Upload
bennett-bertram-davidson
View
214
Download
0
Tags:
Embed Size (px)
Citation preview
Immune ToleranceImmune Tolerance
Kyeong Cheon JungDepartment of PathologySeoul National University College of Medicine
Immune tolerance
Unresponsiveness to an antigen that is induced by previous exposure to that antigen
Self tolerance: The normal lack of the ability to produce an immunological response to autologous (self) antigens.
Transplantation tolerance: the specific absence of a destructive immune response to a transplanted tissue in the absence of immunosuppression
Abbas: Cellular and Molecular Immunology 7E
Self tolerance Central tolerance
Negative selection Receptor editing Generation of regulatory
T cells
Peripheral tolerance Clonal anergy Clonal deletion Regulatory T cells T-T interaction
Abbas: Cellular and Molecular Immunology 7E
Thymocyte Development
Nat Immunol. 2006;7:338-334
Central tolerance of T cells
RegulaotryT cells
Negative selection: mTEC vs DCs
Trends Immunol 2002, 23:364-371
AIRE (Autoimmune Regulator)
A gene or its encoded protein, which functions to stimulate expression of peripheral tissue protein antigens in medullary thymic epithelial cells
AIRE & promiscuous gene expression
Trends Immunol. 2002, 23:364-71
AIRE & central Tolerance
Role of AIRE in self antigen presentation Induction of promiscuous gene expression Induction of antigen presentation
Role of AIRE+ mTEC Clonal deletion Treg induction
Role of DC Uptake & presentation of antigen from AIRE+
mTEC negative selection
Defect in AIRE gene
autoimmune polyendocrinopathy-candidiasis-ectodermaldystrophy (APECED), autoimmune polyglandular syndrome type 1 (APS-1)
AIRE knock-out mouse
Defect in central tolerance: Qualitative difference
Nat Med 2000, 6:56-61
B6
SJL
Thymus
Brain
EAE
Manifestation of APS-1
Clonal anergy: functional
unresponsiveness
Clonal deletion: cell death
Active suppression by regulatory T
cells
T-T interaction
Peripheral tolerance
T cell anergy in the absence of co-stimulatory signals
Costimulatory vs. inhibitory moleccules
B7-2 (CD86) : CD28 B7-1 (CD80) : CD28 CD40 : CD40L (CD154) ICOSL : ICOS CD70 : CD27 OX40L (CD134L) :
OX40 (CD134) 4-1BBL : 4-1BB
B7-2 : CTLA-4 B7-1 : CTLA-4 PD-L1, PD-L2: PD-1
Costimulation(APC : T cell)
Inhibition(APC : T cell)
Circ Res. 2008, 103:1220-1231
CTLA-4/B7 vs. CD28/B7 Interaction
Immunity, 1997, 7: 445-450
Immune dysregulation in humansubjects with heterozygous mutations in CTLA4
Science, 2014, 345: 1623-1627
Development of abatacept & belatacept
J Allergy Clin Immunol 2008, 121:299
PD-1–PD-L pathway contributes directly to T cell dysfunction during chronic viral infection
Nat Immunol 2007, 8:239
PD-L1 KO mice infected with chronic form of virus
Nature 2006, 439:682-687
PD-1–PD-L pathway in peripheral tolerance
Am J Transplant. 2012;12:2575-87
PD-1 signaling
Immunol Rev 2010; 236:219-242
Autoimmunity vs. anti-cancer immunity Anti-CTLA-4: Ipilimumab Anti-PD-1: Pembrozumab
http://melanomamissionary.blogspot.com
Adverse Events in Patients Receiving Anti–PD-L1 Antibody
N Eng J Med 2012, 266:2455-2465
Vitiligo caused by anti-CTLA-4 antibody therapy
http://www.ascopost.com/issues/october-15,-2013/how-to-recognize-and-manage-ipilimumab-induced-dermatologic-adverse-events.aspx
Activation induced cell death (AICD)
Regulatory T cells: Subsets nTreg iTreg Tr1
Th3
PhenotypeCD25 ++ - + +CD103 - ++ - -GITR ++ ++ - ?CTLA-4 +++ +++ + ++Foxp3 ++ ++ -/+ -
Cytokine secretionIL-10 +/- ++ +++ +TGF- + + +++
Differentiation factors TGF-, RA IL-10, IFN- TGF-, IL-4Suppression mechanism
In vitro Diverse Diverse IL-10, TGF- TGF-In vivo Diverse Diverse IL-10, TGF- TGF-
Modidifed from J Leukoc Biol. 2006, 80:458-470 & J Immunol 2003, 171:6323-6327
Yan Xing, and Kristin A. Hogquist Cold Spring Harb Perspect Biol 2012;4:a006957©2012 by Cold Spring Harbor Laboratory Press
Differential TCR signalling in negative selection and Treg cell differentiation
Basic mechanisms used by Treg cells
Nat Rev Immunol. 2008, 8:523-532
*IDO, indoleamine 2,3-dioxygenase
Induction of iTreg by cytokines
TCR stimulation + IL-2 + TGF- iTreg
Retinoic acid TGF- + IL-6 Th17 TGF- + RA Treg CD103+ DC in gut: retinal dehydrogenase RA
Treg (J Exp Med 2007, 204:1757-1764)
Treg deficientyFoxp3 Mutation
Foxp3 mutation In human: IPEX (Immune dysregulation,
polyendocrinopathy, enteropathy, X-linked syndrome)
Mouse: Scurfy mutant
IL-2/IL-2R deficiency
TGF deficiency
Immune regulation by T-T interaction Idiotype-anti-idiotype
network TCR peptide presentation via MHC I
or II molecules Immune suppression by anti-
idiotype T cells
Ergotype-anti-ergotype network CD25 or HSP60 peptide presentation
by MHC class I or II molecules
Immune suppression by anti-ergotypic T cells
Induced tolerance
Front Immunol. 2012;3:274
Arrest of DC maturation in semimature stage via MD-3 Ab treatment- in vitro surface molecules -
Arrest of DC maturation in semimature stage via MD-3 Ab treatment - in vitro cytokine secretion -
Prolongation of porcine islet xenograft survival in humanize mice via MD-3 treatment
ControlAb
MD-3
H&E Insulin CD3 CD68D
Lack of immune cell infiltration in islet xenograft of MD-3-treated group
Long-term survival of islet xenograft in Rhesus monkeys via combined therapy
0 100 200 300 400 500 6000
200
400
600
0
1
2
3
4
5
6Blood glucose level
100
Porcine C-peptide
0.4
6.4
3.7
1.23
Time (day)
Blo
od
glu
co
se
le
ve
ls (
mg
/dl)
Po
rcin
e c
-pe
p(n
g/m
l)
Self tolerance Central tolerance
Negative selection Receptor editing Generation of regulatory T cells
Peripheral tolerance Clonal anergy Clonal deletion Regulatory T cells T-T interaction
Abbas: Cellular and Molecular Immunology 7E