Specific projects

Laboratory of Neuroimmunology

The Laboratory of neuroimmunology run by Prof Renaud Du Pasquier, principal investigator, is linked to other laboratories of research in immunology, in particular the Laboratory of Cellular Immunology and AIDS Immunopathology (Prof. Giuseppe Pantaleo), the Laboratory of experimental neuroimmunology (Prof Caroline Pot), or still the Laboratory of cellular and molecular neurotherapy (Prof. Nicole Déglon).

The Lab’s main research subject is the study of the immuno and neuro-pathogenesis of demyelinating illnesses, first of all Multiple Sclerosis (MS). MS is a disease that encompasses two phases: the inflammatory and the neuro-degenerative one. Whereas major improvements have been realized to tame the inflammatory phase with the famous disease-modifying therapies (DMTs), the neurodegenerative aspect of MS remains unaddressed by therapies 1. In our Laboratory, we try to understand if/how the inflammatory phase of MS influences the neurodegenerative one. This theme is explored through the following lines of research:

1. On an epidemiological basis, Epstein-Barr virus (EBV) is strongly associated with MS. However, whether this association reflects a link of causation remains unknown. Over the past years, we have shown that there was a dysregulation of the EBV-specific CD8+ T cell response in patients with MS, in particular at the early stages of the disease. These findings suggest that EBV may be instrumental in triggering MS 2-4

Multiple sclerosis (MS) is thought to be T-cell mediated, which also supported by our data (see above), but the mechanisms eliciting such a dysregulated adaptative cellular immune response remain enigmatic. Thus, recently, we decided to examine the activation profile of antigen-presenting cells (APC) in MS. We found that B lymphocytes of relapsing MS patients exhibit an increased expression of HLA-DR and CD40 ex-vivo 5 .We are now studying how the antigen-presenting function of B cells in MS patients influences the auto-reactive T cell response.

2. This set of studies has contributed to better explain the immunopathogenesis of MS. However, we are left with a crucial question: why and how does this dysregulated immunity specifically affect the CNS? Interestingly, we have shown that IL-22, a cytokine which has been implicated in MS 6 targeted the astrocytes of MS patients and seemed to protect these astrocytes from the pro-inflammatory effects of TNFa 7. Thus, this study establishes a link between the peripheral immunity and the CNS. To pursue on this path, we decided to launch into a “brain in a dish” program. In other terms, we established in the Lab, the technique of induced pluripotent stem cells (iPSC) 8. Thank to this tool, it is possible to obtain, from 10 ml of blood of a MS patient, autologous CNS cells (Figure 1).

This program opens major perspectives. Indeed, it will be possible to:
- study the effect of cytokines on the CNS
- determine what are the CNS antigens recognized by peripheral auto-reactive T cells
- develop a highly-sophisticated pre-clinical in vitro method to screen candidate neuroprotective compounds 9.
- improve our understanding of the immunopathogenesis of progressive multifocal leukoencephalopathy (PML), a deadly demyelinating viral disease, whose incidence is increased in MS patients treated by certain immunomodulator drugs (e.g. natalizumab) 10-14
- On a longer term, we may even consider the reinfusion of autologous iPSC-derived neural cells (no graft rejection) into patients with progressive MS, thus opening fascinating therapeutical perspectives 15.

3. Always in line with our strong interest for viral diseases affecting the CNS, we have an active line of research on the effects of HIV on the CNS. In particular, we have shown that even well-treated HIV+ persons can develop cognitive disorders 16-18. In order to address this important set-back for HIV+ patients, we have established a Multi-disciplinary plateform (infectiologist, neurologist, neuro-psychologist, psychiatrist, neuro-radiologist) to care for HIV+ patients suffering from neurological and neuro-cognitive complications.

In parallel, with Dr Matthias Cavassini, we are leading the multi-center NAMACO study (Neurocognitive Assessment in the Metabolic and Aging Cohort). This ambitious study, which entails currently 1000 HIV+ patients aged >45 yo, has for goal to better understand the cognitive impairments that affect HIV+ patients. We want to answer a series of research questions: what are the determinants of cognitive disorders in HIV infection? What are there biomarkers in cerebrospinal fluid predictive of cognitive disorder? Can MRI help us in identifying which are the brain structures that are affected in HIV+ patients with cognitive disorders? Dr Cristina Granziera, a neurologist trained in Lausanne and currently at Harvard Medical School, leads the Neuro-HIV MRI sub-project of NAMACO 19.

References

  1. Fox RJ, Rudick RA. The Future of Research in Multiple Sclerosis. JAMA neurology 2015.
  2. Jilek S, Schluep M, Meylan P, et al. Strong EBV-specific CD8+ T-cell response in patients with early multiple sclerosis. Brain 2008;131:1712-1721.
  3. Jaquiery E, Jilek S, Schluep M, et al. Intrathecal immune responses to Epstein-Barr virus in early multiple sclerosis. Eur J Immunol 2010;40:878-887.
  4. Jilek S, Schluep M, Harari A, et al. HLA-B7-restricted EBV-specific CD8+ T cells are dysregulated in multiple sclerosis. J Immunol 2012;188:4671-4680.
  5. Mathias A, Perriard G, Canales M, et al. Increased ex vivo antigen presentation profile of B cells in multiple sclerosis. Mult Scler 2016.
  6. Sawcer S, Hellenthal G, Pirinen M, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011;476:214-219.
  7. Perriard G, Mathias A, Enz L, et al. Interleukin-22 is increased in multiple sclerosis patients and targets astrocytes. J Neuroinflammation 2015;12:119.
  8. Okita K, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells. Nature 2007;448:313-317.
  9. Heilker R, Traub S, Reinhardt P, Scholer HR, Sterneckert J. iPS cell derived neuronal cells for drug discovery. Trends Pharmacol Sci 2014;35:510-519.
  10. Du Pasquier RA, Corey S, Margolin DH, et al. Productive infection of cerebellar granule cell neurons by JC virus in an HIV+ individual. Neurology 2003;61:775-782.
  11. Du Pasquier RA, Kuroda MJ, Schmitz JE, et al. Low frequency of cytotoxic T lymphocytes against the novel HLA-A*0201-restricted JC virus epitope VP1(p36) in patients with proven or possible progressive multifocal leukoencephalopathy. J Virol 2003;77:11918-11926.
  12. Du Pasquier RA, Kuroda MJ, Zheng Y, Jean-Jacques J, Letvin NL, Koralnik IJ. A prospective study demonstrates an association between JC virus-specific cytotoxic T lymphocytes and the early control of progressive multifocal leukoencephalopathy. Brain 2004;127:1970-1978.
  13. Jilek S, Jaquiery E, Hirsch HH, et al. Immune responses to JC virus in patients with multiple sclerosis treated with natalizumab: a cross-sectional and longitudinal study. Lancet Neurol 2010;9:264-272.
  14. Jilek S, Mathias A, Canales M, et al. Natalizumab treatment alters the expression of T-cell trafficking marker LFA-1 alpha-chain (CD11a) in MS patients. Mult Scler 2013.
  15. Isobe K, Cheng Z, Nishio N, Suganya T, Tanaka Y, Ito S. Reprint of "iPSCs, aging and age-related diseases". New biotechnology 2015;32:169-179.
  16. Simioni S, Cavassini M, Annoni JM, et al. Cognitive dysfunction in HIV patients despite long-standing suppression of viremia. AIDS 2010;24:1243-1250.
  17. Simioni S, Cavassini M, Annoni JM, et al. Rivastigmine for HIV-associated neurocognitive disorders: a randomized crossover pilot study. Neurology 2013;80:553-560.
  18. Du Pasquier RA, Jilek S, Kalubi M, et al. Marked increase of the astrocytic marker S100B in the cerebrospinal fluid of HIV-infected patients on LPV/r-monotherapy. AIDS 2013;27:203-210.
  19. Granziera C, Daducci A, Simioni S, et al. Micro-structural brain alterations in aviremic HIV+ patients with minor neurocognitive disorders: a multi-contrast study at high field. PLoS One 2013;8:e72547.

Collaborations

Lausanne:

Switzerland:

Abroad:

  • Prof David Laplaud, INSERM UMR 1064, Nantes, France
  • Dr Guillaume Martin-Blondel and Prof Roland Liblau, INSERM U1043, Toulouse, France
  • Dr Nicholas Schwab and Prof Heinz Wiendl, University Hospital of Münster, Germany

Selected publications

  • Bacchetta F, Mathias A, Schluep M, Du Pasquier RA. Progressive multifocal leukoencephalopathy in two natalizumab-treated stepsisters: an intriguing coincidence. Multiple Sclerosis Journal, 2016, in press.
  • Mathias A, Perriard G, Canales M, Sorenson C, Delorenzi M, Schluep M, Du Pasquier RA. Increased ex vivo antigen presentation profile of B cells in multiple sclerosis. Multiple Sclerosis Journal, 2016 in press. PubMed
  • Mathias A, Perriard G, Canales M, Vuilleumier F, Perrotta G, Schluep M, Du Pasquier RA. The VZV/IE63-specific T cell response prevents herpes zoster in fingolimod-treated patients Neurol Neuroimmunol Neuroinflamm 2016 Feb 10;3(2):e209. doi: 10.1212/NXI.00000000000002090. PubMed
  • Perriard G, Mathias A, Enz L, Canales M, Schluep M, Gentner M, Scharen-Wiemers N, Du Pasquier RA. Interleukin-22 is increased in multiple sclerosis patients and targets astrocytes. J Neuroinflammation 2015 Jun 16;12(1):119. PubMed
  • Schwab N, Schneider-Hohendorf T, Pignolet B, Spadaro M, Görllich D, Meinl I, Windhagen S, Tackenberg B, Breuer J, Cantó E, Kümpfel T, Hohlfeld R, Siffrin V, Luewwi F, Posevitz-Fejfár A, Montalban X, Meuth SG, Zipp F, Gold R, Du Pasquier RA, Kleinschnitz C, Jacobi A, Comabella M, Bertolotto A, Brassat D, Wiendl H. PML risk stratification using anti-JCV antibody index and L-selectin. Multi Scler 2015 Oct 2. pii: 1252458515607651. PubMed
  • Jilek S, Mathias A, Canales M, Lysandropoulos A, Pantaleo G, Schluep M, Du Pasquier RA. Natalizumab treatment alters the expression of T cell trafficking markers LFA-1 a-chain (CD11a) and CXCR3 in MS patients. Mlt Scler J 2014; 20(7):837-42. PubMed
  • Derfuss T, Curtin F, Guebelin C, Bridel C, Rasenack M, Matthey A, Du Pasquier R, Schluep M, Desmeules J, Lang AB, Perron H, Faucard R, Porchet H, Hartung HP, Kappos L, Lalive P. A phase lla randomized clinical study of GNbAC1, a humanized monoclonal antibody against the envelope protein of multiple sclerosis associated endogenous retrovirus in multiple sclerosis patients. Mult Scler J 2014 Nov 12. Epub ahead of print pii: 1352458514554052. PubMed
  • Du Pasquier R.A., Jilek S., Kalubi M., Yerly S., Fux C.A., Gutmann C., Cusini A., Günthard H.F., Cavassini M., Vernazza P.L. and the Swiss HIV Cohort Study. Marked Increase of the Astrocytic Marker S100B in the Cerebrospinal Fluid of HIV-infected Patients on LPV/r-Monotherapy. AIDS 2013, 27:203-210. PubMed
  • Antoniol C., Jilek S., Schluep M., Mercier N., Canales M., Le Goff G., Campiche C., Pantaleo G. and Du Pasquier R.A. Impairement of JCV-specific T cell response by corticotherapy: impact on PML-IRIS management ? Neurology 2012, 79:2258-2264. PudMed
  • Jilek S., Schluep M., Harari A., Canales M., Lysandropoulos A., Zekeridou A., Pantaleo G. and Du Pasquier R.A. HLA-B7-restricted EBV-specific CD8+ T cells are dysregulated in Multiple Sclerosis. J. Immunol. 2012, 188:4671-4680. PubMed
  • Lysandropoulos A.P., Jaquiéry E., Jilek S., Pantaleo G., Schluep M. and Du Pasquier R.A. Vitamin D has a direct immunomodulatory effect on CD8+ T cells of patients with early multiple sclerosis and healthy control subjects. J. Neuroimmunol. 2011, 233:240-244. PubMed
  • Jilek S., Jaquiéry E., Hirsch H.H., Lysandropoulos A., Canales M., Guignard L., Schluep M., Pantaleo G. and Pasquier R.A. Immune responses to JC virus in patients with multiple sclerosis treated with natalizumab: a cross-sectional and longitudinal study. Lancet Neurol. 2010, 9:264-272. PubMed
  • Jaquiéry E., Jilek S., Schluep M., Meylan P., Lysandropoulos A., Pantaleo G. and Du Pasquier R.A. Intrathecal immune responses to Epstein-Barr virus in early multiple sclerosis. Eur. J. Immunol. 2010, 40:878-887. PubMed
  • Simioni S., Cavassini M., Anonni J.-M., Rimbault-Abraham A., Bourquin I., Schiffer V., Calmy A., Chave J.-P., Giacobini E., Hirschel B. and Du Pasquier R.A. Cognitive dysfunction in HIV patients despite long-standing suppression of viremia. AIDS 2010, 24:1243-1250. PubMed
  • Jilek S., Schluep M., Meylan P., Vingerhoets F., Guignard L., Monney A., Kleeberg J., Le Goff G., Pantaleo G. and Du Pasquier R.A. Strong EBV-specific CD8+ T cell response in patients with early multiple sclerosis. Brain 2008, 131:1712-1721. PubMed
  • Jilek S, Kuhle J, Meylan P, Reichhardt M, Pantaleo G, Du Pasquier RA. Severe post-EBV encephalopathy associated with MOG-specific immune response. J Neuroimmunol 2007; 192:192-197. PubMed
  • Jilek S, Schluep M, Rossetti A, Guignard L, Le Goff G, Pantaleo G, Du Pasquier RA. Specific enrichment in highly differentiated CD8+ T cells in the CSF of patients with early multiple sclerosis. Clin Immunol 2007 ;123:105-113. PubMed
 Dernière mise à jour le 28/06/2019 à 08:09