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1
Transplantation
Differences in MHC lead to graft rejection.
Allogenic MHC activates 1-10 T cells in
recipient.
DC from donor
MHCb
T cells from recipient selected by MHCk
1-10 T cells activated
2
Mixed lymphocyte reaction
2 MHC-II difference
1 MHC-II difference
No MHC-II difference
DC with allogenic MHC-II (stimulator)
CD4 T cells (responder)
Proliferation of CD4 T cells
3
Rejection of solid tissue
Perforin/granzyme
Destruction of graft
graft
CTL
TCR/CD8
MHC-I
Injury induces inflammation and activation of
donor DCs
CTL
FasL
Th1
IFN-?
inflammation
TNF-?
Th1
CD4 T
MHC-II
TCR/CD4
Activation of recipient T cells
CD8 T
FasL
inflammation
Lymph node
TNF-?
NO
Lytic enzymes
4
Graft versus host disease (GVHD) in bone marrow
transplant
The hematopoietic system of recipients
depleted. No rejection of donor BM.
Donor bone marrow
HSC
Depletion of T cells by anti-CD3 antibody
Contaminating T cells
Immuosuppression drugs (cyclosporine A)
Bone marrow
Activation
Recipient cells with allogenic MHC
thymus
Attack host cells inflammation
HSC-derived T cells tolerant for recipient MHC
and antigens.
5
Both CD4 and CD8 T cells contribute to graft
rejection.
MHC typing
6
Mixed Lymphocyte Reaction (MLR)
The chance of complete MHC matching is 1/4 among
siblings.
7
Treatment of SCID patients with bone marrow
transplant
T-cell depletion of donor bone marrow is needed
to avoid GVHD.
132 patients (newborn to 21 months) received
HLA-haploidentical or HLA-identical
transplant. 102 (77) survival
1 year 96
Median 5.4 years
5 years 68
10 or more years 37
8
Gene therapy for SCID-X1 (gc deficiency)
10 patients (P1-10)
Bone marrow
Replication deficient retrovirus containing
normal ?c gene
CD34 HSC (?c-)
CD34 HSC (?c)
Patients HSC
?c gene
Viral DNA integrated into host chromosomes
9
Reconstitution of lymphocytes and serum antibodies
11 months
8 months
Normal antibody production
T cells respond to PHA and anti-CD3 stimulation
10
Nine out of ten treated patients developed
adaptive immune system.
Months after gene therapy
P4 and P5 developed T cell leukemia.
Leukemia cells in blood
Treatment for T-acute lymphoblastic leukemia
(T-ALL)
11
Clonal expansion of T cell
Immunoscope analysis of TCR diversity
P5 3 clones of ?? T cells expanded
P4 Vg9Vd1 T cell clone expansion
Length of CDR3 in V?
Length of CDR3 in V?1
12
Leukemia is caused by insertional mutagenesis.
Viral DNA integrated randomly into the genome
(one integration/cell).
Clonal expansion into leukemia
RNA FISH
LMO2
E2
E3
E1
?c
Insertion of the viral promoter activated the
LMO2 gene and led to T-ALL.
viral transcription elements
?c transcript
LMO2 transcript
13
Regulation of Immune Response
Mutation in Fas (CD95) leads to Autoimmune
Lymphoproliferative Syndrome (ALPS).
Similar phenotype in Fas deficient mice (lpr) and
FasL deficient mice (gld)
14
Patients have large number of lymphocytes in
blood. Abnormally large percentage of CD4-8- T
cells. Elevated levels of IgG and IgA.
15
Th1 cells and CTL
FasL
Fas
Activated T and B cells
FADD
Caspase-8
Apoptosis
Fas-induced apoptosis eliminates self-reactive T
and B cells (peripheral tolerance).
T
T
activation
Self antigen
T
Activated T cells express FasL
B
Activated T and B cells express Fas .
T
B
T
B
Self-reactive T and B cells
Self-reactive T cells kill self-reactive B cells
and other self-reactive T cells.
B
FasL is expressed in eye and testis to prevent
autoimmunity.
16
IPEX (immune dysregulation, polyendocrinopathy,
enteropathy, X-linked syndrome).
IPEX patients are deficient in FOXP3.
17
FoxP3 is required for the generation of
Regulatory T cells (Treg).
Treg CD25, FoxP3
5-10 of CD4 T cells in the periphery
LN
Scurfy (sf) mice are deficient in FoxP3 and Treg
cells.
Lymphproliferative disorder of sf mice can be
corrected by transfer of Treg from WT mice.
T cell
Treg cells suppress the activation of
conventional T cells.
T cell Treg
18
Treg are selected by self-antigens in the thymus.
FoxP3
FoxP3-
Thymus
Self-antigen
Central tolerance
Positively selected by self-antigen
mTEC
Treg
No self-reactivity
Negative selection against self-reactivity
Self-reactive T cells escape negative selection
Secondary lymphoid tissues Peripheral tissues
after activation
Treg
Immunity
Peripheral tolerance
autoimmunity
19
Treg maturation and function require IL-2.
Mice deficient in IL-2, IL-2R?, IL-2R? develop
lymphoproliferative disease and autoimmunity.
LN of IL-2R?/ or -/- mice?
CD25
Cell size
Activation marker
Self antigen
suppression
Treg
Self-reactive T cells
IL-2
20
Suppression mechanism of Treg
Model-1
Treg constitutively express CTLA-4.
CTLA-4 to B7 signaling induces IDO (indolamine
2,3-dioxygenase) in DC.
CTLA-4
B7
Treg
IDO degrades Trptophan, and inhibits T cell
activation by DC.
TCR
DC
Self Ag
Self Ag/MHC
Self-reactive T cell
TCR
Model-2
Treg
TCR
CTLA-4
Self Ag
DC
B7
Activated T cells express B7. CTLA-4 sends
negative signal through B7.
TCR
Self Ag
21
Treg may be used to prevent graft rejection.
Donor cells
Recipient
Isolate Treg
Treg
IL-2
Treg specific for donor antigens
Activation and expansion of Treg specific for
donor antigens.
Donor
Treg specific for donor antigens
transplantation
T cells
Treg inhibit T cell-mediated rejection.
Graft-specific tolerance without
affecting immunity to other antigens.
22
Treg may suppress autoimmunity.
NOD mice Nonobese diabetic mice (Model of type I
diabetes)
NOD mice
TCR transgenic for islet ? cell antigen
Treg specific for autoantigen of islet ? cells
CD4CD25- T cells (containing T cells
specific for islet ? cell autoantigen)
DC presenting autoantigen
IL-2
Expansion of Treg against autoantigen
NOD/scid mice
23
IL23 and Th17 in autoimmune diseases
IL-12p35
IL-12p40
IL-23p19
MOG(myelin oligodendrocyte glycoprotein) CFA
(complete Freunds Adjuvant)
IL-12
IL-23
p35-/-
WT
mouse
p19/-
p19-/-, p40-/-
EAE
IL-23
Autoimmune encephalomyelitis (mouse model of
multiple sclerosis)
T cell-mediated inflammation of central nerves
system
Spinal cord staining for CD11b (monocyte marker)
24
IL-23 is involved in autoimmune joint
inflammation.
Collagen CFA (complete Freunds Adjuvant)
mouse
EAE
Autoimmune joint inflammation (mouse model of
rheumatoid arthritis)
T cell-mediated inflammation of joint
Normal joint
Joint inflammation with cartilage erosion.
25
IL-23 contributes to inflammatory bowel disease
(IBD)
IL-10-/-, IL-23-/-
IL-23 deficiency prevents IBD in IL-10 deficient
mice.
IL-10-/-
IL-10 deficient mice develop IBD.
26
IL-23, IL-6, and TGF-? are involved in Th17
development.
Defense against bacteria, fungi, virus
Th1
Autoimmunity Defense against bacteria
IL-12, IFN-?
C. rodentium K. pneumoniae
IL-23
TGF-?, IL-6
Th17
Th17
expansion
commitment
Naïve T cell
IL-4
Th2
Defense against helminth parasite Allergy
IL-23 contributes to defense against C.
rodentium infection in intestine.
27
IFN-? and IL-4 inhibit Th17 differentiation.
IL-23 anti-IL-4 anti-IFN-?
IL-23 anti-IFN-?
IL-23 IL-4 anti-IFN-?
IL-23 anti-IFN-?
IL-6 and TGF-? induce Th17 differentiation.
IL-17
CD4
28
ROR?t is important for Th17 differentiation.
ROR?t is an orphan nuclear receptor expressed in
Th17 cells in intestine lamina propria.
T-bet
GATA-3
29
Increases in autoimmune disease and allergy
correlate with reduction in infectious diseases.
30
Questions
Why does Fas deficiency cause lymphoproliferative
disease?
What is the marker for Treg? How is Treg
generated? What is the function of Treg?
Which cytokines induce the differentiation of
Th17 cells?
What is the relationship between Th17 and Th1,
Th2 cells?
How is Th17 cell implicated in autoimmune
diseases?
Relevant parts in textbook
p406-413