Shimaoka Lecture on Integrins and Immune Cell Trafficking at Hiroshima University


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島岡 要(三重大学)

Dr. Shimaoka will be giving a lecture on leukocyte trafficking and integrin activation at Hiroshima University on June 18th, 2012.

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Shimaoka Lecture on Integrins and Immune Cell Trafficking at Hiroshima University

  1. 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. 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. 3. •  Prioritization•  Motivation•  Context
  4. 4. Thomas S. Kuhn (1922 – 1996) “Paradigm Shift”
  5. 5. is NOT simplythe Current TheoryBUTthe Entire Worldviewin which it exists,& all of the implicationswhich comes with it
  6. 6. 鴨 or ?
  7. 7. Normal science’  does resemble thestandard cumulative picture ofscientific progress, on the surface atleast. — Thomas S. Kuhn— 7
  8. 8. Standing on the shoulders of giants"One who develops future intellectual pursuits byunderstanding and building on the research and workscreated by notable thinkers of the past,” -Wikipedia-
  9. 9. The Crafoord Prizeis presented by the Royal Swedish Academy of Sciences since 1982 “to promote international basic research … with particular emphasis on Ecology and Polyarthritis”.
  10. 10. ・・・ ・・・ ・・・
  11. 11. Eugene C. Butcher Timothy A. Springer
  12. 12.
  13. 13. Three-Step ModelSelectins, Chemokines, and Integrins sequentially support leukocyte-endothelial adhesive interactions
  14. 14. Zip Code ModelTissue-specific homing is dictated by combinations of Chemokines and Adhesion Molecules on HEVs
  15. 15. Switch Blade ModelIntegrin affinity is enhanced by global conformational changes
  16. 16. 3 AREAS OF PUZZLE SOLVING� Integrin Activation •  Integrin Activation •  Cell Migration •  Therapeutics (von Andrian, NEJM, 2000) "
  17. 17. 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 !
  18. 18. Cytoplasmic proteins interacting with β integrin tails Legate KR, J Cell Sci 2009
  19. 19. Talin and Kindlin activate integrin Moser M, Science 2009
  20. 20. Talin activates integrin Moser M, Science 2009
  21. 21. Talin activates integrin at the membrane-cytoplasmic interface Moser M, Science 2009
  22. 22. How do Talin and Kindlin act together on integrin? Moser M, Science 2009
  23. 23. Talin and Kindlin can simultaneously bind to the β integrin tail Bass MS, Nat Cell Biol 2011
  24. 24. Affnity-upregulated integrin binds ligand, inducing lateral association (a.k.a. integrin clustering) Margadant C, Curr Opin Cell Biol 2011
  25. 25. Which comes first: affinity or avidity? Carman CV, Curr Opin Cell Biol 2003
  26. 26. Puzzles to be solved (1)Biophysical basis of integrin activation: How forceinduces integrin conformational activation?Integrin adhesion dynamism: How integrin activationand inactivation are coordinated?
  27. 27. 3 AREAS OF PUZZLE SOLVING� •  Integrin Activation Cell Migration •  Cell Migration •  Therapeutics (von Andrian, NEJM, 2000) "
  28. 28. More than 3 steps…… Nourshargh S, Nat Rev Mol Cell Biol 2010
  29. 29. Two Distinct Routes for Transendothelial Migration Carman CV, J Cell Sci 2009
  30. 30. Crawling Leukocytes Display Podosomes, probing thesurface 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
  31. 31. After EC migration, neutrophils crawl along pericyteprocesses to gaps between adjacent pericytes in anICAM-1–, Mac-1–, and LFA-1–dependent manner Proebstl D, J Exp Med 2012
  32. 32. Integrin-independent Interstitial Migration Integrin-null dendritic cells
  33. 33. Integrin-independent Interstitial MigrationAmoeboid Cell Migration uses actin-network expansion that promotes protrusive flowing of the leading edge Nourshargh S, Nat Rev Mol Cell Biol 2010
  34. 34. Puzzles to be solved (2)Homing of specific cells to and within specificorgans: How stem cells migrate in the body?Homing in human: How mouse immunology begeneralized to human?
  35. 35. 3 AREAS OF PUZZLE SOLVING� •  Integrin Activation •  Cell Migration Therapeutics •  Therapeutics (von Andrian, NEJM, 2000) "
  36. 36. Selective inhibition of the integrin(s) required for tissue-specific homingLuster AD, Nat Immunol 2005 Von Andrian UH, N Engl J Med 2000
  37. 37. Anti-integrin therapies validated in Phase III clinical trial
  38. 38. F.D.A. Approves Biotechnology Drug for Psoriasis February 1, 2003F.D.A. Approves a Multiple Sclerosis Drug November 24, 2004
  39. 39. PML associated with anti-integrin therapies Major EO, Annu Rev Med 2010
  40. 40. Sales Halted In Biotech Drug Because of Link To a Death March 1, 2005F.D.A. Panel Recommends M.S. Drug Despite Lethal Risk March 9, 2006F.D.A. Approves Drug for Intestinal Disease January 15, 2008
  41. 41. Genentech Starts Pulling Back Psoriasis Drug April 8, 2009
  42. 42. PML associated with anti-integrin therapies plus α Carson KR, Lancet Oncol 2009
  43. 43. PML associated with anti-integrin therapies plus α Major EO, Annu Rev Med 2010
  44. 44. New Analysis of Risk Stratification for TYSABRI® - Use of Biomarker has Potential to Advance Personalized Treatment for MS Patients - May 18, 2012
  45. 45. Small-molecule inhibitor to α4 integrin alleviates MS No PML case was seen in 149 patients receiving firategrast
  46. 46. Puzzles to be solved (3)How to prevent PML: Better biomarker, betterunderstanding anti-JC virus immunityNovel small-molecule inhibitors: Allosteric ?,blockade of integrin signaling ?
  47. 47. Thank You!!