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Shimaoka Lecture on Integrins and Immune Cell Trafficking at Hiroshima University
- 1. 免疫細胞のコミュニケーション・体内動態 島岡 要 （しまおか もとむ） 三重⼤大学⼤大学院・医学系研究科 分⼦子病態学 The authors declare no competing financial interest. 1
- 2. 科学教育における 教師の役割？ or 教科書を読む だけで⼗十分では？
- 3. • Prioritization • Motivation • Context
- 4. Thomas S. Kuhn (1922 – 1996) “Paradigm Shift”
- 5. is NOT simply the Current Theory BUT the Entire Worldview in which it exists, & all of the implications which comes with it
- 6. 鴨 or ?
- 7. 'Normal science’ does resemble the standard cumulative picture of scientific progress, on the surface at least. — Thomas S. Kuhn— 7
- 9. Standing on the shoulders of giants "One who develops future intellectual pursuits by understanding and building on the research and works created by notable thinkers of the past,” -Wikipedia-
- 10. The Crafoord Prize is presented by the Royal Swedish Academy of Sciences since 1982 “to promote international basic research … with particular emphasis on Ecology and Polyarthritis”.
- 11. ・・・ ・・・ ・・・
- 12. Eugene C. Butcher Timothy A. Springer
- 14. Three-Step Model Selectins, Chemokines, and Integrins sequentially support leukocyte-endothelial adhesive interactions http://www.kva.se/Documents/Priser/Crafoord/2004/prog_crafoorddays_2004.pdf
- 15. Zip Code Model Tissue-specific homing is dictated by combinations of Chemokines and Adhesion Molecules on HEVs http://www.kva.se/Documents/Priser/Crafoord/2004/prog_crafoorddays_2004.pdf
- 16. Switch Blade Model Integrin affinity is enhanced by global conformational changes http://www.kva.se/Documents/Priser/Crafoord/2004/prog_crafoorddays_2004.pdf
- 17. 3 AREAS OF PUZZLE SOLVING� Integrin Activation • Integrin Activation • Cell Migration • Therapeutics (von Andrian, NEJM, 2000) "
- 18. LFA-1のグローバルな� ICAM-1! コンフォメーション変化� 7. Ligand binding! 6. Activation of I domain by downward movement of its C- terminal ”pull spring"! 5. Swing-out of hybrid domain and activation of I- like domain! 3. Separation of α and β 4. Switchblade-like upward 1. Cellular tailpieces! movement of headpiece ! activation! α β 2. Binding of factors to Integrin integrin cytoplasmic Integrin binding binding factor! factor! domains !
- 19. Cytoplasmic proteins interacting with β integrin tails Legate KR, J Cell Sci 2009
- 20. Talin and Kindlin activate integrin Moser M, Science 2009
- 21. Talin activates integrin Moser M, Science 2009
- 22. Talin activates integrin at the membrane-cytoplasmic interface Moser M, Science 2009
- 23. How do Talin and Kindlin act together on integrin? Moser M, Science 2009
- 24. Talin and Kindlin can simultaneously bind to the β integrin tail Bass MS, Nat Cell Biol 2011
- 25. Affnity-upregulated integrin binds ligand, inducing lateral association (a.k.a. integrin clustering) Margadant C, Curr Opin Cell Biol 2011
- 26. Which comes first: affinity or avidity? Carman CV, Curr Opin Cell Biol 2003
- 27. Puzzles to be solved (1) Biophysical basis of integrin activation: How force induces integrin conformational activation? Integrin adhesion dynamism: How integrin activation and inactivation are coordinated?
- 28. 3 AREAS OF PUZZLE SOLVING� • Integrin Activation Cell Migration • Cell Migration • Therapeutics (von Andrian, NEJM, 2000) "
- 29. More than 3 steps…… Nourshargh S, Nat Rev Mol Cell Biol 2010
- 30. Two Distinct Routes for Transendothelial Migration Carman CV, J Cell Sci 2009
- 31. Crawling Leukocytes Display Podosomes, probing the surface of ECs for an TEM point (a.k.a. hotspot) Shulman Z, Nat Immunol 2012 Park EJ, Blood 2010 Carman CV, J Cell Sci 2009
- 32. After EC migration, neutrophils crawl along pericyte processes to gaps between adjacent pericytes in an ICAM-1–, Mac-1–, and LFA-1–dependent manner Proebstl D, J Exp Med 2012
- 33. Integrin-independent Interstitial Migration Integrin-null dendritic cells
- 34. Integrin-independent Interstitial Migration Amoeboid Cell Migration uses actin-network expansion that promotes protrusive flowing of the leading edge Nourshargh S, Nat Rev Mol Cell Biol 2010
- 35. Puzzles to be solved (2) Homing of specific cells to and within specific organs: How stem cells migrate in the body? Homing in human: How mouse immunology be generalized to human?
- 36. 3 AREAS OF PUZZLE SOLVING� • Integrin Activation • Cell Migration Therapeutics • Therapeutics (von Andrian, NEJM, 2000) "
- 37. Selective inhibition of the integrin(s) required for tissue-specific homing Luster AD, Nat Immunol 2005 Von Andrian UH, N Engl J Med 2000
- 38. Anti-integrin therapies validated in Phase III clinical trial
- 39. F.D.A. Approves Biotechnology Drug for Psoriasis February 1, 2003 F.D.A. Approves a Multiple Sclerosis Drug November 24, 2004
- 40. PML associated with anti-integrin therapies Major EO, Annu Rev Med 2010
- 41. Sales Halted In Biotech Drug Because of Link To a Death March 1, 2005 F.D.A. Panel Recommends M.S. Drug Despite Lethal Risk March 9, 2006 F.D.A. Approves Drug for Intestinal Disease January 15, 2008
- 42. Genentech Starts Pulling Back Psoriasis Drug April 8, 2009
- 43. PML associated with anti-integrin therapies plus α Carson KR, Lancet Oncol 2009
- 44. PML associated with anti-integrin therapies plus α Major EO, Annu Rev Med 2010
- 45. New Analysis of Risk Stratification for TYSABRI® - Use of Biomarker has Potential to Advance Personalized Treatment for MS Patients - May 18, 2012
- 46. Small-molecule inhibitor to α4 integrin alleviates MS No PML case was seen in 149 patients receiving firategrast
- 47. Puzzles to be solved (3) How to prevent PML: Better biomarker, better understanding anti-JC virus immunity Novel small-molecule inhibitors: Allosteric ?, blockade of integrin signaling ?
- 48. Thank You!!