SIXTH INTERNATIONAL SYMPOSIUM ON STEM CELL THERAPY AND - PowerPoint PPT Presentation

Loading...

PPT – SIXTH INTERNATIONAL SYMPOSIUM ON STEM CELL THERAPY AND PowerPoint presentation | free to download - id: 695269-NmZiN



Loading


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation
Title:

SIXTH INTERNATIONAL SYMPOSIUM ON STEM CELL THERAPY AND

Description:

sixth international symposium on stem cell therapy and cardiovascular innovations madrid, april 23th-24th, 2009 is it time to use allogeneic stem cells? – PowerPoint PPT presentation

Number of Views:35
Avg rating:3.0/5.0
Slides: 56
Provided by: ReemAl
Learn more at: http://celltherapy.s3.amazonaws.com
Category:

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: SIXTH INTERNATIONAL SYMPOSIUM ON STEM CELL THERAPY AND


1
SIXTH INTERNATIONAL SYMPOSIUM ON STEM CELL
THERAPY AND CARDIOVASCULAR INNOVATIONS
Madrid, April 23th-24th, 2009
IS IT TIME TO USE ALLOGENEIC STEM CELLS?
AN IMMUNOLOGICAL PERSPECTIVE
Dominique CHARRON, MD-PhD (Dominique.Charron_at_sls.a
php.fr) Hôpital Saint Louis, IUH - INSERM U 940
CIB-HOG Université Paris Diderot
2
ALLOGENIC IMMUNITY I MOLECULAR BASIS
SYSTEM STRUCTURE POLYMORPHISM EXPRESSION Abs C OUTCOME
ABO CARBOHYDRATE RESIDUES GLYCOLIPIDS LIMITED ALL CELLS PREFORMED HYPER ACUTE REJECTION
MHC HLA SCLASS I CLASS II 3000 100 ALL CELLS APC ACTIVATED ENDO/EPITHELIA PRE T (Pregnancy/ Transfusion) POST T De novo - ACUTE REJECTION CHRONIC REJECTION
m H Ag PRESENTED By MHC VARIABLE Variable ? GVH
HLA
MICA
3
Nat.Rev.Cancer.2004. 4371-380
4
ALLOGENEIC IMMUNITY II CELLULAR RESPONSES
INDUCTION/TRIGGERING/ EFFECTOR PHASE (REJECTION)
Preexisting Allogeneic T Cells (CD8/CD4)
Immediate Response 1- 5 of Circulating T Cells
vslt 0.5 for Ag 2 pathways Direct Indirect
5
Allogeneic (Donor) Cell
MHC or other molecules are shed
taken up and processed by host APC
Tc Cytotoxic T-cell
Direct allorecognition
Th Helper T-cell
Host APC (recipient)
Pathways of allorecognition
Peptide derived from allo molecules presented on
host MHC to Host T-cells
Indirect allorecognition
6
IMMUNE RECOGNITION SELF VS NON SELF VS ALLO
SELECTION - MHC RESTRICTION - SELECTION -
SELF TOLERANCE
  • ALLO RECOGNITION ALLO RESPONSES
  • 5
  • ALLO CMH SELF X (Ag)

7
ALLOGENEIC SC ARE NOT IMMUNO PRIVILEGED !!!
THREE SUPPORTING PAPERS
  1. MHC EXPRESSION
  2. IMMUNOGENEICITY INCREASES UPON DIFFERENCIATION
  3. IN VIVO REJECTION

8
1
Characterization of the expression of MHC
proteins in human embryonic stem cells
Micha Drukker, Gil Katz, Achia Urbach, Maya
Schuldiner, Gal Markel, Joseph Itskovitz-Eldor,
Benjamin Reubinoff, Ofer Mandelboim, and Nissim
Benvenisty
PNAS, 2002, 999864
9
Expression of MHC proteins in undifferentiated
and differentiated human ES cells
10
IFN-g induction of MHC-I in human ES cells is
dose and time dependent
11
2
Embryonic Stem Cell Immunogenicity Increases Upon
Differentiation After Transplantation Into
Ischemic Myocardium Rutger-Jan Swijnenburg, MS
Masashi Tanaka, MD Hannes Vogel, MD Jeanette
Baker, PhD Theo Kofidis, MD Feny Gunawan, BS
Darren R. Lebl, MS Anthony D. Caffarelli, MD
Jorg L. de Bruin, MD Eugenia V. Fedoseyeva, PhD
Robert C. Robbins, MD
Circulation. 2005112I-166-I-172
12
Graft infiltration of immune cells after
transplantation of in vivo differentiated ESCs
13
3
Immunosuppressive therapy mitigates immunological
rejection of human embryonic stem cell
xenografts Rutger-Jan Swijnenburg, Sonja
Schrepfer, Johannes A. Govaert, Feng Cao, Katie
Ransohoff, Ahmad Y. Sheikh, Munif Haddad, Andrew
J. Connolly, Mark M. Davis, Robert C. Robbins,
and Joseph C. Wu
PNAS, 2008,10512991
14
In vivo visualization of hESC survival
15
MEDICAL CONSEQUENCES OF ALLORECOGNITION
16
(No Transcript)
17
HLA incompatibility (Ab 0)
18
Three-year graft survival rates (A) and frequency
of rejection treatment during first year (B) in
relation to number of HLA-A, -B, and -DR
mismatches in patients transplanted from 2000 to
2004. plt0.001
19
PRE IMPLANT Ab (TRANSFUSION/PREGNANCY)
Ab DETECTION CROSS MATCH
20
Terasaki et al. Predictive Value of HLA
Antibodies and Serum Creatinine in Chronic
Rejection Results of a 2-year Prospective
Trial Transplantation 200580 11941197
21
De Novo ANTI HLA ANTIBODIES ( CD 4d deposit)
DEVELOP AFTER RENAL TRANSPLANTATION
PROLONGED ABSENCE OF ANTIBODY CORRELATES WITH
GOOD FUNCTION WHILE 86 OF GRAFT FAILURE HAVE
ANTI HLA AND/OR MICA Abs
PROSPECTIVE STUDY HEART LUNG
22
1910 RENAL TRANSPLANTATION ANTIBODIES AGAINST
MICA ANTIGENS 217 (11.4)
1 YEAR ALLOGRAFT SURVIVAL
ALL CASES 88.3 vs 93 p0.01 FIRST
TRANSPLANT 87 vs 93.5 p0.005 WELL HLA
MATCHED 83.2 vs 95.1 p0.002
Zav et al. NEJM 357, 1293, 2008
23
HSCT
HLA MATCHED SIBLINGS GVHD 30 UP
PERFECT HLA MATCH OPTIMAL GENETIC MAKE UP
OUTCOMES
GENES
GVHD - REJECTION INFECTIONS TRM
RELAPSE SURVIVAL
HLA NON HLA MHC NON MHC
INTEGRATED GENETICS
ADAPTED TREATMENT
DONOR SELECTION
PREVENTION / PROPHYLAXIS
24
Unrelated BMT
Survival according to number of HLA disparities
11 (n48)
11-12 (n62)
12 (n14)
10 (n34)
6-10 (n59)
6-9 (n25)
25
Risk of of severe bacterial infections
HLA-E0101/0101 donor genotype
53?18 vs 25?12 PGray test 0.035
Risk of transplant-related mortality
HLA-E0101/0101 donor genotype
53?18 vs 27?14 PGray test 0.08
26
(No Transcript)
27
CYTOKINES - INFLAMMATION
ALLELES/GENOTYPE PHENOTYPE (LEVEL PRODUCTION) HSCT OUTCOMES
PROINFLAMMATORY IL6-174 G HIGH a GVHD c GVHD
TNF ? ---------------------------- ?, ?, R d 3 ------------------------------------ HIGH ------------------------------- - a GVHD (- mCB) --------------------------------- C GVHD
INT ? 2/2 3/3 HIGH LOW GVHD GVHD
ANTI INFLAMMATORY IL 10 PROMOTOR GCC ATA ACC HIGH INTERMEDIATE LOW a GVHD c GVHD SURVIVAL (- mCB)
TGF? promotor -509 codon 25 C/T - - HIGH 0 GVHD
28
HSCT INNATE IMMUNOGENETICS
Frequency/Severity of infectious (viral,
bacterial, fungal) events
Intricated with GVHD
TRM - Survival
INFECTIONS/GVHD TRM
GENES
GENOTYPES
  • MPO AG or AA (non CC)
  • MBL MBL2
  • Fc? RII a (CD 32) R 131
  • Fc? RIII b HNA-1a
  • TLR 4 -
  • NOD2/CARD 15 SNP 8, 12, 13
  • Oestrogen Receptor intron 1
  • Vitamin D Receptor intron 8
  • Fas - 670 G

29
STEM CELL/RECIPIENT COMPATIBILITY
PREDICTION ANTI- HLA/MIC A DETECTION
(quarterly), IDENTIFICATION CROSS MATCHING
PRE TRANSPLANT (FINAL TEST)
Best acheviable HLA A, B, DR, DQ,
Typing C, DP mandatory if antibodies present
Post transplantation FOLLOW UP
Donor specific Ab HLA - MIC
30
IMMUNOGENETIC MATCHING
STEM CELL BANKS
ABO COMPATIBILITY feasible
HLA COMPATIBILITY Level 1 Generic matching
(OT) Level 2 Intermediate matching
(CB) Level 3 Full matching (UD BMT) m Hag
COMPATIBILITY !!!
31
LOOKING FORWARD
  • IMMUNOGENETIC SELECTION

?
MATCHING - REDUCING MISMATCHING
  • STEM CELL BANKS
  • STEM CELL INGENEERING
  • INNOVATIVE IMMUNOSUPPRESSION/INDUCTION OF
    TOLERANCE

T CELLS COSTIMULATION BLOCKADE REGULATORY T
CELLS B CELLS IV Ig
CD 40 L BY ANTI CD 40 L B7 BY CTLA 4 Ig ANTI LFA1
CD 20 VELCADE
  • GENERATION OF MIXED CHIMERISM/ THYMIC INGENEERING
  • STANDARD CHRONIC IMMUNO SUPPRESSION
  • INFECTIONS/CANCER, AGENT SPECIFIC KIDNEY
    FAILURE, DIABETES, OSTEOPOROSIS,
    HYPERTENSION

32
THE STORY BOARD OF MEDICINE
PREDICTIVE MEDICINE
MYTH
ANTICIPATIVE
GENETICS/ PHARMACOGENETICS INDIVIDUALIZED
SUSCEPTIBILITY
GOD OF HEALING
1st HOSPITAL
PREVENTIVE MEDICINE
MEDICINE
HIPPOCRATES OF KOS
HOLISTIC
PUBLIC HEALTH INDIVIDUAL POPULATION
INTEGRATIVE
1st SCHOOL OF MEDICINE
EMPIRISM
ECONOMICS
SCIENCE
33
  • Immunogenicity and Allogenicity A Challenge of
    Stem Cell Therapy
  • Dominique Charron.Caroline Suberbielle-Boissel.Ree
    m Al-Daccak
  • J.of Cardiovasc.Trans.Res.2009,8- 9062-9

34
(No Transcript)
35
(No Transcript)
36
(No Transcript)
37
(No Transcript)
38
AGING OF HSC
39
Aging and HSC
  • Increased number of HSC with age in certain
    strains of mice
  • (Morrison et al 1996, Nature Med)
  • Increased number of HSC in cycle
  • (Rossi et al 2005, PNAS)
  • Expression of senescence marker (p16)
  • (Janzen et al 2006, Nature,)
  • Decreased reconstitution capacity - lymphoid
    compartment.
  • (Sudo et al 2000, JEM)
  • Intrinsic changes in the lymphoid potential of
    HSC ?

40
Quantitative in vitro analysis of HSC
differentiation potential
Old 18-24m
Young 1-2m

Bone marrow
CLP fraction
HSC fraction
(Lin-Sca1hicKithiIL7Ra-)
(Lin-Sca1locKitloIL7Ra)
Plate in 96 wells at limiting dilution
OP9 IL7
OP9 IL7
Facs sort wells
  • Frequency CD19 (B cells)
  • Frequency CD11b (Myeloid)

41
HSC decreased B but not myeloid potential with
age
Old
Young
Young
Old
42
Transduction of EBF and Pax5 in CLP from old mice
Young (1-2m)
Old (18-24m)
Isolate CLP Lin-IL-7RSca-1c-Kit
Transduction CONTEBF,Pax5
Measure B cell potential
In vitro differentiation OP9 IL-7, c-KitL, Flt3
Frequency of B cell clones (CD19)
43
EBF expression restores B cell potential of CLP
from old mice
IRES
CONT
LTR
LTR
P
GFP
B potential
Old
1/570
negative wells
OldEBF
1/43
1/18
Young
Number of cells / well
44
Pax5 expression restores B cell potential of CLP
from old mice
IRES
Pax5
LTR
LTR
P
GFP
Pax5
IRES
CONT
LTR
LTR
P
GFP
B Potential
Old
1/285
negative wells
OldPax5
1/41
1/9
Young
Number of cells / well
45
Conclusion
T/NK prgenitor
Aging
HSC
CLP
Pro-B
Pre-B
immature B cell
EBF Pax5
  • Intrinsic loss of B cell potential of HSC with
    age
  • Due to decreased expression of EBF and Pax5

46
IMMUNOSCENESCENCE
  • DECREASES LYMPHOPOEISIS
  • THYMIC INVOLUTION AND DECLINE IN T CELL
    FUNCTION
  • SUBSTANTIAL CHANGES IN AN B CELL COMPARTMENTS
  • AGE-RELATED HSC DEFECT ??

47
THE IMMUNE CLOCK
48
(No Transcript)
49
Nat.Rev.Cancer.2004. 4371-380
50
Fifth International Symposium on Stem Cell
Therapy and Applied Cardiovascular Biotechnology
MADRID, April 24th-25th, 2008
 IMMUNITY AND ALLOGENEICITY STEMCELLNESS
EDUCATION VS AND DIVERSITY 
Dominique CHARRON, MD-PhD (Dominique.Charron_at_sls.a
php.fr) Hôpital Saint Louis, IUH - INSERM U 662
CIB-HOG Université Paris Diderot
UNIVERSITE DE PARIS 7 DENIS DIDEROT
51
HSCT
HLA MATCHED SIBLINGS GVHD 30 UP
PERFECT HLA MATCH OPTIMAL GENETIC MAKE UP
OUTCOMES
GENES
GVHD - REJECTION INFECTIONS TRM
RELAPSE SURVIVAL
HLA NON HLA MHC NON MHC
INTEGRATED GENETICS
ADAPTED TREATMENT
DONOR SELECTION
PREVENTION / PROPHYLAXIS
52
Human HLA and non HLA Immunogenetics HLA HLA
Class I A B C Class II DRB 1, 3, 4,
5 DQA1/DQB1 DPB1 HLA E DMA/B MIC
A/B HLA Related systems
Minor Histocompatibility antigens CD1
a-e HY KIR/ NKR/ HSP 70 HA. 1.2.3
Cytokines
Chemokines Receptors TNFab IL1b IL6 IL10 IFN
? CCR5 CTL4 IL1 - R IL4 R IL4 IL1 R
antagonist Innate Immunity Toll
receptors TLR2, TLR4 E selectin/ICAM-1/PECAM
MBL MPO NOD2
IMMUNOGENETIC INDEX INDIVIDUALIZED
MEDICINE PREDICTION PREVENTION
53
HUMAN AGING
  • EXPONENTIAL INCREASE IN CANCER INCIDENCE WITH
    AGE

Tumor growth
  • GENETIC ALTERATION
  • IMMUNO SENESCENCE

Dissemination
  • INFECTIONS INCIDENCE SEVERITY

LESS RESPONSES TO VACCINES (30 to 50 of
individuals over 65 do not respond to flu vaccine)
INCREASE INCIDENCE OF AUTO IMMUNE DISEASES
54
Fifth International Symposium on Stem Cell
Therapy and Applied Cardiovascular Biotechnology
MADRID, April 24th-25th, 2008
 IMMUNITY AND ALLOGENEICITY  STEMCELLNESS -
EDUCATION VS DIVERSITY
Dominique CHARRON, MD-PhD (Dominique.Charron_at_sls.a
php.fr) Hôpital Saint Louis, IUH - INSERM U 662
CIB-HOG Université Paris Diderot
UNIVERSITE DE PARIS 7 DENIS DIDEROT
55
(No Transcript)
About PowerShow.com