. 07/2010; 67(7):881-3.

  To study clinical and paraclinical effects of natalizumab in a patient with chronic inflammatory demyelinating polyneuropathy (CIDP). Case report. Department of Neurology, Heinrich-Heine University,To study clinical and paraclinical effects of natalizumab in a patient with chronic inflammatory demyelinating polyneuropathy (CIDP). Case report. Department of Neurology, Heinrich-Heine University, Düsseldorf, Germany. Patient A patient with highly active CIDP who did not respond to standard therapies. Intervention Standard therapy then treatment with natalizumab (300 mg). Clinical disability, magnetic resonance imaging, and saturation of the alpha(4) integrin on T lymphocytes. T cells expressing the alpha(4) integrin were found in the inflamed peripheral nerve. Natalizumab bound with high affinity to the alpha(4) integrin on T lymphocytes in our patient. However, the patient's clinical condition deteriorated and as seen on magnetic resonance imaging without any measurable effect after treatment with this antibody. Although experimental evidence suggests that natalizumab could theoretically be effective in immune-mediated disorders of the peripheral nervous system, our patient with CIDP did not benefit from this therapeutic approach. Natalizumab cannot be recommended in CIDP at present and should only be explored in controlled clinical trials.

• Effects of natalizumab treatment on Foxp3+ T regulatory cells.

  Authors: Max-Philipp Stenner, Anne Waschbisch, Dorothea Buck, Sebastian Doerck, Hermann Einsele, Klaus V Toyka, Heinz Wiendl

  PLoS ONE. 02/2008; 3(10):e3319.

  BACKGROUND: Natalizumab, a monoclonal humanized antibody targeting the alpha-4 chain of very late activation antigen 4 (VLA-4) exerts impressive therapeutic effects in patients withBACKGROUND: Natalizumab, a monoclonal humanized antibody targeting the alpha-4 chain of very late activation antigen 4 (VLA-4) exerts impressive therapeutic effects in patients with relapsing-remitting multiple sclerosis. Our objective was to study impacts of Natalizumab therapy on Foxp3+ T regulatory cells (Tregs) in multiple sclerosis (MS) patients. METHODOLOGY: A combined approach of in vitro and ex vivo experiments using T cells isolated from the peripheral blood of healthy donors and Natalizumab treated MS patients was chosen. We determined binding of Natalizumab and its effects on the frequency, transmigratory behaviour and suppressive function of Tregs. PRINCIPAL FINDINGS: Binding of Natalizumab and expression of CD49d (alpha-4 chain of VLA-4) differed between non-regulatory and regulatory cells. Albeit Foxp3+ Tregs had lower levels of CD49d, Natalizumab blocked the transmigration of Foxp3+ Tregs similar to non-regulatory T cells. The frequency of peripheral blood Tregs was unaffected by Natalizumab treatment. Natalizumab does not alter the suppressive capacity of CD4+CD25(high)CD127(low)Foxp3+ Tregs under in vitro conditions. Furthermore, the impaired function of Tregs in MS patients is not restored by Natalizumab treatment. CONCLUSIONS: We provide a first detailed analysis of Natalizumab effects on the regulatory T cell population. Our prospective study shows that Foxp3+ Tregs express lower levels of VLA-4 and bind less Natalizumab. We further the understanding of the mechanisms of action of Natalizumab by demonstrating that unlike other immunomodulatory drugs the beneficial therapeutic effects of the monoclonal antibody are largely independent of alterations in Treg frequency or function.

• FOXP3+ T regulatory cells in idiopathic inflammatory myopathies

  Authors: Anne Waschbisch, Nicholas Schwab, Tobias Ruck, Max-Philipp Stenner, Heinz Wiendl

  Journal of Neuroimmunology.

  FOXP3+ T regulatory cells (Tregs) are considered key players in the maintenance of immune homeostasis. Here we studied the presence and potential role of FOXP3+ Tregs in myositis. CD3 and FOXP3FOXP3+ T regulatory cells (Tregs) are considered key players in the maintenance of immune homeostasis. Here we studied the presence and potential role of FOXP3+ Tregs in myositis. CD3 and FOXP3 expression in dermatomyositis, polymyositis and inclusion body myositis was assessed by immunohistochemistry and real-time PCR. FOXP3+ Tregs were found in close proximity to effector cells and their numbers correlated with the degree of inflammation. Despite divergent pathogenetic concepts, we observed no differences in the frequency of FOXP3 immunoreactive cells or FOXP3 mRNA expression between different myositis entities. Functional assays using human myoblasts as targets of CD8+ cells demonstrate that Tregs are capable to inhibit the lytic activity of cytotoxic cells. Our data suggest that FOXP3 Tregs serve to counterbalance muscle destruction by cytotoxic T cells in myositis.

• Correction: Effects of Natalizumab Treatment on Foxp3+ T Regulatory Cells

  Authors: Max-Philipp Stenner, Anne Waschbisch, Dorothea Buck, Sebastian Doerck, Hermann Einsele, Klaus V Toyka, Heinz Wiendl