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
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?
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？
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 !
Cytoplasmic proteins interacting with β integrin tails Legate KR, J Cell Sci 2009
3 AREAS OF PUZZLE SOLVING� • Integrin Activation Cell Migration • Cell Migration • Therapeutics (von Andrian, NEJM, 2000) "
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) Shulman Z, Nat Immunol 2012 Park EJ, Blood 2010 Carman CV, J Cell Sci 2009
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
QuizQ1. Name 2 routes of leukocyteendothelial transmigration.Q2. What are the roles of pericytes?32
3 AREAS OF PUZZLE SOLVING� • Integrin Activation • Cell Migration Therapeutics • Therapeutics (von Andrian, NEJM, 2000) "
Selective inhibition of the integrin(s) required for tissue-specific homing Luster AD, Nat Immunol 2005 Von Andrian UH, N Engl J Med 2000
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 Sclerosis Drug November 24, 2004
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 Recommends M.S. Drug Despite Lethal Risk March 9, 2006F.D.A. Approves Drug for Intestinal Disease January 15, 2008
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 MS Patients - May 18, 2012
Small-molecule inhibitor to α4 integrin alleviates MS No PML case was seen in 149 patients receiving firategrast
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