Bio


Dr. Tobias V. Lanz is a postdoctoral fellow in the laboratory of Prof. William Robinson at the Department of Rheumatology / Immunology at Stanford School of Medicine, with a strong interest in basic and translational neuroimmunology. He studied medicine at the Eberhard Karls University in Tübingen, Germany and at the University College of London and performed his MD thesis at Prof. Michael Platten's laboratory at the Hertie Institute for Clinical Brain Research in Tübingen, Germany. In 2007/2008 he worked as a research scholar in the neuroimmunological laboratory of Prof. Lawrence Steinman at Stanford. After medical school he pursued his scientific and clinical training at the German Cancer Research Center (DKFZ) and the Department of Neurology at the University Hospital in Heidelberg, Germany. Dr. Lanz's current research focus is on the detection of new antigenic targets of B cells in Multiple Sclerosis.

Honors & Awards


  • Oppenheim Award for Multiple Sclerosis Research, Novartis (2017)
  • Postdoc Scholarship, German Research Foundation (2015 - 2017)
  • Carl Liebermeister Prize for outstanding medical doctoral thesis, University of Tübingen, Germany (2011)
  • Postdoc Scholarship, University of Heidelberg, Germany (2010 - 2012)
  • Academic Scholarship, German National Academic Foundation (Studienstiftung des Deutschen Volkes) (2007 - 2010)
  • IZKF Poster Prize, Interdisciplinary Center of Clinical Research (IZKF), Tübingen, Germany (2006)
  • Research Scholarship, Interdisciplinary Center of Clinical Research (IZKF), University of Tübingen, Germany (2006 - 2007)

Professional Education


  • Doctor of Medicine, Eberhard Karls Universitat Tubingen (2011)
  • MD, Eberhard Karls University of Tübingen, Germany, Medicine (2010)
  • Cand Med, University College of London, UK, Neurology (2009)
  • Research Scholar, Stanford School of Medicine, Neuroimmunology (2008)

Stanford Advisors


All Publications


  • Suppression of Th1 differentiation by tryptophan supplementation in vivo. Amino acids Lanz, T. V., Becker, S., Mohapatra, S. R., Opitz, C. A., Wick, W., Platten, M. 2017

    Abstract

    Metabolism of the essential amino acid tryptophan (trp) is a key endogenous immunosuppressive pathway restricting inflammatory responses. Tryptophan metabolites promote regulatory T cell (Treg) differentiation and suppress proinflammatory T helper cell (Th)1 and Th17 phenotypes. It has been shown that treatment with natural and synthetic tryptophan metabolites can suppress autoimmune neuroinflammation in preclinical animal models. Here, we tested if oral intake of tryptophan would increase immunosuppressive tryptophan metabolites and ameliorate autoimmune neuroinflammation as a safe approach to treat autoimmune disorders like multiple sclerosis (MS). Without oral supplementation, systemic kynurenine levels decrease during the initiation phase of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, indicating systemic activation of tryptophan metabolism. Daily oral gavage of up to 10 mg/mouse/day was safe and increased serum kynurenine levels by more than 20-fold for more than 3 h after the gavage. While this treatment resulted in suppression of myelin-specific Th1 responses, there was no relevant impact on clinical disease activity. These data show that oral trp supplementation at subtoxic concentrations suppresses antigen-specific Th1 responses, but suggest that the increase in trp metabolites is not sustained enough to impact neuroinflammation.

    View details for DOI 10.1007/s00726-017-2415-4

    View details for PubMedID 28421297

  • Tryptophan-2,3-Dioxygenase (TDO) deficiency is associated with subclinical neuroprotection in a mouse model of multiple sclerosis SCIENTIFIC REPORTS Lanz, T. V., Williams, S. K., Stojic, A., Iwantscheff, S., Sonner, J. K., Grabitz, C., Becker, S., Boehler, L., Mohapatra, S. R., Sahm, F., Kueblbeck, G., Nakamura, T., Funakoshi, H., Opitz, C. A., Wick, W., Diem, R., Platten, M. 2017; 7

    Abstract

    The catabolism of tryptophan to immunosuppressive and neuroactive kynurenines is a key metabolic pathway regulating immune responses and neurotoxicity. The rate-limiting step is controlled by indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO). IDO is expressed in antigen presenting cells during immune reactions, hepatic TDO regulates blood homeostasis of tryptophan and neuronal TDO influences neurogenesis. While the role of IDO has been described in multiple immunological settings, little is known about TDO's effects on the immune system. TDO-deficiency is neuroprotective in C. elegans and Drosophila by increasing tryptophan and specific kynurenines. Here we have determined the role of TDO in autoimmunity and neurodegeneration in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. We created reporter-TDO mice for in vivo imaging to show that hepatic but not CNS TDO expression is activated during EAE. TDO deficiency did not influence myelin-specific T cells, leukocyte infiltration into the CNS, demyelination and disease activity. TDO-deficiency protected from neuronal loss in the spinal cord but not in the optic nerves. While this protection did not translate to an improved overt clinical outcome, our data suggest that spatially distinct neuroprotection is conserved in mammals and support TDO as a potential target for treatment of diseases associated with neurodegeneration.

    View details for DOI 10.1038/srep41271

    View details for Web of Science ID 000392482100001

  • Tryptophan-2,3-Dioxygenase (TDO) deficiency is associated with subclinical neuroprotection in a mouse model of multiple sclerosis. Scientific reports Lanz, T. V., Williams, S. K., Stojic, A., Iwantscheff, S., Sonner, J. K., Grabitz, C., Becker, S., Böhler, L. I., Mohapatra, S. R., Sahm, F., Küblbeck, G., Nakamura, T., Funakoshi, H., Opitz, C. A., Wick, W., Diem, R., Platten, M. 2017; 7: 41271

    Abstract

    The catabolism of tryptophan to immunosuppressive and neuroactive kynurenines is a key metabolic pathway regulating immune responses and neurotoxicity. The rate-limiting step is controlled by indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO). IDO is expressed in antigen presenting cells during immune reactions, hepatic TDO regulates blood homeostasis of tryptophan and neuronal TDO influences neurogenesis. While the role of IDO has been described in multiple immunological settings, little is known about TDO's effects on the immune system. TDO-deficiency is neuroprotective in C. elegans and Drosophila by increasing tryptophan and specific kynurenines. Here we have determined the role of TDO in autoimmunity and neurodegeneration in experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. We created reporter-TDO mice for in vivo imaging to show that hepatic but not CNS TDO expression is activated during EAE. TDO deficiency did not influence myelin-specific T cells, leukocyte infiltration into the CNS, demyelination and disease activity. TDO-deficiency protected from neuronal loss in the spinal cord but not in the optic nerves. While this protection did not translate to an improved overt clinical outcome, our data suggest that spatially distinct neuroprotection is conserved in mammals and support TDO as a potential target for treatment of diseases associated with neurodegeneration.

    View details for DOI 10.1038/srep41271

    View details for PubMedID 28117398

  • Normal mast cell numbers in the tissues of AhR-deficient mice EXPERIMENTAL DERMATOLOGY Pilz, C., Feyerabend, T., Sonner, J., Redaelli, C., Peter, K., Kunze, A., Haas, K., Esser, C., Schaekel, K., Wick, W., Rodewald, H., Lanz, T. V., Platten, M. 2016; 25 (1): 62-63

    Abstract

    The transcription factor aryl hydrocarbon receptor (AhR) acts as an immunomodulatory molecule in several immune cell lineages. Recently, it has been implicated in development and maintenance of immune cells in barrier tissues such as skin and mucosa. To investigate its role on mast cell development and maintenance in skin, peritoneal exudate cells (PECs) and lymph nodes, we studied in depth their phenotype in AhR-deficient mice. Our findings do not provide any evidence for a suspected role of the AhR in mast cell homeostasis.

    View details for DOI 10.1111/exd.12864

    View details for Web of Science ID 000367837500013

    View details for PubMedID 26443189

  • General control non-derepressible 2 (GCN2) in T cells controls disease progression of autoimmune neuroinflammation. Journal of neuroimmunology Keil, M., Sonner, J. K., Lanz, T. V., Oezen, I., Bunse, T., Bittner, S., Meyer, H. V., Meuth, S. G., Wick, W., Platten, M. 2016; 297: 117–26

    Abstract

    Relapsing-remitting multiple sclerosis (MS)(2) is characterized by phases of acute neuroinflammation followed by spontaneous remission. Termination of inflammation is accompanied by an influx of regulatory T cells (Tregs).(3) The molecular mechanisms responsible for directing Tregs into the inflamed CNS tissue, however, are incompletely understood. In an MS mouse model we show that the stress kinase general control non-derepressible 2 (GCN2),(4) expressed in T cells, contributes to the resolution of autoimmune neuroinflammation. Failure to recover from acute inflammation was associated with reduced frequencies of CNS-infiltrating Tregs. GCN2 deficient Tregs displayed impaired migration to a CCL2 gradient. These data suggest an important contribution of the T cell stress response to the resolution of autoimmune neuroinflammation.

    View details for DOI 10.1016/j.jneuroim.2016.05.014

    View details for PubMedID 27397084

  • Toxicity of teriflunomide in aryl hydrocarbon receptor deficient mice. Biochemical pharmacology Redaelli, C., Gaffarogullari, E. C., Brune, M., Pilz, C., Becker, S., Sonner, J., Jäschke, A., Gröne, H., Wick, W., Platten, M., Lanz, T. V. 2015; 98 (3): 484-492

    Abstract

    The intracellular transcription factor aryl hydrocarbon receptor (AHR) is bound and activated by xenobiotics, thereby promoting their catabolism by inducing expression of cytochrome P450 oxidase (CYP) genes through binding xenobiotic response elements (XRE) in their promoter region. In addition, it is involved in several cellular pathways like cell proliferation, differentiation, regeneration, tumor invasiveness and immune responses. Several pharmaceutical compounds like benzimidazoles activate the AHR and induce their own metabolic degradation. Using newly generated XRE-reporter mice, which allow in vivo bioluminescence imaging of AHR activation, we show here that the AHR is activated in vivo by teriflunomide (TER), which has recently been approved for the treatment of multiple sclerosis. While we did not find any evidence that the AHR mediates the immunomodulatory effects of TER, AHR activation led to metabolism and detoxification of teriflunomide, most likely via CYP. Mice deficient for the AHR show higher blood levels of teriflunomide, suffer from enhanced thrombo- and leukopenia and elevated liver enzymes as well as from severe gastrointestinal ulcers and bleeding which are lethal after 8-11 days of treatment. Leukopenia, acute liver damage and diarrhea have also been described as common side effects in human trials with TER. These data suggest that the AHR is relevant for detoxification not only of environmental toxins but also of drugs in clinical use, with potential implications for the application of AHR-modifying therapies in conjunction to TER in humans. The XRE-reporter mouse is a useful novel tool for monitoring AHR activation using in vivo imaging.

    View details for DOI 10.1016/j.bcp.2015.08.111

    View details for PubMedID 26341389

  • Aryl hydrocarbon receptor control of a disease tolerance defence pathway NATURE Bessede, A., Gargaro, M., Pallotta, M. T., Matino, D., Servillo, G., Brunacci, C., Bicciato, S., Mazza, E. M., Macchiarulo, A., Vacca, C., Iannitti, R., Tissi, L., Volpi, C., Belladonna, M. L., Orabona, C., Bianchi, R., Lanz, T. V., Platten, M., Della Fazia, M. A., Piobbico, D., Zelante, T., Funakoshi, H., Nakamura, T., Gilot, D., Denison, M. S., Guillemin, G. J., Duhadaway, J. B., Prendergast, G. C., Metz, R., Geffard, M., Boon, L., Pirro, M., Iorio, A., Veyret, B., Romani, L., Grohmann, U., Fallarino, F., Puccetti, P. 2014; 511 (7508): 184-?

    Abstract

    Disease tolerance is the ability of the host to reduce the effect of infection on host fitness. Analysis of disease tolerance pathways could provide new approaches for treating infections and other inflammatory diseases. Typically, an initial exposure to bacterial lipopolysaccharide (LPS) induces a state of refractoriness to further LPS challenge (endotoxin tolerance). We found that a first exposure of mice to LPS activated the ligand-operated transcription factor aryl hydrocarbon receptor (AhR) and the hepatic enzyme tryptophan 2,3-dioxygenase, which provided an activating ligand to the former, to downregulate early inflammatory gene expression. However, on LPS rechallenge, AhR engaged in long-term regulation of systemic inflammation only in the presence of indoleamine 2,3-dioxygenase 1 (IDO1). AhR-complex-associated Src kinase activity promoted IDO1 phosphorylation and signalling ability. The resulting endotoxin-tolerant state was found to protect mice against immunopathology in Gram-negative and Gram-positive infections, pointing to a role for AhR in contributing to host fitness.

    View details for DOI 10.1038/nature13323

    View details for Web of Science ID 000338649800036

    View details for PubMedID 24930766

  • Immature mesenchymal stem cell-like pericytes as mediators of immunosuppression in human malignant glioma JOURNAL OF NEUROIMMUNOLOGY Ochs, K., Sahm, F., Opitz, C. A., Lanz, T. V., Oezen, I., Couraud, P., von Deimling, A., Wick, W., Platten, M. 2013; 265 (1-2): 106-116

    Abstract

    Malignant gliomas are primary brain tumors characterized by profound local immunosuppression. While the remarkable plasticity of perivascular cells - resembling mesenchymal stem cells (MSC) - in malignant gliomas and their contribution to angiogenesis is increasingly recognized, their role as potential mediators of immunosuppression is unknown. Here we demonstrate that FACS-sorted malignant glioma-derived pericytes (HMGP) were characterized by the expression of CD90, CD248, and platelet-derived growth factor receptor-β (PDGFR-β). HMGP shared this expression profile with human brain vascular pericytes (HBVP) and human MSC (HMSC) but not human cerebral microvascular endothelial cells (HCMEC). CD90+PDGFR-β+perivascular cells distinct from CD31+ endothelial cells accumulated in human gliomas with increasing degree of malignancy and negatively correlated with the presence of blood vessel-associated leukocytes and CD8+ T cells. Cultured CD90+PDGFR-β+HBVP were equally capable of suppressing allogeneic or mitogen-activated T cell responses as human MSC. HMGP, HBVP and HMSC expressed prostaglandin E synthase (PGES), inducible nitric oxide synthase (iNOS), human leukocyte antigen-G (HLA-G), hepatocyte growth factor (HGF) and transforming growth factor-β (TGF-β). These factors but not indoleamine 2,3-dioxygenase-mediated conversion of tryptophan to kynurenine functionally contributed to immunosuppression of immature pericytes. Our data provide evidence that human cerebral CD90+ perivascular cells possess T cell inhibitory capability comparable to human MSC and suggest that these cells, besides their critical role in tumor vascularization, also promote local immunosuppression in malignant gliomas and possibly other brain diseases.

    View details for DOI 10.1016/j.jneuroim.2013.09.011

    View details for Web of Science ID 000329005100013

    View details for PubMedID 24090655

  • Clinically isolated syndrome NERVENARZT Platten, M., Lanz, T., Bendszus, M., Diem, R. 2013; 84 (10): 1247-1257

    Abstract

    A clinically isolated syndrome (CIS) is a term which describes the first clinical onset of a potential multiple sclerosis (MS). It ought to be defined as an MS stage rather than a separate disease entity; however, with respect to the diagnostic work-up, differential diagnoses to be considered, prognostic factors for the development of a clinically confirmed MS and initiation of an immunomodulatory therapy, there are some important considerations supported by recent studies. These considerations as well as the current guidelines are critically discussed in this review article. Additionally, recommendations are given regarding the management of radiologically isolated syndrome (RIS) an imaging-based diagnosis of a potential preclinical stage of MS.

    View details for DOI 10.1007/s00115-013-3845-1

    View details for Web of Science ID 000325127500015

    View details for PubMedID 24081277

  • Protein kinase C beta as a therapeutic target stabilizing blood-brain barrier disruption in experimental autoimmune encephalomyelitis PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Lanz, T. V., Becker, S., Osswald, M., Bittner, S., Schuhmann, M. K., Opitz, C. A., Gaikwad, S., Wiestler, B., Litzenburger, U. M., Sahm, F., Ott, M., Iwantscheff, S., Grabitz, C., Mittelbronn, M., von Deimling, A., Winkler, F., Meuth, S. G., Wick, W., Platten, M. 2013; 110 (36): 14735-14740

    Abstract

    Disruption of the blood-brain barrier (BBB) is a hallmark of acute inflammatory lesions in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis. This disruption may precede and facilitate the infiltration of encephalitogenic T cells. The signaling events that lead to this BBB disruption are incompletely understood but appear to involve dysregulation of tight-junction proteins such as claudins. Pharmacological interventions aiming at stabilizing the BBB in MS might have therapeutic potential. Here, we show that the orally available small molecule LY-317615, a synthetic bisindolylmaleimide and inhibitor of protein kinase Cβ, which is clinically under investigation for the treatment of cancer, suppresses the transmigration of activated T cells through an inflamed endothelial cell barrier, where it leads to the induction of the tight-junction molecules zona occludens-1, claudin 3, and claudin 5 and other pathways critically involved in transendothelial leukocyte migration. Treatment of mice with ongoing experimental autoimmune encephalomyelitis with LY-317615 ameliorates inflammation, demyelination, axonal damage, and clinical symptoms. Although LY-317615 dose-dependently suppresses T-cell proliferation and cytokine production independent of antigen specificity, its therapeutic effect is abrogated in a mouse model requiring pertussis toxin. This abrogation indicates that the anti-inflammatory and clinical efficacy is mainly mediated by stabilization of the BBB, thus suppressing the transmigration of encephalitogenic T cells. Collectively, our data suggest the involvement of endothelial protein kinase Cβ in stabilizing the BBB in autoimmune neuroinflammation and imply a therapeutic potential of BBB-targeting agents such as LY-317615 as therapeutic approaches for MS.

    View details for DOI 10.1073/pnas.1302569110

    View details for Web of Science ID 000323886200057

    View details for PubMedID 23959874

  • Angiotensin II sustains brain inflammation in mice via TGF-beta JOURNAL OF CLINICAL INVESTIGATION Lanz, T. V., Ding, Z., Ho, P. P., Luo, J., Agrawal, A. N., Srinagesh, H., Axtell, R., Zhang, H., Platten, M., Wyss-Coray, T., Steinman, L. 2010; 120 (8): 2782-2794

    Abstract

    The renin-angiotensin-aldosterone system (RAAS) is a key hormonal system regulating blood pressure. However, expression of RAAS components has recently been detected in immune cells, and the RAAS has been implicated in several mouse models of autoimmune disease. Here, we have identified Ang II as a paracrine mediator, sustaining inflammation in the CNS in the EAE mouse model of MS via TGF-beta. Ang II type 1 receptors (AT1Rs) were found to be primarily expressed in CNS-resident cells during EAE. In vitro, astrocytes and microglia responded to Ang II treatment by inducing TGF-beta expression via a pathway involving the TGF-beta-activating protease thrombospondin-1 (TSP-1). TGF-beta upregulation in astrocytes and microglia during EAE was blocked with candesartan (CA), an inhibitor of AT1R. Treatment of EAE with CA ameliorated paralysis and blunted lymphocyte infiltration into the CNS, outcomes that were also seen with genetic ablation of AT1Ra and treatment with an inhibitor of TSP-1. These data suggest that AT1R antagonists, frequently prescribed as antihypertensives, may be useful to interrupt this proinflammatory, CNS-specific pathway in individuals with MS.

    View details for DOI 10.1172/JCI41709

    View details for Web of Science ID 000280492100015

    View details for PubMedID 20628203

    View details for PubMedCentralID PMC2912186

  • Mouse Mesenchymal Stem Cells Suppress Antigen-Specific TH Cell Immunity Independent of Indoleamine 2,3-Dioxygenase 1 (IDO1) STEM CELLS AND DEVELOPMENT Lanz, T. V., Opitz, C. A., Ho, P. P., Agrawal, A., Lutz, C., Weller, M., Mellor, A. L., Steinman, L., Wick, W., Platten, M. 2010; 19 (5): 657-668

    Abstract

    Due to their immunosuppressive properties, human mesenchymal stem cells (hMSC) represent a promising tool for cell-based therapies of autoimmune diseases such as multiple sclerosis (MS). Mouse MSC (mMSC) have been used extensively to characterize and optimize route of administration, motility, cellular targets, and immunosuppressive mechanisms in mouse models of autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE). Tryptophan (trp) catabolism by indolamine-2,3-dioxygenase 1 (IDO1) is a chief endogenous metabolic pathway that tightly regulates unwanted immune responses through depletion of trp and generation of immunosuppressive kynurenines (kyn). IDO1 activity contributes to the immunosuppressive phenotype of hMSC. Here, we demonstrate that although IDO1 is inducible in bone marrow-derived mMSC by proinflammatory stimuli such as interferon-g (IFN-g) and ligands of toll-like receptors (TLR), it does not lead to catabolism of trp in vitro. This failure to catabolize trp is not due to defective TLR signaling as demonstrated by induction of interleukin 6 (IL-6) by TLR activation. While mMSC suppressed the activation of antigen-specific myelin oligodendrocyte glycoprotein (MOG)-reactive T-cell receptor (TCR) transgenic T-helper (TH) cells in co-culture, neither pharmacologic inhibition nor genetic ablation of IDO1 reversed this suppressive effect. Finally, systemic administration of both, IDO1-proficient and phenotypically identical IDO1-deficient mMSC, equally resulted in amelioration of EAE. mMSC, unlike hMSC, do not display IDO1-mediated suppression of antigen-specific T-cell responses.

    View details for DOI 10.1089/scd.2009.0385

    View details for Web of Science ID 000277972300009

    View details for PubMedID 19886804

    View details for PubMedCentralID PMC3377946

  • Blocking angiotensin-converting enzyme induces potent regulatory T cells and modulates TH1-and TH17-mediated autoimmunity PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Platten, M., Youssef, S., Hur, E. M., Ho, P. P., Han, M. H., Lanz, T. V., Phillips, L. K., Goldstein, M. J., Bhat, R., Raine, C. S., Sobel, R. A., Steinman, L. 2009; 106 (35): 14948-14953

    Abstract

    The renin-angiotensin-aldosterone system (RAAS) is a major regulator of blood pressure. The octapeptide angiotensin II (AII) is proteolytically processed from the decapeptide AI by angiotensin-converting enzyme (ACE), and then acts via angiotensin type 1 and type 2 receptors (AT1R and AT2R). Inhibitors of ACE and antagonists of the AT1R are used in the treatment of hypertension, myocardial infarction, and stroke. We now show that the RAAS also plays a major role in autoimmunity, exemplified by multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Using proteomics, we observed that RAAS is up-regulated in brain lesions of MS. AT1R was induced in myelin-specific CD4+ T cells and monocytes during autoimmune neuroinflammation. Blocking AII production with ACE inhibitors or inhibiting AII signaling with AT1R blockers suppressed autoreactive TH1 and TH17 cells and promoted antigen-specific CD4+FoxP3+ regulatory T cells (Treg cells) with inhibition of the canonical NF-kappaB1 transcription factor complex and activation of the alternative NF-kappaB2 pathway. Treatment with ACE inhibitors induces abundant CD4+FoxP3+ T cells with sufficient potency to reverse paralytic EAE. Modulation of the RAAS with inexpensive, safe pharmaceuticals used by millions worldwide is an attractive therapeutic strategy for application to human autoimmune diseases.

    View details for DOI 10.1073/pnas.0903958106

    View details for Web of Science ID 000269481000040

    View details for PubMedID 19706421

    View details for PubMedCentralID PMC2736463

  • Toll-Like Receptor Engagement Enhances the Immunosuppressive Properties of Human Bone Marrow-Derived Mesenchymal Stem Cells by Inducing Indoleamine-2,3-dioxygenase-1 via Interferon-beta and Protein Kinase R STEM CELLS Opitz, C. A., Litzenburger, U. M., Lutz, C., Lanz, T. V., Tritschler, I., Koeppel, A., Tolosa, E., Hoberg, M., Anderl, J., Aicher, W. K., Weller, M., Wick, W., Platten, M. 2009; 27 (4): 909-919

    Abstract

    Mesenchymal stem cells (MSC) display unique suppressive properties on T-cell immunity, thus representing an attractive vehicle for the treatment of conditions associated with harmful T-cell responses such as organ-specific autoimmunity and graft-versus-host disease. Toll-like receptors (TLR) are primarily expressed on antigen-presenting cells and recognize conserved pathogen-derived components. Ligation of TLR activates multiple innate and adaptive immune response pathways to eliminate and protect against invading pathogens. In this work, we show that TLR expressed on human bone marrow-derived MSC enhanced the immunosuppressive phenotype of MSC. Immunosuppression mediated by TLR was dependent on the production of immunosuppressive kynurenines by the tryptophan-degrading enzyme indoleamine-2,3-dioxygenase-1 (IDO1). Induction of IDO1 by TLR involved an autocrine interferon (IFN)-beta signaling loop, which was dependent on protein kinase R (PKR), but independent of IFN-gamma. These data define a new role for TLR in MSC immunobiology, which is to augment the immunosuppressive properties of MSC in the absence of IFN-gamma rather than inducing proinflammatory immune response pathways. PKR and IFN-beta play a central, previously unidentified role in orchestrating the production of immunosuppressive kynurenines by MSC.

    View details for DOI 10.1002/stem.7

    View details for Web of Science ID 000265529400019

    View details for PubMedID 19353519