Modulation of immune responses by natural recombinant proteins


Systemic and CNS immune responses and inflammation are thought to have a high impact on the outcome of stroke and MS. The interplay between the infiltrating immune cells and resident microglia/astrocyte regulate the balance between Th1/M1 and Th2/M2 responses that are thought to be destructive and beneficial, respectively. The safest approach to modulate the immune or inflammatory pathways and cellular mechanisms is to either enhance or prevent these natural responses by administration of recombinant proteins of immune modulators produced also by the cells in the body. This approach is widely exploited both in stroke by using tPA as an acute phase therapy, and in MS by using interferon-β (INF-β). While the benefit of both of these approaches is evident, the tPA therapy is applicable only for a fraction of stroke patients and a recent Canadian clinical study comprising over 2,500 MS patients showed that INF-β therapy does not significantly reduce the long-term disability. It is thus obvious that additional proteins produced by the human cells in these diseases displaying a potential benefit for CNS diseases need to be identified. Partner 7 has run a preliminary screen of natural immune modulators and identified a novel protein with neuroprotective properties in animal models. Within this work package partner 7 will take full advantage of a human iPSC-derived cell model to develop a platform for screening libraries of immune modulators. This platform will be made available to partners in the ITN. In cooperation with partner 9 the identified proteins will be investigated for their immune modulatory function in microglial cell culture. Then, partner 7 will test the relevance of the identified proteins using human blood and CSF samples of stroke and MS patients that are available through collaboration with partners 1, 2, 14, and 16. The identified proteins with the highest relevance will eventually be tested in various animal models of stroke and MS using 2-photon and optical imaging, MRI and microPET methods that are further developed within this consortium by partner 10. The motor functions will also be evaluated using the Catwalk gait analysis system.


    • Magga J, Savchenko E, Malm T, Rolova T, Pollari E, Valonen P, Lehtonen S, Jantunen E, Aarnio J, Lehenkari P, Koistinaho M, Muona A, Koistinaho J (2012). Production of monocytic cells from bone marrow stem cells: therapeutic usage in Alzheimer's disease. J Cell Mol Med. 16:1060-73
    • Kanninen K, Heikkinen R, Malm T, Rolova T, Kuhmonen S, Leinonen H, Ylä-Herttuala S, Tanila H, Levonen AL, Koistinaho M, Koistinaho J.(2009) Intrahippocampal injection of a lentiviral vector expressing Nrf2 improves spatial learning in a mouse model of Alzheimer's disease. Proc Natl Acad Sci USA. 106(38):16505-10

    Tasks and methodology

      • iPSC-derived cell model
      • microglial cell culture
      • Experimental models of stroke and EAE
      • Micro-PET and MRI

      Planned secondment

      Partner 9, Nencki Institute of Experimental Biology, effect of recombinant proteins on microglial gene expression, 8 month

      Host Organisation:
      Department of Neurobiology - Itä-Suomen Yliopisto
      Bozena Kaminska, Nencki Institute of Experimental Biology
      Jari Koistinaho
      Early Stage Researcher: