Transcript Document

Clinical Differences
Between
Anti-HLA and
Anti-ABO Antibodies
In Renal
Transplantation
The 7th Banff
Conference on
Allograft Pathology
Millie Samaniego, MD
Johns Hopkins
School of Medicine
Controversies In Transplant
Immunology
• Humoral theory of
graft rejection
• Cellular theory
of graft rejection
Sir Peter Medawar (1915-1987)
MH Sayeh and LA Turka. N Engl J Med 1998; 338(25):1813-21
REMAINING BARRIERS TO
RENAL TRANSPLANTATION
Waiting Time (days)
Nearly 30% of the
52,000 patients on the
kidney waiting list are
sensitized due to
previous transplant,
blood transfusion, or
pregnancy.
2500
2000
>79
1500
1000
20-79
500
<20
0
PRA
MHC MOLECULES
HLA-A20201 with bound peptide
1-chain
2-chain
2m
3-chain
REMAINING BARRIERS TO
RENAL TRANSPLANTATION
There is a 35% chance that any 2
individuals will be ABO incompatible:
•1/3 of potential live donors are
excluded immediately due to ABO
incompatibility.
ABO GROUP ANTIGENS
G
are
Q rap
uickTi
needed
hics
m e™
deco
toand
se
mpresso
eathis pi
r cture.
C ad ave r d o n o rs
P ts in W aitin g L ist
100 000
100 000
100 00
100 00
100 0
100 0
100
100
10
10
1
O
C ad ave r
d o n o rs
260 2
P ts in W aitin g 251 22
L ist
A
B
AB
207 9
618
189
132 81
818 3
124 5
Source: OPTN/SRTR DATA as of August 1, 2001
LAG BETWEEN CLINICAL
AND BENCH RESEARCH
• Characterization of the ‘humoral” response to
transplantation antigens:
– Targets of antibody response:
• HLA versus Non-HLA antigens (ABO,
polymorphic tissue antigens, endothelial cell
antigens)
– Animal models
• Which is/are the effector (s) of injury: Antibody
or the Complement System?
• Poor understanding of the role of the B-cell in
rejection:
– APC, Effector, co-stimulator?
Immunomodulation and
Accommodation
in Kidneys Transplanted
Across
Donor Specific HLA Antibodies
and ABO Incompatibility
MD Samaniego, AA Zachary, KE King,
L Racusen, M Haas, RA Montgomery
Johns Hopkins University
INCLUSION CRITERIA AND
END-POINTS
• PRE-EMPTIVE PROTOCOL:
– Positive Donor specific X-match before Tx.
– Identification of donor-specific anti-HLA Ab pre-Tx.
• End-point:
Negative Donor specific X-match before Tx.
• RESCUE PROTOCOL:
– Histologic and immunofluorescent features of
humoral rejection.
– Identification of donor-specific anti-HLA Ab postTx.
• End-point:
Biopsy-proven resolution of rejection
Elimination of donor-specific anti-HLA Ab
PP/CMV-IVIg Protocol
• Plasmapheresis:
– Delivered via COBE Spectra cell
separator.
– Removal of 1 plasma volume, replaced
with albumin or FFP.
– Given QOD until endpoint:
• Pre-emptive group = Neg cytotoxic donor-specific X-match
• Rescue = Elimination of DSA
PP/CMV-IVIg Protocol
• CMV Hyperimmune globulin:
–Infusion followed each
plasmapheresis
–Each patient received 100
mg/kg/dose
PP/CMV-IVIg Protocol
Immunosuppression:
• Rescue Group:
• Pre-Emptive Group:
– Methylprednisolone pulse
(500 mg/d x 3 days)
–
Steroid taper
–
–
FK506 – trough 10-15 ng/ml
MMF – 2g/d
– At 1st PP/CMV-IVIg session
• FK506 – trough 10-15 ng/ml
• MMF – 2g/d
– At time of Transplant
• Daclizumab x 5 doses
• Methylprednisolone pulse
(500 mg/d x 3 days)
• Steroid taper
CLINICAL OUTCOMES:
PRE-EMPTIVE PP/CMV-Ig THERAPY
FOR A POSITIVE CROSSMATCH
PATIENT
CHARACTERISTICS
# of Patients
MEDIAN AGE (RANGE)
46
45 (20-69)
ALLOGRAFT
PERFORMANCE
Acute Rejection
(+) AHG at the time of
Tx
28/46
10/46
20/46
9 days
Previous
Transplants
21
ANTIBODY-MEDIATED
REJECTION
Median time to rejection
PRE-TRANSPLANT
PP/CMV-Ig
TREATMENTS ()
4.7
MEAN CURRENT
SERUM Cr (mg/dl)
1.3 + 0.7
MEDIAN FOLLOW-UP
TIME
14 mos
(1 – 60)
POST-TRANSPLANT
PP/CMV-Ig
TREATMENTS ()
2.3
(4.3 for Rx)
* 6 graft losses: 1 noncompliance; 1 pt death due to sepsis;
1 pt death due to biopsy complication; 1 recurrent disease; 2 AMRx
CLINICAL OUTCOMES:
AMRx RESCUE USING PP/CMV-Ig
PATIENT
CHARACTERISTICS
# of Patients
AGE (RANGE)
33
49 (13-67)
ALLOGRAFT PERFORMANCE
AMR IN DAYS POST-TX
DAYS
(RANGE)
9 (2-750)
6.0 + 3.4
LIVE / CADAVERIC
DONOR
11 / 24
SCr AT TIME OF AMR
(mg/dl±SD)
DSA Identified
Class I/Class II
26
15/11
MEAN F/U TIME
(Mos)
28.8
MEDIAN #
PP/CMV-IG
TREATMENTS
6.5 (2-50)
MEAN CURRENT SCr
(mg/dl±SD)
1.9 + 1.0
* 8 graft losses: 2 recurrent Dz, 2 chronic rejection, 2 death with normal renal Fx,
1 surgical complication, 1 with recalcitrant AMRx
Risk Factors
Previous Tx
Repeat Mismatches
No. Tx
No. Pts
No. mm
No. Pts
0
29
0
39
1
14
1
5
>1
7
>1
5
CM
or
HW
10
Antibody Present Present at Developed
Strength Before Tx
Tx
After Tx
Total
CDC+
14
8
1
14
FCXM+
29
21
5
34
Impact on HLA-Specific
Antibodies
Antibody Specificity
time of
evaluation
Donor HLA
eliminated
end of
treatment
follow-up
31 (63%)
34 (89%)
persistent
18
4
3rd Party HLA
eliminated
11 (27%)
6 (19%)
persistent
30
2=11.9
P<0.001
26
2=35.5
P<0.0001
Of the 49 patients:
 3 graft losses: 2 to rejection, 1 to Bx-related incident
 1 patient died with functioning graft, 3 years post-Tx
 1 year graft survival ~91%
ELISA vs C4d Staining
C4d+Ab+
C4d+Ab-
C4d-Ab+
C4d-Ab-
30
7
7
13
4 ABO incompatible
3 DSA+ 1 week earlier
CONCLUSIONS-1
Anti-HLA Antibodies:
Donor specific unresponsiveness
•Anti-HLA DSA remains undetectable in
all patients treated pre-emptively with
PP/IVIG for a (+) Xmatch and in 28 of 33
patients in the rescue protocol
•3rd party anti-HLA Ab often returns
ABOI-TRANSPLANT PROTOCOL
End-point: Isoagglutinin titer  1:16 by AHG
• Plasmapheresis
• CMV-IVIg 100 mg/Kg after plasmapheresis
• Pre-Tx splenectomy
• Immunosuppression:
– Daclizumab x 5 doses
– Methylprednisolone pulse (500 mg/d x 3 days)
– Steroid taper
– FK506 – trough 10-15 ng/ml
– MMF – 2g/d
Characteristics of ABOI Kidney
Transplant Recipients
PT
Donor
ABO
Recip
ABO
Starting
titer
Titer
at Tx
Current
titer
Current
Scr
(mg/dl)
F/U
(mos)
1
A2B
B
1:32
1:4
1:16
1.2
45
2
3
4
5
6
7
8
A2
A2
A1
A1
A1
A1
A1
B
O
O
O
O
O
O
1:256
1:8
1:64
1:256 1:8 1:32
1:1024 1:16 1:16
1:128 1:16 1:32
1:128 1:8
1:8
1:256 1:16 1:8
1:256 1:4
1:8
1.0
1.4
1.2
1.2
1.4
1.0
0.9
39
25
16
14
12
NA
2.5
ABO Incompatible Transplants
With Rituximab in lieu of Splenectomy
PT
Donor
ABO
Recip
ABO
Starting
titer
Titer at Current
Tx
titer
Current
Scr
(mg/dl)
F/U
(mos)
1
B
O
1:64 1:16
1:4
1.4
3
2
A2
O
1:128 1:4
1:8
1.1
2.5
3
A2
B
1:16
1:2
1:2
1.0
2
4
AB
A
1:32
1:8
1:2
1.4
1
Blood Group Antigen Expression
on ABOI Transplanted Kidneys
Pre-Tx
Post-Tx
1 Week
1 Month
H&E
Anti-A1
No decrease in blood group antigen staining has been observed in
any sections examined thus far, suggesting that decreased antigen
expression on the donor kidney does not explain accommodation.
CONCLUSIONS-2
• ABO Isoagglutinins:
Accommodation
• Isoagglutinin titers rebound after
cessation of PP/IVIG but this does
not appear to have consequences
for the graft
•C4d+ staining is not indicative of
rejection unless other features are
present
SPEAKER OBJECTIVES
• To recognize that antibody responses to HLA and
ABO molecules are qualitatively different
• To recognize that early graft acceptance in
patients with preformed HLA usually requires
elimination of DSA
• To recognize that in ABOI transplants low levels
on ABO isoagglutinins may facilitate engraftment
• A regimen of plasmapheresis, IVIg and anti-B
cells monoclonal antibodies enables renal
transplantation across a DSA or ABO
incompatibility barrier
ACKNOWLEDGEMENTS
• INKT PROGRAM
–
–
–
–
Bob Montgomery
Andrea Zachary
Matt Cooper
Karen King
• Renal Pathology
– Lorraine Racusen
– Mark Haas
• Baldwin Laboratory
– Wink Baldwin
– Barbara Wasowska
• RIST Investigators
–
–
–
–
Yolanda Becker
Nina Tolkoff-Rubin
Mark Pescovitz
Gonzalo GonzalezStawinski