Chi Wang Ip

Publications of Chi Wang Ip

• Ectopic T-cell specificity and absence of perforin and granzyme B alleviate neural damage in oligodendrocyte mutant mice.

  Authors: Antje Kroner, Chi Wang Ip, Johannes Thalhammer, Klaus-Armin Nave, Rudolf Martini

  The American journal of pathology. 02/2010; 176(2):549-55.

  In transgenic mice overexpressing the major myelin protein of the central nervous system, proteolipid protein, CD8+ T-lymphocytes mediate the primarily genetically caused myelin and axon damage. InIn transgenic mice overexpressing the major myelin protein of the central nervous system, proteolipid protein, CD8+ T-lymphocytes mediate the primarily genetically caused myelin and axon damage. In the present study, we investigated the cellular and molecular mechanisms underlying this immune-related neural injury. At first, we investigated whether T-cell receptors (TCRs) are involved in these processes. For this purpose, we transferred bone marrow from mutants carrying TCRs with an ectopic specificity to ovalbumin into myelin mutant mice that also lacked normal intrinsic T-cells. T-lymphocytes with ovalbumin-specific TCRs entered the mutant central nervous system to a similar extent as T-lymphocytes from wild-type mice. However, as revealed by histology, electron microscopy and axon- and myelin-related immunocytochemistry, these T-cells did not cause neural damage in the myelin mutants, reflecting the need for specific antigen recognition by cytotoxic CD8+ T-cells. By chimerization with bone marrow from perforin- or granzyme B (Gzmb)-deficient mice, we demonstrated that absence of these cytotoxic molecules resulted in reduced neural damage in myelin mutant mice. Our study strongly suggests that pathogenetically relevant immune reactions in proteolipid protein-overexpressing mice are TCR-dependent and mediated by the classical components of CD8+ T-cell cytotoxicity, perforin, and Gzmb. These findings have high relevance with regard to our understanding of the pathogenesis of disorders primarily caused by genetically mediated oligodendropathy.

• Collateral neuronal apoptosis in CNS gray matter during an oligodendrocyte-directed CD8(+) T cell attack.

  Authors: Kerstin Göbel, Nico Melzer, Alexander M Herrmann, Michael K Schuhmann, Stefan Bittner, Chi Wang Ip, Thomas Hünig, Sven G Meuth, Heinz Wiendl

  Glia. 09/2009;

  Demyelination and death of oligodendrocytes accompanied by transection of neurites and neuronal apoptosis are pathological hallmarks of cortical and subcortical gray matter lesions in demyelinatingDemyelination and death of oligodendrocytes accompanied by transection of neurites and neuronal apoptosis are pathological hallmarks of cortical and subcortical gray matter lesions in demyelinating viral and autoimmune inflammatory CNS disorders. In these disorders, leukocortical lesions, containing the perikarya of most efferent neurons, display pronounced infiltration by CD8(+) T cells of putative specificity for oligodendrocyte- and myelin-related antigens. Hence, neuronal apoptosis in gray matter lesions may be a collateral effect of an oligodendrocyte-directed attack by CD8(+) T cells. To challenge this hypothesis, we transferred activated antigen-specific CD8(+) T cells (OT-I T cells) into acute coronal brain slices from mice selectively expressing ovalbumin as a cytosolic neo-self-antigen in oligodendrocytes (ODC-OVA mice). We studied mechanisms and kinetics of oligodendroglial and neuronal apoptosis in the neocortex and hippocampus, using multicolor staining for different cell types and activated caspase-3. Within the gray matter, a single OT-I T cell caused simultaneous caspase-3 activation in about 30 ODCs and 10 neurons within 6 h in a strictly antigen-dependent manner. Experiments with OT-I T cells genetically deficient for perforin or the granzyme B-cluster and with blocking anti-FasL antibodies as well as proinflammatory cytokines revealed, that collateral apoptosis of neurons was likely due to a spillover of perforin and granzyme(s) from the OT-I T cell itself or the immunological synapse that it selectively formed with antigen-presenting oligodendrocytes. Collateral neuronal apoptosis could contribute to substantial neuronal loss in gray matter lesions and cause persistent neurological impairment in both acute and chronic gray matter lesions in various inflammatory CNS disorders. (c) 2009 Wiley-Liss, Inc.

• Accelerated Course of Experimental Autoimmune Encephalomyelitis in PD-1-Deficient Central Nervous System Myelin Mutants.

  Authors: Antje Kroner, Nicholas Schwab, Chi Wang Ip, Sonja Ortler, Kerstin Göbel, Klaus-Armin Nave, Mathias Mäurer, Rudolf Martini, Heinz Wiendl

  The American journal of pathology. 06/2009;

  It is assumed that the onset and course of autoimmune inflammatory central nervous system (CNS) disorders (eg, multiple sclerosis) are influenced by factors that afflict immune regulation as well asIt is assumed that the onset and course of autoimmune inflammatory central nervous system (CNS) disorders (eg, multiple sclerosis) are influenced by factors that afflict immune regulation as well as CNS vulnerability. We challenged this concept experimentally by investigating how genetic alterations that affect myelin (primary oligodendrocyte damage in PLPtg mice) and/or T-cell regulation (deficiency of PD-1) influence both the onset and course of an experimental autoimmune CNS inflammatory disease [MOG35-55-induced experimental autoimmune encephalomyelitis (EAE)]. We observed that double pathology was associated with a significantly earlier onset of disease, a slight increase in the neurological score, an increase in the number of infiltrating cells, and enhanced axonal degeneration compared with wild-type mice and the respective, single mutant controls. Double-mutant PLPtg/PD-1(-/-) mice showed an increased production of interferon-gamma by CNS immune cells at the peak of disease. Neither PD-1 deficiency nor oligodendropathy led to detectable spread of antigenic MHC class I- or class II-restricted epitopes during EAE. However, absence of PD-1 clearly increased the propensity of T lymphocytes to expand, and the number of clonal expansions reliably reflected the severity of the EAE disease course. Our data show that the interplay between immune dysregulation and myelinopathy results in a stable exacerbation of actively induced autoimmune CNS inflammation, suggesting that the combination of several pathological issues contributes significantly to disease susceptibility or relapses in human disease.

• PD-1 regulates neural damage in oligodendroglia-induced inflammation.

  Authors: Antje Kroner, Nicholas Schwab, Chi Wang Ip, Christoph Leder, Klaus-Armin Nave, Mathias Mäurer, Heinz Wiendl, Rudolf Martini

  PLoS ONE. 02/2009; 4(2):e4405.

  We investigated the impact of immune regulatory mechanisms involved in the modulation of the recently presented, CD8+ lymphocyte mediated immune response in a mouse model of oligodendropathy-inducedWe investigated the impact of immune regulatory mechanisms involved in the modulation of the recently presented, CD8+ lymphocyte mediated immune response in a mouse model of oligodendropathy-induced inflammation (PLPtg-mutants). The focus was on the role of the co-inhibitory molecule PD-1, a CD28-related receptor expressed on activated T- and B-lymphocytes associated with immune homeostasis and autoimmunity. PLPtg/PD-1-deficient double mutants and the corresponding bone marrow chimeras were generated and analysed using immunohistochemistry, light- and electron microscopy, with particular emphasis on immune-cell number and neural damage. In addition, the immune cells in both the CNS and the peripheral immune system were investigated by IFN-gamma elispot assays and spectratype analysis. We found that mice with combined pathology exhibited significantly increased numbers of CD4+ and CD8+ T-lymphocytes in the CNS. Lack of PD-1 substantially aggravated the pathological phenotype of the PLPtg mutants compared to genuine PLPtg mutants, whereas the PD-1 deletion alone did not cause alterations in the CNS. CNS T-lymphocytes in PLPtg/PD-1-/- double mutants exhibited massive clonal expansions. Furthermore, PD-1 deficiency was associated with a significantly higher propensity of CNS but not peripheral CD8+ T-cells to secrete proinflammatory cytokines. PD-1 could be identified as a crucial player of tissue homeostasis and immune-mediated damage in a model of oligodendropathy-induced inflammation. Alterations of this regulatory pathway lead to overt neuroinflammation of high pathogenetic impact. Our finding may have implications for understanding the mechanisms leading to the high clinical variability of polygenic or even monogenic disorders of the nervous system.

• Transient widespread blood-brain barrier alterations after cerebral photothrombosis as revealed by gadofluorine M-enhanced magnetic resonance imaging.

  Authors: Guido Stoll, Christoph Kleinschnitz, Sven G Meuth, Stefan Braeuninger, Chi Wang Ip, Carsten Wessig, Ingo Nölte, Martin Bendszus

  Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 10/2008;

  Magnetic resonance imaging (MRI) is a powerful tool to assess brain lesions, but currently available contrast agents are limited in the assessment of cellular and functional alterations. By use ofMagnetic resonance imaging (MRI) is a powerful tool to assess brain lesions, but currently available contrast agents are limited in the assessment of cellular and functional alterations. By use of the novel MRI contrast agent gadofluorine M (Gf) we report on imaging of transient and widespread changes of blood-brain barrier (BBB) properties as a consequence of focal photothrombotic brain lesions in rats. After i.v. application, Gf led to bright contrast in the lesions, but also the entire ipsilateral cortex on T1-weighted MRI. In contrast, enhancement after application of gadolinium diethylenetriamine-pentaacetic acid (Gd-DTPA), a common clinical indicator of BBB leakage was restricted to the lesions. Remote Gf enhancement was restricted in time to the first 24 h after photothrombosis and corresponded to a transient breakdown of the BBB as revealed by extravasation of the dye Evans blue. In conclusion, our study shows that Gf can visualize subtle disturbances of the BBB in three dimensions not detectable by Gd-DTPA. Upon entry into the central nervous system Gf most likely is locally trapped by interactions with extracellular matrix proteins. The unique properties of Gf hold promise as a more sensitive contrast agent for monitoring BBB disturbances in neurologic disorders, which appear more widespread than anticipated previously.Journal of Cerebral Blood Flow & Metabolism advance online publication, 29 October 2008; doi:10.1038/jcbfm.2008.129.

• Origin of CD11b+ macrophage-like cells in the CNS of PLP-overexpressing mice: Low influx of haematogenous macrophages and unchanged blood-brain-barrier in the optic nerve.

  Authors: Chi Wang Ip, Bianca Kohl, Christoph Kleinschnitz, Bernhard Reuss, Klaus-Armin Nave, Antje Kroner, Rudolf Martini

  Molecular and cellular neurosciences. 06/2008;

  We have recently reported that overexpression of proteolipid protein in oligodendrocytes leads to a pathologically relevant increase of both CD8+ T-lymphocytes and CD11b+ cells in the CNS. We nowWe have recently reported that overexpression of proteolipid protein in oligodendrocytes leads to a pathologically relevant increase of both CD8+ T-lymphocytes and CD11b+ cells in the CNS. We now focussed on the origin of the CD11b+ cells in the optic nerve, a well established structure for the analysis of the mutant, using bone marrow chimeric mice. Although there is an age-related increase in CD11b+ cells in the myelinated part of the optic nerve of the mutants, the percentage of infiltrating cells was not increased, but enhanced proliferation was detectable. In the non-myelinated optic nerve head, the rate of infiltrating CD11b+ cells and albumin extravasation was high in both genotypes. However, albumin extravasation was also high in the rostral myelinated part, where CD11b+ cell influx was low. Our study demonstrates an intrinsic origin of CD11b+ cells in the presence of an unchanged blood-brain-barrier in a CNS myelin mutant.

• Monocyte chemoattractant protein-1 is a pathogenic component in a model for a hereditary peripheral neuropathy.

  Authors: Stefan Fischer, Christoph Kleinschnitz, Marcus Müller, Igor Kobsar, Chi Wang Ip, Barrett Rollins, Rudolf Martini

  Molecular and cellular neurosciences. 03/2008; 37(2):359-66.

  Macrophages are critically involved in the pathogenesis of genetically caused demyelination, as it occurs in models for inherited demyelinating neuropathies. It is presently unknown which factorsMacrophages are critically involved in the pathogenesis of genetically caused demyelination, as it occurs in models for inherited demyelinating neuropathies. It is presently unknown which factors link the Schwann cell-based myelin mutation to the activation of endoneurial macrophages. Here we identified the chemokine monocyte chemoattractant protein-1 (MCP-1) as a first and crucial factor upregulated in Schwann cells of mice heterozygously deficient for the myelin protein zero. The chemokine could be identified as an important mediator of macrophage immigration into peripheral nerves. Furthermore, a 50% reduction of chemokine expression by crossbreeding with MCP-1-deficient mice reduced the increase in macrophage numbers in the mutant nerves and lead to a robust amelioration of pathology. Surprisingly, the complete absence of MCP-1 aggravated the disease. Our findings show that reducing but not eliminating chemokine expression can rescue genetically caused demyelination that may be an interesting target in treating demyelinating diseases of the peripheral nervous system.

• Antigen therapy of experimental autoimmune encephalomyelitis selectively induces apoptosis of pathogenic T cells.

  Authors: Denise Tischner, Andreas Weishaupt, Jens van den Brandt, Chi Wang Ip, Thomas Kerkau, Ralf Gold, Holger M Reichardt

  Journal of neuroimmunology. 03/2007; 183(1-2):146-50.

  Administration of high-dose myelin antigen induces massive T cell apoptosis in experimental autoimmune encephalomyelitis (EAE) but the nature of the target cells remains elusive. Here we have used aAdministration of high-dose myelin antigen induces massive T cell apoptosis in experimental autoimmune encephalomyelitis (EAE) but the nature of the target cells remains elusive. Here we have used a cell line established in eGFP-transgenic Lewis rats to distinguish between pathogenic and bystander T cells in adoptive transfer EAE. Intravenous application of gpMBP strongly reduced the amount of encephalitogenic cells in spinal cord and spleen while the number of the other T cells remained constant. This could be attributed to their differential sensitivity to apoptosis. Thus, antigen therapy selectively targets pathogenic T cells and should therefore limit potential adverse effects.

• Sialoadhesin deficiency ameliorates myelin degeneration and axonopathic changes in the CNS of PLP overexpressing mice.

  Authors: Chi Wang Ip, Antje Kroner, Paul R Crocker, Klaus-Armin Nave, Rudolf Martini

  Neurobiology of disease. 02/2007; 25(1):105-11.

  PLP overexpressing mice display demyelination and axonopathic changes, accompanied by an elevation of CD8+ T-lymphocytes and CD11b+ macrophages in the CNS. By crossbreeding these mutants withPLP overexpressing mice display demyelination and axonopathic changes, accompanied by an elevation of CD8+ T-lymphocytes and CD11b+ macrophages in the CNS. By crossbreeding these mutants with RAG-1-deficient mice lacking mature lymphocytes, we could recently demonstrate a pathogenetic impact of the CD8+ cells. In the present study, we investigated the pathogenetic impact of CD11b+ macrophages by crossbreeding the myelin mutants with knockout mice deficient for the macrophage-restricted adhesion molecule sialoadhesin (Sn). In the wild-type mice, Sn is barely detectable on CD11b+ cells, whereas in the myelin mutants, almost all CD11b+ cells express Sn. In the double mutants, upregulation of CD8+ T-cells and CD11b+ macrophages is reduced and pathological alterations are ameliorated. These data indicate that in a primarily genetically caused myelin disorder of the CNS macrophages expressing Sn partially mediate pathogenesis. These findings may have substantial impact on treatment strategies for leukodystrophic disorders and some forms of multiple sclerosis.

• Polyclonal expansion of regulatory T cells interferes with effector cell migration in a model of multiple sclerosis.

  Authors: Denise Tischner, Andreas Weishaupt, Jens van den Brandt, Nora Müller, Niklas Beyersdorf, Chi Wang Ip, Klaus V Toyka, Thomas Hünig, Ralf Gold, Thomas Kerkau, Holger M Reichardt

  Brain : a journal of neurology. 11/2006; 129(Pt 10):2635-47.

  Recruitment of naturally occurring CD4+ CD25+ regulatory T (T(reg)) cells is a highly promising approach for the treatment of experimental autoimmune encephalomyelitis (EAE), a widely used model ofRecruitment of naturally occurring CD4+ CD25+ regulatory T (T(reg)) cells is a highly promising approach for the treatment of experimental autoimmune encephalomyelitis (EAE), a widely used model of multiple sclerosis. Here, we studied the in vivo interaction of T(reg) cells, induced by the monoclonal anti-CD28 antibody JJ316, with encephalitogenic T cell lines established from eGFP-transgenic rats. By tracking these fluorescent cells using flow cytometry and confocal microscopy, we found that the activation and expansion of T(reg) cells inhibited infiltration of the CNS by pathogenic T cells. Interference with effector cell migration occured within the secondary lymphoid organs, since the early therapeutic effects were achieved despite the absence of T(reg) cells in the spinal cord. However, the delayed homing to the CNS seen after prophylactic JJ316 administration indicates that T(reg) cells may play an additional role within the target tissue. In addition, the blood-brain barrier remained largely intact after JJ316 treatment, the secretion of T(H)2 cytokines was augmented and the encephalitogenic T cells exhibited a reduced secretion of IFN-gamma. This in turn resulted in a reduced expression of the chemokine receptor CXCR-3 on effector T cells which may interfere with their capacity to infiltrate the CNS. Importantly, these effects were not achieved by direct action of JJ316 on the encephalitogenic cells. Our data rather suggest that polyclonal activation of T(reg) cells in the secondary lymphoid organs is instrumental in preventing the pathological transmigration of encephalitogenic T cells into the CNS. We anticipate that these results may help to better understand the role of T(reg) cells in controlling autoimmunity in the CNS.

• Immune cells contribute to myelin degeneration and axonopathic changes in mice overexpressing proteolipid protein in oligodendrocytes.

  Authors: Chi Wang Ip, Antje Kroner, Martin Bendszus, Christoph Leder, Igor Kobsar, Stefan Fischer, Heinz Wiendl, Klaus-Armin Nave, Rudolf Martini

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 09/2006; 26(31):8206-16.

  Overexpression of the major myelin protein of the CNS, proteolipid protein (PLP), leads to late-onset degeneration of myelin and pathological changes in axons. Based on the observation that in whiteOverexpression of the major myelin protein of the CNS, proteolipid protein (PLP), leads to late-onset degeneration of myelin and pathological changes in axons. Based on the observation that in white matter tracts of these mutants both CD8+ T-lymphocytes and CD11b+ macrophage-like cells are numerically elevated, we tested the hypothesis that these cells are pathologically involved in the primarily genetically caused neuropathy. Using flow cytometry of mutant brains, CD8+ cells could be identified as activated effector cells, and confocal microscopy revealed a close association of the T-cells with MHC-I+ (major histocompatibility complex class I positive) oligodendrocytes. Crossbreeding the myelin mutants with mice deficient in the recombination activating gene-1 (RAG-1) lacking mature T- and B-lymphocytes led to a reduction of the number of CD11b+ cells and to a substantial alleviation of pathological changes. In accordance with these findings, magnetic resonance imaging revealed less ventricular enlargement in the double mutants, partially because of more preserved corpora callosa. To investigate the role of CD8+ versus CD4+ T-lymphocytes, we reconstituted the myelin-RAG-1 double mutants with bone marrow from either CD8-negative (CD4+) or CD4-negative (CD8+) mice. The severe ventricular enlargement was only found when the double mutants were reconstituted with bone marrow from CD8+ mice, suggesting that the CD8+ lymphocytes play a critical role in the immune-related component of myelin degeneration in the mutants. These findings provide strong evidence that a primary glial damage can cause secondary immune reactions of pathological significance as it has been suggested for some forms of multiple sclerosis and other leukodystrophies.

• Role of immune cells in animal models for inherited peripheral neuropathies.

  Authors: Chi Wang Ip, Antje Kroner, Stefan Fischer, Martin Berghoff, Igor Kobsar, Mathias Mäurer, Rudolf Martini

  Neuromolecular medicine. 02/2006; 8(1-2):175-90.

  Mice expressing half of the normal dose of protein zero (P0+/- mice) or completely deficient gap-junction protein connexin 32 -/- mice mimic demyelinating forms of inherited neuropathies, such asMice expressing half of the normal dose of protein zero (P0+/- mice) or completely deficient gap-junction protein connexin 32 -/- mice mimic demyelinating forms of inherited neuropathies, such as Charcot-Marie-Tooth (CMT) neuropathies type 1B and CMT type 1X, respectively. In both models, an almost normal myelin formation is observed during the first months of life, followed by a slowly progressing demyelinating neuropathy. In both models, there is a substantial increase of CD8+ T-lymphocytes and macrophages within the demyelinating nerves. Recently, this has also been observed in mice mildly overexpressing human peripheral myelin protein 22 kD mimicking the most common form of CMT, CMT type 1A. In all demyelinating models, the macrophages show close contacts with intact myelin sheaths or demyelinated axons, suggesting an active role of these cells in myelin degeneration. Additionally, fibroblast-like cells contact macrophages, suggesting a functional role of fibroblast-like cells in macrophage activation. By cross-breeding P0+/- and gap-junction protein connexin 32-/- mice with immunodeficient recombination activating gene-1-deficient mutants, a substantial alleviation of the demyelinating phenotype was observed. Similarly, cross-breeding of P0+/- mice with mutants with a defect in macrophage activation led to an alleviated phenotype as well. These findings demonstrate that the immune system is involved in the pathogenesis of demyelinating neuropathies. In contrast, in P0-/- mice, which display a compromised myelin compaction and axonal loss from onset, immune cells appear to have a neuroprotective effect because cross-breeding with recombination activating gene-1 mutants leads to an aggravation of axonopathic changes. In the present review, we discuss the influence of the immune system on inherited de- and dysmyelination regarding disease mechanisms and possible clinical implications.

• The co-inhibitory molecule PD-1 modulates disease severity in a model for an inherited, demyelinating neuropathy

  Authors: Antje Kroner, Nicholas Schwab, Chi Wang Ip, Claudia Sommer, Carsten Wessig, Heinz Wiendl, Rudolf Martini

  Neurobiology of Disease.

  We have previously shown that mice heterozygously deficient for P0 are characterized by a late onset myelin disorder implicating CD8+ T-lymphocytes and macrophages. We now investigated the impact ofWe have previously shown that mice heterozygously deficient for P0 are characterized by a late onset myelin disorder implicating CD8+ T-lymphocytes and macrophages. We now investigated the impact of the co-inhibitory molecule “programmed death” (PD)-1 (CD279), a CD28-related receptor expressed on activated T- and B-lymphocytes on the pathogenic phenotype of CD8+ T-lymphocytes in the P0 myelin mutants. PD-1 deficiency in P0+/− mice leads to a stronger increase of CD8+ T-lymphocytes and a substantially aggravated histological phenotype in the PNS compared to P0+/− mice expressing PD-1. Correspondingly, functional down-stream features, such as electrophysiological parameters, walking coordination and mechano-sensation are more affected than in PD-1-expressing myelin mutants. Our study demonstrates that a monogenic nerve disorder can be substantially modified by immune-controlling mechanisms. Thus, understanding the implication of disease-modifiers in inherited demyelination could be of pivotal interest for limiting the detrimental impact of primarily genetically-mediated myelin disorders by fostering immuno-regulatory pathways.

• Monocyte chemoattractant protein-1 is a pathogenic component in a model for a hereditary peripheral neuropathy

  Authors: Stefan Fischer, Christoph Kleinschnitz, Marcus Müller, Igor Kobsar, Chi Wang Ip, Barrett J. Rollins, Rudolf Martini

  Molecular and Cellular Neuroscience.

  Macrophages are critically involved in the pathogenesis of genetically caused demyelination, as it occurs in models for inherited demyelinating neuropathies. It is presently unknown which factorsMacrophages are critically involved in the pathogenesis of genetically caused demyelination, as it occurs in models for inherited demyelinating neuropathies. It is presently unknown which factors link the Schwann cell-based myelin mutation to the activation of endoneurial macrophages. Here we identified the chemokine monocyte chemoattractant protein-1 (MCP-1) as a first and crucial factor upregulated in Schwann cells of mice heterozygously deficient for the myelin protein zero. The chemokine could be identified as an important mediator of macrophage immigration into peripheral nerves. Furthermore, a 50% reduction of chemokine expression by crossbreeding with MCP-1-deficient mice reduced the increase in macrophage numbers in the mutant nerves and lead to a robust amelioration of pathology. Surprisingly, the complete absence of MCP-1 aggravated the disease. Our findings show that reducing but not eliminating chemokine expression can rescue genetically caused demyelination that may be an interesting target in treating demyelinating diseases of the peripheral nervous system.

• Tacrolimus (FK506) causes disease aggravation in models for inherited peripheral myelinopathies

  Authors: Chi Wang Ip, Antje Kroner, Bianca Kohl, Carsten Wessig, Rudolf Martini

  Neurobiology of Disease.

  Mice hetero- or homozygously deficient for myelin protein zero (P0+/−, P0−/− mice) are models for distinct forms of inherited de- or dysmyelinating neuropathies, respectively. P0+/− mice show aMice hetero- or homozygously deficient for myelin protein zero (P0+/−, P0−/− mice) are models for distinct forms of inherited de- or dysmyelinating neuropathies, respectively. P0+/− mice show a demyelinating neuropathy with a pathogenetic implication of CD8+ T-lymphocytes and macrophages, while P0−/− mice show dysmyelination with axonal loss. It was, therefore, of interest to treat both mutants with FK506 (Tacrolimus), an agent with immunosuppressive and neuroprotective properties. Treatment of P0+/− mice led to an aggravation of demyelination, without affecting nervous CD8+ T-lymphocytes, but reducing splenic CD4+ cells. Treatment of P0-/− mice resulted in a substantial increase of the dysmyelination-related axon loss. Treatment of wildtype mice did not cause pathological changes in peripheral nerves.Our study shows that FK506 may not be suitable for the treatment of the human nerve disorders. Furthermore, when used as an immunosuppressant, the drug may generate detrimental neurological side effects in patients with an additional hereditary neuropathy.