Current Projects
The purpose of our research is to understand and reveal the pathogenesis of immune-mediated neurological diseases and to search after better therapies for them. Although we are interested in all of immune-mediated diseases affecting nervous system, our main energy is now being devoted to the study of multiple sclerosis (MS). We briefly introduce our current activities in the main topics in the laboratory.
1. Studies on the immunoregulation of MS
MS is believed to be an autoimmune disorder in which autoimmune T cells play a critical role. Since it has been proved that such autoimmune T cells are part of normal T cell repertoire, we believe that crucial regulatory mechanisms may be defective and underlie the pathogenesis of MS.
On the basis of our studies of animal model for MS, experimental autoimmune encephalomyelitis (EAE) (see below), particular focus is now placed on NK and CD1d-restricted NKT cells. In this context we recently reported two exciting discoveries.
First, in the remission of MS, NK cells producing IL-5, referred to as
NK2 cells, were found to be predominant and such NK2 cells have the ability to inhibit T helper 1 (Th1) shift of peripheral T cells via soluble factors including IL-5. This observation suggests that NK cells can play an active role in inhibiting autoimmune Th1 cells, thereby maintaining the remission of MS (
Takahashi K et al. J. Clin. Invest. 107: R23-R29, 2001). Second, we found a great reduction of NKT cells in the peripheral blood of large part of MS patients (
Illes Zs et al. J. Immunol. 164: 4375-4381, 2000). We have recently clarified that the reduction of NKT cells is mainly restricted to the CD4-CD8- subset, whereas the CD4+ NKT cells are relatively spared (
Araki M et al. manuscript in preparation). This intriguing observation may shed light on the role of NKT cells in the physiological regulation against autoimmunity.
We are also interested in the role of CD4+CD25+ regulatory cells and CD3+CD56+ regulatory cells in MS. The preliminary data suggest that these cells may also play an essential role in the regulation of MS.
2. Regulation of autoimmune encephalomyelitis by NK and NKT cells
Natural killer (NK) cells exert a variety of immunologic and homeostatic functions in eradicating tumor and infectious agents. In 1997, we proved for the first time that NK cells play a critical role in the prototype autoimmune disease EAE (
Zhang B. et al. J. Exp. Med. 186:1677-1687, 1997). Mice depleted for NK cells were shown to develop serious EAE without remission, while control mice developed mild EAE. More recently, we are attempting to treat EAE by adoptive transfer of IL-2 activated NK cells. Preliminary data showed that transfer of the activated NK cells significantly suppressed the signs of EAE. Using this passive transfer system, the NK cell-mediated regulation of EAE is being further defined.
NKT cells are a unique lymphocyte population expressing both T and NK cell markers. They exhibit various biological functions including production of Th1 and Th2 cytokines. The unique property of NKT cells is their recognition of a glycolipid antigen associated with the CD1d molecule. a-Galactosylceramide (a-GC) derived from marine sponge is now known to be a ligand for NKT cells. We examined the effect of synthetic a-GC on actively induced EAE. A series of experiments showed that partial (but not full) stimulation of NKT cells would lead to Th2 cytokine production and to reduction of Th1-mediated disease EAE. EAE was significantly suppressed by a-GC injection together with blockade of costimulatory molecule such as B7.2 (
Pal E et al. J. Immunol. 166: 662-668, 2001) or injection of a-GC analogue partially activating NKT cells (
>Miyamoto K et al. submitted for publication). As such, partial activation of NKT cells can be a new strategy for autoimmune disease.
3. NK/NKT cells and neurological diseases
We recently added a rare form of dementia, membranous lipodystrophy so called Nasu-Hakola Disease (NHD), to a list of our research. The Finnish NHD was reported to be due to a point mutation in DAP12, a transmembrane polypeptide with an intracytoplasmic immunoreceptor tyrosine-based activation motif (ITAM). DAP12 is associated with several activating cell surface receptors in myeloid cells, NK cells and neurons. It is possible that the defective expression of DAP12 caused by the mutation may somehow cause dementia and pathological fractures. However, our discovery of a new mutation in DAP12 and identification of the patients normally expressing DAP12 would indicate that Japanese NHD patients are genetically more heterogeneous than Finnish NHD.
Our scope of investigation is actually extending into more basic aspects of immunology, such as the repertoire selection of autoimmune T cells and signal transduction molecules in T cells and NK cells. These works are also producing exciting results that are of basic and clinical relevance. They will be published soon and are to be presented in the future version of this homepage.