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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. 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. 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. 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？
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. 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. 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”.
15. 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
16. 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
17. The Zip (Highway) Code of T Cell Trafficking
Marelli-Berg FM, J Pathol 2007
18. Switch Blade Model
Integrin affinity is enhanced by global conformational changes
http://www.kva.se/Documents/Priser/Crafoord/2004/prog_crafoorddays_2004.pdf
19. Quiz
Q1. Name 3 steps in leukocyte-
endothelial interactions.
Q2. Explain Zip code model
19
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 !
28. More than 3 steps……
Nourshargh S, Nat Rev Mol Cell Biol 2010
29. Two Distinct Routes for Transendothelial Migration
Carman CV, J Cell Sci 2009
30. 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
31. 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
32. Quiz
Q1. Name 2 routes of leukocyte
endothelial transmigration.
Q2. What are the roles of pericytes?
32
33. 3 AREAS OF PUZZLE SOLVING�
• Integrin Activation
• Cell Migration
Therapeutics
• Therapeutics
(von Andrian, NEJM, 2000) "
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
38. 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
40. PML associated with anti-integrin therapies plus α
Carson KR, Lancet Oncol 2009
41. PML associated with anti-integrin therapies plus α
Major EO, Annu Rev Med 2010
42. New Analysis of Risk Stratification for TYSABRI®
- Use of Biomarker has Potential to Advance
Personalized Treatment for MS Patients
-
May 18, 2012
43. Small-molecule inhibitor to α4 integrin alleviates MS
No PML case was seen in 149 patients receiving firategrast
44. Quiz
Q1. Which organ is inflamed in
multiple sclerosis patients?
Q2. Which integrin plays a cirial role
in multiple sclerosis?
Q3. What is the major adverse
effect of natalizumab (TysabriTM)?
Q4. How to mitigate the risk of PML
(progressive multifocal leukoencephalopathy)?
44
