December 4th, 2012免疫細胞のコミュニケーション・体内動態	   Leukocyte trafficking in heath and diseases!                        島岡  要	        ...
⾼高校と⼤大学の勉強の違いってなんだろう?	       What	  do	  you	  expect	  	    to	  University	  Education?	                  AND     What	 ...
Reading through an immunology textbook is enough?      What is the role of teachers ? 科学教育における	    教師の役割?	       or  教科書を読...
•  Prioritization•  Motivation•  Context
膿 (うみ)        abscess5	  
Skin abscess	            Tooth abscess	www.humanillnesses.com/	      www.aae.org
Leukocyte migration from blood vessels to inflamed tissues                                                Kupper. NEJM 2003
(von Andrian, NEJM, 2000) "Leukocyte-Endthelial Cell Interactions:•  Selectins•  Chemokines•  Integrins
感染部位に膿 (うみ)        のできない病態とは?        Infection without        abscess and pus?9	  
ーGenetic Defect of Leukocyte IntegrinsーLeukocyte Adhesion Deficiency (LAD)    •  Primary immune defect                    ...
The Crafoord Prizeis presented by the Royal Swedish Academy of Sciences	 since 1982 “to promote international basic resear...
・・・	・・・	・・・
Eugene C. Butcher   Timothy A. Springer
http://www.kva.se/Documents/Priser/Crafoord/2004/prog_crafoorddays_2004.pdf
Three-Step ModelSelectins, Chemokines, and Integrins sequentially support        leukocyte-endothelial adhesive interactio...
Zip Code ModelTissue-specific homing is dictated by combinations of   Chemokines and Adhesion Molecules on HEVs           ...
The Zip (Highway) Code of T Cell Trafficking                                          	                           Marelli-B...
Switch Blade ModelIntegrin affinity is enhanced by global conformational changes                                          ...
QuizQ1. Name 3 steps in leukocyte-endothelial interactions.Q2. Explain Zip code model19	  
3 AREAS OF PUZZLE SOLVING�                                Integrin Activation                                 •  Integrin ...
LFA-1のグローバルな�     コンフォメーション変化�     1. Cellular     activation!                                  α	      β	2. Binding of fa...
LFA-1のグローバルな�                                                                      ICAM-1                                 ...
Cytoplasmic proteins interacting with β integrin tails                                       Legate KR, J Cell Sci 2009
Talin activates integrin                           Moser M, Science 2009
Affnity-upregulated integrin binds ligand, inducing   lateral association (a.k.a. integrin clustering)                    ...
QuizQ1. Explain how integrin isactivated.26	  
3 AREAS OF PUZZLE SOLVING�                                •  Integrin Activation                                Cell Migra...
More than 3 steps……            Nourshargh S, Nat Rev Mol Cell Biol 2010
Two Distinct Routes for Transendothelial Migration                                    Carman CV, J Cell Sci 2009
Crawling Leukocytes Display Podosomes, probingthe surface of ECs for an TEM point (a.k.a. hotspot)                        ...
After EC migration, neutrophils crawl along pericyteprocesses to gaps between adjacent pericytes in anICAM-1–, Mac-1–, and...
QuizQ1. Name 2 routes of leukocyteendothelial transmigration.Q2. What are the roles of pericytes?32	  
3 AREAS OF PUZZLE SOLVING�                                 •  Integrin Activation                                 •  Cell ...
Selective inhibition of the integrin(s) required for              tissue-specific homing Luster AD, Nat Immunol 2005   Von...
Anti-integrin therapies validated in Phase III clinical trialα4 (α4β1 + α4β7)	αLβ2 (LFA-1)
F.D.A. Approves Biotechnology Drug for Psoriasis                                February 1, 2003F.D.A. Approves a Multiple...
PML associated with anti-integrin therapies                              Major EO, Annu Rev Med 2010
Sales Halted In Biotech Drug Because of Link To a Death                                    March 1, 2005F.D.A. Panel Recom...
Genentech Starts Pulling Back Psoriasis Drug                                  April 8, 2009
PML associated with anti-integrin therapies plus α                                   Carson KR, Lancet Oncol 2009
PML associated with anti-integrin therapies plus α	                                    Major EO, Annu Rev Med 2010
New Analysis of Risk Stratification for TYSABRI®  - Use of Biomarker has Potential to Advance   Personalized Treatment for ...
Small-molecule inhibitor to α4 integrin alleviates MS              No PML case was seen in 149 patients receiving firategr...
QuizQ1. Which organ is inflamed inmultiple sclerosis patients?Q2. Which integrin plays a cirial rolein multiple sclerosis?Q...
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島岡要 広島大歯・免疫学授業(2012年12月4日)Leukocyte Trafficking in Health and Diseases

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島岡要 広島大歯・免疫学授業(2012年12月4日)Leukocyte Trafficking in Health and Diseases

  1. 1. December 4th, 2012免疫細胞のコミュニケーション・体内動態   Leukocyte trafficking in heath and diseases! 島岡  要   (しまおか  もとむ)   Motomu Shimaoka, M.D., Ph.D. 三重⼤大学⼤大学院・医学系研究科   分⼦子病態学   Dept Molecular Pathobiology Mie University School of Medicine   The authors declare no competing financial interest. 1
  2. 2. ⾼高校と⼤大学の勉強の違いってなんだろう?   What  do  you  expect     to  University  Education?   AND What  are  the  differences   between    High-‐‑‒school  and  University   Educations?    
  3. 3. Reading through an immunology textbook is enough? What is the role of teachers ? 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?  
  4. 4. •  Prioritization•  Motivation•  Context
  5. 5. 膿 (うみ) abscess5  
  6. 6. Skin abscess Tooth abscess www.humanillnesses.com/ www.aae.org
  7. 7. Leukocyte migration from blood vessels to inflamed tissues Kupper. NEJM 2003
  8. 8. (von Andrian, NEJM, 2000) "Leukocyte-Endthelial Cell Interactions:•  Selectins•  Chemokines•  Integrins
  9. 9. 感染部位に膿 (うみ) のできない病態とは? Infection without abscess and pus?9  
  10. 10. ーGenetic Defect of Leukocyte IntegrinsーLeukocyte Adhesion Deficiency (LAD) •  Primary immune defect Nor. neutophils LAD I: •  Defects β2 integrins (LFA-1, Mac-1, etc) LAD. neutophils •  Recurrent and often fatal bacterial infection LAD II: periodontitis Lekstrom-Himes JA et al NEJM 2000 •  Defect in selectin ligands LAD III: •  Defects signaling moleclue(s) leading to integrin activation
  11. 11. 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”.
  12. 12. ・・・ ・・・ ・・・
  13. 13. Eugene C. Butcher Timothy A. Springer
  14. 14. http://www.kva.se/Documents/Priser/Crafoord/2004/prog_crafoorddays_2004.pdf
  15. 15. Three-Step ModelSelectins, Chemokines, and Integrins sequentially support leukocyte-endothelial adhesive interactions http://www.kva.se/Documents/Priser/Crafoord/2004/prog_crafoorddays_2004.pdf
  16. 16. Zip Code ModelTissue-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
  17. 17. The Zip (Highway) Code of T Cell Trafficking Marelli-Berg FM, J Pathol 2007
  18. 18. Switch Blade ModelIntegrin affinity is enhanced by global conformational changes http://www.kva.se/Documents/Priser/Crafoord/2004/prog_crafoorddays_2004.pdf
  19. 19. QuizQ1. Name 3 steps in leukocyte-endothelial interactions.Q2. Explain Zip code model19  
  20. 20. 3 AREAS OF PUZZLE SOLVING� Integrin Activation •  Integrin Activation •  Cell Migration •  Therapeutics (von Andrian, NEJM, 2000) "
  21. 21. LFA-1のグローバルな� コンフォメーション変化� 1. Cellular activation! α β 2. Binding of factors Integrin to integrin Integrin binding binding factor!cytoplasmic domains ! factor!
  22. 22. 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 Integrin to integrin Integrin binding binding factor! factor!cytoplasmic domains !
  23. 23. Cytoplasmic proteins interacting with β integrin tails Legate KR, J Cell Sci 2009
  24. 24. Talin activates integrin Moser M, Science 2009
  25. 25. Affnity-upregulated integrin binds ligand, inducing lateral association (a.k.a. integrin clustering) Margadant C, Curr Opin Cell Biol 2011
  26. 26. QuizQ1. Explain how integrin isactivated.26  
  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, probingthe 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
  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. QuizQ1. Name 2 routes of leukocyteendothelial transmigration.Q2. What are the roles of pericytes?32  
  33. 33. 3 AREAS OF PUZZLE SOLVING� •  Integrin Activation •  Cell Migration Therapeutics •  Therapeutics (von Andrian, NEJM, 2000) "
  34. 34. Selective inhibition of the integrin(s) required for tissue-specific homing Luster AD, Nat Immunol 2005 Von Andrian UH, N Engl J Med 2000
  35. 35. Anti-integrin therapies validated in Phase III clinical trialα4 (α4β1 + α4β7) αLβ2 (LFA-1)
  36. 36. F.D.A. Approves Biotechnology Drug for Psoriasis February 1, 2003F.D.A. Approves a Multiple Sclerosis Drug November 24, 2004
  37. 37. PML associated with anti-integrin therapies Major EO, Annu Rev Med 2010
  38. 38. 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
  39. 39. Genentech Starts Pulling Back Psoriasis Drug April 8, 2009
  40. 40. PML associated with anti-integrin therapies plus α Carson KR, Lancet Oncol 2009
  41. 41. PML associated with anti-integrin therapies plus α Major EO, Annu Rev Med 2010
  42. 42. New Analysis of Risk Stratification for TYSABRI® - Use of Biomarker has Potential to Advance Personalized Treatment for MS Patients - May 18, 2012
  43. 43. Small-molecule inhibitor to α4 integrin alleviates MS No PML case was seen in 149 patients receiving firategrast
  44. 44. QuizQ1. Which organ is inflamed inmultiple sclerosis patients?Q2. Which integrin plays a cirial rolein multiple sclerosis?Q3. What is the major adverseeffect of natalizumab (TysabriTM)?Q4. How to mitigate the risk of PML(progressive multifocal leukoencephalopathy)?44  

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