Evolution of antidonor alloimmunity

1
Evolution of anti-donor alloimmunity following
transplantation - implications for CAN Maria
Hernandez-Fuentes Richard Baker Wan Fai Ng Osquel
Barroso-Herrera
2
Allorecognition the two pathways
Indirect allorecognition
Direct allorecognition
CD8
CD4
I
allo APC
CD8
CD4
Shed allogeneic MHC
IL-2
II
IL-2
Taken up and processed by auto APC
I
II
allo APC
Auto APC
3
HTLp IL-2
4
CD45RA (Naïve) and CD45RO (Memory) T cells have
different patterns of recirculation.
THYMUS
BLOODSTREAM
THORACIC DUCT
RA circuit
HEV
LYMPH NODE
tissue parenchymal cell
RO circuit
5
A significant drop in the anti-donor response is
only observed in the CD4CD45RO fraction.
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3rd party ratios close to unity mean that
immunosuppression has not significantly affected
the lymphocyte response as can be observed for
both fractions.
6
Mechanisms of peripheral tolerance
deletion
deletion
anergy
anergy
?
regulation
ignorance
7
Experimental Design
LDA
adherence
PBMC
on plastic
CD4 cells
Cocktails of mAb
1 hr
Followed by magnetic beads to remove non-CD4 cells
IL2 (30 U/ml) for 3 days
Wash and rest for 1 day
LDA
8
Donor-specific hyporesponsiveness was reversed in
5 out of 5 patients with IL-2
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C.S.
T.H.
J.W.
S.E.
J.B.
A.W.
D.T.
K.M.
P.K.
G.K.
M.M.
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9
Elevated frequencies of T cells with indirect
anti-donor allospecificity in patients with
chronic transplant rejection Vella et al, 97
Transplantation renal transplant
recipients Ciubotariu et al, 98 JCI heart
transplant recipients Hornick et al,
00 Circulation .. ..
.. SivaSai et al, 99 Transplantation lung
transplant recipients Baker et al,
2001 JI renal transplant recipients
10
1
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1/frequency
1
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C
A
N
C
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11
Direct pathway
Indirect pathway
Lymph Node
12
Mechanisms of peripheral tolerance
Evolution of anti-donor direct and indirect
alloresponses following transplantation using
conventional immunosuppression
Direct pathway - memory T cells
deletion
anergy
?
regulation
ignorance
Indirect pathway T cells - in some patients
13
Tolerant to A
B
The T cells that transfer tolerance appear to
have indirect allospecificity
CD4
A
B
Graft acceptance
14
Indirect recognition by helper T cells can
induce donor-specific cytotoxic T lymphocytes in
vivo RS Lee, . H Auchincloss Jr. J. Exp.
Med. 1994 179865
15
Donor parenchymal cells
Immature recipient DC
CD8
Unlinked help or suppression?
Mature recipient DC presenting donor MHC
indirectly
CD4
Lymph Node
16
Co-culture of MHC-mismatched DC leads to class I
and II exchange
17
MHC transfer between DCs can occur in the
absence of cell contact
18
Transferred MHCpeptide complexes are recognised
by T cells
19
DCs acquire MHC class I from g-IFN-treated ECs
20
MHC transfer between ECs and DCs is unidirectional
CFSE-labelled C57BL/6 DCs
21
DCs acquire MHC class I and II molecules in vivo
22
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25
Linking direct and indirect pathway T cells
Donor parenchymal cells
Immature recipient DC
Help or suppression
CD8
CD4
Mature recipient DC presenting donor MHC
directly and indirectly
Lymph Node
26
Conclusions Dendritic cells acquire MHC class
I and class II molecules from other DCs and from
ECs The acquired MHC molecules are recognised
by T cells MHC acquisition by DCs occurs in
vivo, as well as in vitro This raises the
possibility that direct alloresponses are
maintained after donor DCs are deleted
This phenomenon may provide a mechanism whereby T
cells with indirect allospecificity can help
or suppress T cells with direct anti-donor
allospecificity.
27
Speculation.. the acquisition of MHCpeptide
complexes by DCs trafficking through tissues
provides a failsafe mechanism to ensure the
presentation in lymphoid tissue of the viral
peptideMHC complexes that are most highly
represented in the infected tissue an
alternative to cross-priming.?
28
DC MHC acquisition as an alternative to
cross-priming
infected parenchymal cells
Immature recipient DC
Mature recipient DC presenting viral
peptideclass I complexes to CD8 T cells
Help
CD8
CD4
Lymph Node