多発性硬化症（MS）は人生の開花 ... - amed.go.jp

1 16ek0109084h0002 .. I.. Practical Research Project for Rare/Intractable Diseases . Development of a new disease modifying drug for multiple sclerosis .. National Institute of Neuroscience, National Center of Neurology and Psychiatry, Director, Takashi Yamamura .. II.. MS . MS .. PML HPS . OCH . 1. Nature 413:531, 2001 STEP1 . OCH MS . STEP1 OCH .. STEP2 .. STEP2 . DNA OCH . MS OCH . MRI .. Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) that primarily affects young adults. The prevalence of MS is rapidly increasing in Japan. Although several disease-modifying drugs for MS are available, current drugs for MS pose lots of burden for patients in terms of efficacy, side effects and adherence. OCH. is a synthetic alpha-GalCer analog which respond to human invariant NKT cells to exert immunomodulatory effects. The purpose of this study is to develop an oral drug OCH as a new disease-modifying therapy for MS.

2 Investigator-initiated phase 1 clinical trial (First-in-human trial) was conducted in NCNP hospital. Single oral administration of OCH to healthy subjects completed with good safety profiles and pharmacokinetics/pharmacodynamics data as well as immunological changes after OCH. administrations. During the 28th year of Heisei era, we conducted the trial with repetitive administrations of OCH for relapsing-remitting MS patients. So far, we observed no serious side effects. The biomarker analyses using blood samples from subjects before and after OCH administration suggested substantial immunological 2. changes, presumably improving the MS immune-pathology. In addition, Magnetic Resonance Imaging analyses were performed. Finally, non-clinical studies including repetitive administrations of OCH to mice and primates completed. III.. 13 10 .. 1. Yamamura T, Ashtamker N, Ladkani D, Fukazawa T, Houzen H, Tanaka M, Miura T, and Knappertz V: Once-daily glatiramer acetate decreases MRI disease activity in Japanese patients with relapsing-remitting multiple sclerosis.

3 Clin Exp Neuroimmunol doi: , 2017. 2. Saida T, Kira JI, Kishida S, Yamamura T, Sudo Y, Ogiwara K, Tibung JT, Lucas N, and Subramanyam M. Efficacy, safety, and pharmacokinetics of natalizumab in Japanese multiple sclerosis patients: A double-blind, randomaized controlled trial and open-label pharmacokinetic study. Mult Scler Relat Disord. 11:25-31, 2017. 3. Saida T, Kira JI, Kishida S, Yamamura T, Ohtsuka N, Dong Q, and Tibung JT: Natalizumab for achieving relapse-free, T1 gadolinium-enhancing-lesion-free, and T2 lesion-free status in Japanese multiple sclerosis patients: A phase 2 trial subanalysis. Neurol Ther doi: , 2017. 4. Saida T, Kira , Kishida S, Yamamura T, Ohtsuka N, Ling Y, Torii S, Lucas N, Kuesters G, Steriner D, and Tibung JT: Saefety and efficacy of natalizumab in Japanese patients with relapsing-remitting multiple sclerosis: Open-label extension study of a phase 2 trial. Neurol Ther , 2016. 5. Kleiter I, Ayzenberg I, Araki M, Yamamura T, and Gold R: Tocilizumab, MS, and NMOSD.

4 Mult Scler 2016 Apr 11. Pii: 1352458516643395. 6. Kadowaki A, Miyake S, Saga R, Chiba A, Mochizuki H, and Yamamura T: Gut environment-induced intraepithelial autoreactive CD4+ T cells suppress central nervous system autoimmunity via Communications 7:11639, 2016.. 1. Yamamura T: Gut microbiota: A possible role in the pathogenesis of multiple sclerosis. Gastro-Neuro-Immunology. (Edited by Cris Constantinescu, Razvan Arernescu, Violeta Arsenescu), Springer, pp181-187, 2016. 2. Sato W, and Yamamura T: Cellular Immunity and Multiple Sclerosis: Current understanding. Neuroimmunological Diseases. (Edited by Susumu Kusunoki). Springer pp3-20, 2016. 3.. [ 4 ] .. ( , ) pp202-209, 2017. 4.. [ 4 ] .. ( , ). pp40-45, 2017. 3. 5. , 16S .. NGS .. pp54-57 , 2016.. 1. Sato W, and Yamamura T : Ribonucleic acid sequencing data mining: A new tool for understanding neuroimmunological conditions. Clin Exp Neuroimmunol 7:7-9, 2016. 2. Yamamura T, Raveney BJE, and Oki S : Study of eomesodermin-expressing CD4+ T cells sheds new light on the pathogenesis of secondary progressive multiple sclerosis.

5 Clin Exp Neuroimmunol 7 1-2, 2016. 3. , CD4+ T . 67: 195-202, 2017. 4.. 24: 45-49, 2016. 5.. Current Therapy 34: 43-48, 2016. 6.. 5) . 105: 1717-1721, 2016. 7.. 258: 1009-1012, 2016. 8.. Research, 24 266-270, 2016. 9. , . IL-6 -. 91: 1159-1167, 2016. 10.. Medical Science Digest (MSD) 42: 366-369, 2016. 11.. Brain and Nerve 68: 617-622, 2016 (6 ). 12. , Superior dominant peptide T . inverse vaccination . I .. 65 281-289, 2016.. 1. MS . MS No. 172. 10-19pp, 2016. 2. IL-6 . IL-6 .. Keynote RA 4:118, 2016. 3.. vol37 , 8, 2016. 4. , . 33: 625-626, 2016.. 1. Yamamura T : Treatment failures in NMO are due to specific immunologic mechanisms. 9th Annual International Roundtable Conference of NMO, Los Angeles, USA, 2017. 2. IL-6 . PMDA 2.. Repurposing-3. , , 2016. 3. ME/CFS .. ME/CFS -ME/CFS . , , 2016. 4. Yamamura T: Invariant NKT cells regulation of neuroinflammation. Symposium. The double edged sword of immunity in neurodegeneration.

6 ISNI 2016, Jerusalem, Israel, , 2016. 4. 5. , .. 41 . , , , 2016. 6.. , , 2016. 7. Yamamura T: Sendai lecture. Secondary progressive multiple sclerosis and neuroinflammation. Sendai Conference 2016. Sendai, , 2016. 8.. , , 9. Kadowaki A, Saga R, Miyake S, and Yamamura T: Gut intraepithelial autoreactive CD4+ T cells influenced by environment suppress central nervous system autoimmunity via LAG-3. FOCIS 2016, Boston, USA, , 2016. 10. Raveney BJE, Oki S, Nakamura M, Lin Y, Sato W, and Yamamura T: Identification of eomes-positive T helper cells as a pathogenic factor in chronic neuroinflammation. FOCIS 2016, Boston, USA, , 2016. 11. precision medicine .. , , 2016. 12.. 2.. , , 2016.. 1. Sato W, Ono H, Nakamura M, Yamamura T: Dysregulation of B lymphocytes in chronic fatigue syndrome. The 13th ISNI Congress, Jerusalem, ,2016. 2. Lin Y, Massilamany C, Reddy J, and Yamamura T Inverse vaccination with superior dominant peptide may eradicate multiple sclerosis via sequential induction of stabilized hybrid regulatory T cells with antigen specificity and tissue repair capacity 13th International Congress of Neuroimmunology, Jerusalem, Israel, ~9/29.

7 3. Kadowaki A, Saga R, Lin Y, Sato W, and Yamamura T: Potential Regulation of Multiple Sclerosis by Gut Homing CCR9+ TH cells, The 13th International Congress of NeuroImmunology 2016, Jerusalem, Israel, ~9/29. 4. Sato W, Ono H, Nakamura M, and Yamamura T: Dysregulation of B lymphocytes with reduced diversity and increased clonality in chronic fatigue syndrome. 12th International IACFS/ME Conference, Fort Lauderdale, USA, 5. Araki M, Nakamura M, Sato W, and Yamamura T: Potential benefits of the anti-IL-6 receptor antibody tocilizumab in patients with multiple sclerosis and seronegative neuromyelitis optica spectrum disorders. The 13th ISNI Congress, Jerusalem, ,2016. 6. Raveney B, Oki S, Hohjoh H, Nakamura M, Sato W, Murata M, and Yamamura T: Identification of Pathogenic T Helper Cells in Chronic Autoimmune International Congress of Immunology (ICI2016), Melbourne, Aug., 21st-26th, 2016. 7. Lin Y, and Yamamura T Antigen-specificity of superior dominant encephalitogenic peptide confers inductivity, stability, and hybrid signatures to CD69+CD103+ subset of Treg responsible for sustainable inhibition of CNS autoimmune diseases.

8 16th International Congress of Immunology, Melbourne, Australia, ~8/26. 5. 8. Saika R, Sakuma H, Noto D, Yamaguchi S, Yamamura T, and Miyake S: MicroRNA-101a regulates microglial development and inflammation. FOCIS 2016. Boston, USA , 2016. 9. Raveney B, Oki S, Namamura M, Lin Y, Sato W, and Yamamura T: Identification of Eomes-positive T helper cells as a pathogenic factor in chronic Annual Conference of FOCIS (FOCIS2016), Boston, Jun. 22nd-25th, 2016. 10. Kadowaki A, Miyake S, Chiba A, and Yamamura T: Gut intraepithelial myelin reactive CD4+ T. cells influenced by environment suppress central nervous system autoimmunity via LAG-3. FOCIS. annual meeting, Boston, June 24th , 2016. 11. Sato W, Ikeguchi R, Chihara N, Okamoto T, and Yamamura T: Chemokine receptor expression on CD4+ T cells in chronic inflammatory demyelinating polyneuropathy. FOCIS 2016. Boston, USA. , 2016. 12. Kimura K, Fukuoka M, Sato W, Takahashi R, Hohjoh H, and Yamamura T: Suppression of regulatory T cells by exosomes a pathogenic role of exosomes in multiple sclerosis.

9 FOCIS 2016. Boston, USA , 2016. 13. Kadowaki A, Miyake S, Saga R, and Yamamura T. Gut intraepithelial myelin reactive CD4+ T cells suppress central nervous system autoimmunity via LAG-3. American Association of Immunologists meeting, Seattle, May 15th , 2016.. 1. ONO H, SATO W, YAMAMURA T Dysregulation of B cells in Myalgic encephalomyelitis/Chronic Fatigue Syndrome. 45 , , ,2016. 2. , : Exosomes suppress regulatory T cells in multiple sclerosis. 45 . , , 2016. 3. : . T . 28 . , , 2016. 4. , Ben Raveney, NR4A2 T . 28 , , 2016. 5. , , . IL-6 . 28 , , 2016. 6. , , , , , T . : .. , 2016. 7. : T .. 8 RNAi 3 . , , 2016. 8. , , : IL-6 57 . , ,2016. 9. , , , , , , , . Investigator-Initiated Clinical Trial (first-in-human, Phase I) of invariant NKT cell ligand OCH 57 . , ,2016. 6. 10. Dominant peptide therapy may conquer MS by turning antigen-specificity and stability to hybrid Treg. 57 . , ,2016. 11. Suppression of regulatory T cells by exosomes in multiple sclerosis.

10 57 . , ,2016. 12. , , . 57 ,2016. 13. Atsushi Kadowaki, Sachiko Miyake, Ryoko Saga, Asako Chiba, Takashi Yamamura. Gut intraepithelial myelin responsive CD4+ T cells suppress CNS autoimmunity via LAG-3. 57. , , , 2016. 14. , ,Ben Raveney, , Development of Eomes+ helper T cells in association with CNS-derived antigen-presenting cells. 45 . ,2016. 15. Ben Raveney, , Functional characterization of authentic pathogenic T helper cells in autoimmune disease. 45 ,2016. 16. , Ben Raveney, , , T cell-intrinsic role of NR4A2 for pathological symptoms in lupus-prone mice. 45 ,2016.. 1. MS NMO 8 . 2016/04/24. 2. MS . 2016/06/11. 3. 2016 . 2016/07/16. 4. 9 . 2016/12/4. 5.. 2017/03/09. 6.. , . , , 2017. 7. , 2017. 8.. , , 2017. 9.. MS Expert Seminar in MIKAWA.. , , 2017. 10.. Web . , , , 2017. 11. , , , , , , , : .. 9 , , , , 2016. 12.. in . , , 2016. 7. 13.. in . , , 2016. 14.. , , 2016. 15.. - .. , , 2016. 16. MS . MS .. , 2016. 17.