The Roles Of iNKT Cells In Asthma
Upcoming SlideShare
Loading in...5
×
 

The Roles Of iNKT Cells In Asthma

on

  • 1,655 views

 

Statistics

Views

Total Views
1,655
Views on SlideShare
1,650
Embed Views
5

Actions

Likes
0
Downloads
29
Comments
0

1 Embed 5

http://www.slideshare.net 5

Accessibility

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment

The Roles Of iNKT Cells In Asthma The Roles Of iNKT Cells In Asthma Presentation Transcript

  • พญ . รังสิมา เหรียญตระกูล IMMUNOLOGY DIVISION DEPARTMENT OF MICROBIOLOGY FACULTY OF MEDICINE CHULALONGKORN UNIVERSITY The Role of iNKT Cells in Asthma
  • Allergic Bronchial Asthma
    • Inflammatory state: massive infiltration of eosinophils, lymphocytes and mast cells
    • Concomitant with various Th2 cytokines
    • Th2-biased responses
    • IL-13 : inflammation initiator, goblet cell hyperplasia, AHR, airway fibrosis
    • IL-4 : induction of Th2 responses???
  • NKT Cells
    • Discovery of NKT Cells
    • Definition of NKT Cells
    • NKT cell Role
    • Classification of NKT Cells
  • Discovery of NKT Cells
    • Unexpected finding in examining the TCR repertoire of a series of suppressor T cell hybridomas
    • High frequency for a single TCR chain
    V  14 J  18 Imai et al., 1986 Koseki et al., 1989 Lantz and Bendelec, 1994 Makino et al., 1995 Cui et al., 1997
    • Presence of CD4-CD8- double negative (DN) cells expressing V  8
    • CD44+, CD5+, NK1.1+
    • Copious amounts of cytokine production
    Budd et al., 1987 Fowlkes et al., 1987 Ballas and Rasmussen, 1990 Sykes, 1990
    • V  8+, CD5high and CD44+ thymocyte hybridoma has the mRNA for the V  14 TCR chain
    • V  14+ cells in peripheral tissues express V  and NK1.1
    Lantz and Bendelac. J.Exp.Med. 1994 Makino et al. Int. Immunol. 1995 Taniguchi et al. Proc. Natl.Acad.Sci. 1996
  • “ NKT Cell”
    • What is an NKT cell?
    • Recognizes Ag presented by class-I like MHC molecule CD1d, NK1.1, CD5+high, CD44+high
    • Usually semi-invariant TCR V  14J  18 TCR  chain and most often V  8 TCR  chains
    • True TCR  T cells
    • NK markers
  • NKT Cell Role
    • Rapid cytokine response from preformed mRNA
    • NKT’s IL-4 could promote Th2 responses & IgE production
    • NKT cells recognize bacterial glycosphingolipids
    Stetson et al. J.Exp.Med. 2003 IFN-  IL-4 Yoshimoto et al. Science.1995 Kinjo et al. Nature., 2005
  • Classification of NKT Cells Type I NKT Cells
    • Invariant ab TCRs (Va14Ja18 in mice/Va24-Ja18 in humans)
    • CD1d restricted
    Type II NKT Cells
    • Diverse TCR repertoire
    • CD1d restricted
    Type III NKT Cells
    • MHC class I & II other than CD1d
  • Type I NKT Cells
    • Three properties:
    • 1. invariant V  14J  18 in mice/V  24J  18 in humans
    • 2. limited repertoire of TCRs
    • 3.  -GalCer recognition by CD1d
    • Other indefinite markers: NK1.1, Ly49 NK receptors, CD69, CD44
    Kawano et al., 1997
  • Type I NKT Subsets
    • Human DN type I NKT cells  Th1 cytokines
    • CD4+ type I NKT cells  Th1 & Th2 cytokines
    Gumperz et al., 2002 Lee et al., 2002a
  • iNKT Microbial Recognition
    •  -glucoronosylceramide (  -GalCer)
      • Gram negative, LPS negative bacteria
      • Sphingomonas species
      • Ehrlichia species
    • Phosphoinositolmannoside (PIM)
      • Mycobacteria
    • Leishmania glycoinositol phospholipids
    • Schistosome-derived glycoconjugate
    Terabe M et al. Adv.Canc.Res. 2008
  • iNKT Self-Antigen Recognition
    • Glycosylphosphatidyl inositols
    • Phosphotidyl choline
    • Phosphotidyl inositol from soybeans
    • Phospholipid from pollen  a role in allergy???
    • Glycosphingolipid isoglobotrihexosylceramide ( iGb3 )
    Terabe M et al. Adv.Canc.Res. 2008
  • Asthma and NKT Cells
    • Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity.
    • 1. AHR fails to develop
    • 2. inability to produce Th2 responses
    • 3. adoptive transfer reverses the failure of AHR development
    Akbari et al. Nat Med 2003
    • Invariant V alpha 14 NKT cells are required for allergen are required for allergen-induced airway inflammation and hyperreactivity in an experimental asthma model.
    • 1. impaired AHR
    • 2. adoptive transfer reconstitutes capacity to develop asthma
    • 3. anti-CD treatment
    Lisbonne et al. J.Immunol. 2003
  • iNKT Cells in the Induction of AHR
    • CD1d-/- mice fail to develop allergen-induced AHR
    • J  18-/- mice failed to develop AHR and showed reduced airway eosinophilia
    • Yet, allergen-specific Th2-driven responses still develop normally.
    Lisbonne et al. J.Immunol.2003 Akbari et al. Nat. Med. 2003
  • The Importance iNKT Cells in AHR Development
    • Anergized iNKT cell treatment prevent development of allergen-induced AHR
    • Direct activation of pulmonary iNKT cells were sufficient to induce AHR
    Matsuda et al. Am.J.Respir.Cell.Mol.Biol.2005 Hachem et al. Eur.J.Immunol.2005 Morishima et al. Eur.J.Immunol. 2005 Meyer et al. Proc.Natl.Acad.Sci. 2006
    • AHR develops in absence of conventional CD4+ T cells and adaptive immunity, eosinophils, B cells
    • iNKT may not be required in all forms of AHR
    •  2-microglobulin-/- mice develops AHR normally
    Meyer et al. Annu.Rev.Med. 2008 Maeda et al. J.Immunol. 2004 Zhang et al. J.Exp. Med. 1996
  • iNKT Cells in Human Asthma
    • Moderate-to-severe 14 persistent asthmatic patients, 5 stage II sarcoidosis, 6 healthy controls
    • Specimen: BALF
    • Staining of iNKT with CD1d tetramer loaded with  -GalCer and 6B11 mAb
    CD4+ Invariant T-Cell-Receptor+ Natural Killer T Cells in Bronchial Asthma Akbari O et al. NEJM. 2006
  •  
  •  
    • Staining of FITC 6B11 mAb
    Akbari O et al. NEJM. 2006
    • Red : phycoerythrin-conjugated CD4
    • Blue : FITC 6B11 mAb
    • Pink : Overlay
    Akbari O et al. NEJM. 2006
  • Corticosteroid-treated Corticosteroid-untreated Akbari O et al. NEJM. 2006
    • RT-PCR
    Akbari O et al. NEJM. 2006
    • One subgroup of iNKT cells is selectively recruited or expanded in lungs of bronchial asthmatic patients.
    Akbari O et al. NEJM. 2006
  • Akbari O et al. NEJM. 2006
  • iNKT Cells in Human Asthma
    • Specimen: peripheral V24 i NKT cells
    V alpha 24-invariant NKT cells from patients with allergic asthma express CCR9 at high frequency and induce Th2 bias of CD3+ T cells upon CD226 engagement Sen Y et al . J.Immunol. 2005
  • 87% Sen Y et al . J.Immunol. 2005
    • Highly increased frequency of asthmatic CCR9-expressing V24i NKT cells
    Sen Y et al . J.Immunol. 2005
  • CCR9 and V24 i NK T cell distribution Sen Y et al . J.Immunol. 2005
  • Asthmatic CCR9-expressing V24i NKT cells induced Th2 bias in CD3 T cells IL-4 IL-13 Sen Y et al . J.Immunol. 2005
  • IL-4 IL-13 Sen Y et al . J.Immunol. 2005
  • Confirm the function of different V24 i NKT cells IL-4 IL-13 Sen Y et al . J.Immunol. 2005
  • Transwell stimulations Sen Y et al . J.Immunol. 2005
  • CD226 expression in V24 i NKT cells Sen Y et al . J.Immunol. 2005
  • Sen Y et al . J.Immunol. 2005
  • CCR9 and CD226 activation Sen Y et al . J.Immunol. 2005
  • Sen Y et al . J.Immunol. 2005
  • Kay AB.NEJM. 2006 The Two Pathways
  • iNKT Cells in the Current Asthma Model Umetsu. Nature. 2006
  • iNKT Cells in Human Asthma
    • Five of the seven reports confirm that the lungs of asthmatic patients contain more iNKT cells than normal controls
    Spinozzi et al. Immmunol. Allergy Clin. North Am. 2007 Pham-Thi N et al. JACI. 2006 Pham-Thi N et al. NEJM. 2006 Hamzaoui A et al. Mediat. Inflamm. 2006 Sen Y et al. J. Immunol. 2005
    • The other two reports concluded that iNKT cells are not increased in asthma
    • Up to 2% of the T cells in the lungs of asthmatic patients are iNKT cells
    Thomas SY et al. NEJM. 2006 Vijayanad P et al. NEJM. 2007
    • A new report suggesting the number of pulmonary iNKT cells may not relate to asthma severity and control.
    • 5 severe, 8 well-controlled, 5 non-asthmatic patients
    • BALF analyzed by flow cytometry and stained with PBS57 and anti-CD3-Alexa750
    Natural killer T Cells in the lungs of patients with asthma Umetsu et al. JACI. 2009
  • Adjusted percentages of iNKT cells/Tcells
  • Asthma Phenotypes Mild-moderate asthma Persistent severe asthma Th2 cell iNKT cell iNKT cell
  • Therapeutic Potentials
    • Controversial
    • Glycolipid therapy
      • IV administration  shift towards Th1 cytokine response
      • Intranasal administration  induces Th2 polarization and worsens eosinophilic infiltration and induces AHR
    Oki and Miyake. Allergol.Internat. 2007
  • Thank You!