9/30/2016 1 1 The ABC’s of HLA: Beginners to Advanced Rajalingam Raja, Ph.D, D(ABHI) Professor of Clinical Surgery Director of Immunogenetics and Transplantation Laboratory University of California, San Francisco Phone: 415-476-0647 Email: [email protected]2 HLA class I Cell HLA Antibody 23% In peripheral blood Cytotoxic T cell TCR CD8 Every cell expresses a HLA to present antigens to T lymphocytes Infection Perforine, Granzyme, Granulysin HLA class II APC Helper T cell TCR CD4 48% B cell BCR 11% IL2, IFN-γ 3 HLA is the Challenging Barrier to Transplantation HLA mismatched Allograft Recipient • Transplantation • Pregnancy • Transfusion Antibody Depletion Plasmaphoresis Antibody Blocking IVIG Anti-C5a Unacceptable Antigens HLA antibodies Plasma cell Rejection Lymphocytes T T T T T T T T T T T T T T T NK NK NK NK B B B B B B B B B NK NK NK NK NK NK NK NK Maintenance Therapy Immunosuppression Cyclosporine MMF Steroids Induction Therapy Lymphocytes Depletion Anti-Thymoglobulin → T & NK cells Anti-CD3 → T cells Anti-CD25 → Activated T cells Anti-CD52 → mature lymphocytes Anti-CD20 → B cells 4 Consequences of Pre-formed Donor-Specific HLA Antibodies • Hyperacute rejection • Delayed graft function • Accelerated acute rejection • Chronic rejection • Prolonged waiting times • No transplantation
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9/30/2016
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The ABC’s of HLA:Beginners to Advanced
�Rajalingam Raja, Ph.D, D(ABHI)�Professor of Clinical Surgery�Director of Immunogenetics and Transplantation Laboratory�University of California, San Francisco
• Increase priority for sensitized candidates/CPRA sliding scale
• Replace SCD/ECD with KDPI• Add longevity matching• Include pre ‐registration dialysis time• Incorporate A2/A2B to B• Base pediatric priority on KDPI• Remove payback system• Remove variances
• 100 Color-coded Polystyrene beads using a blend of different fluorescent intensities of two dyes• Each bead is conjugated with oligonucleotide probe specific for a HLA allele (s)
� Locus-specific (<Cw)� Allele-specific (<B44)� Tissue-specific (<neuronal tissue)� Cytokine-induced (IFN- γ)� Down regulation by viral infection
and tumor transformation.
HLA Expression Variation
50
Single Class I DSA MFI vs. T cell Crossmatch MCS
2000
50
51
Single Class II DSA MFI vs. B cell Crossmatch MCS
2000
120
0
50
100
150
200
250
300
350
400
450
500
0 5000 10000 15000 20000 25000 30000
MCS
MFI
DPB1DRB1DQB1DQA1DRB345
Few / well defined HLA-A,B,C, DR, DQB and/or DQAAntibodies only
- Typically >1000 MFI- CREG with any MFI
VXM- (DSA-)
HLA lab Protocol for Deceased Donor Kidney Transpla ntationHLA lab Protocol for Deceased Donor Kidney Transpla ntation
Single antigen bead HLA antibody identification (At least 2 sera are tested that are drawn within a year)Single antigen bead HLA antibody identification (At least 2 sera are tested that are drawn within a year)
HLA Antibodies Negative
HLA Antibodies Positive
None
VXM- (DSA-)
Unacceptable HLA Antigens
Crossmatch
All VXM are retrospectively confirmed by FXM
PXM - Call Lab/ Director PXM - Call Lab/ Director
Well defined antibodies and/or• DPβ, DPα Ab• Allele-specific Ab• Unstable Ab• Too many weak Ab
>2000 MFI
VXM FXM (pronase)
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Tray List ; quarterly sera
~900 Active Candidates• with total points of >7• all AB-blood group• consented for KDPI
>85%
Virtual XMcandidate Update
Unacceptable Antigens in UNet
Transplant
Antibody by Single HLA Beads
Physical XMcandidate
every 3 months
every 3 months
Waiting List (n=5416)
New Kidney Allocation System
New Candidate
HLA Typing
Antibodies by Single HLA Beads
& List Unacceptable Antigens;Receives points per CPRA
<20% CPRA
54
5.5%17.9%
31.7% 28.8%
61.2%37.6%
74.8%60% 62.5%
33%56.9%
7.3% 8.3% 8.7% 5.8%
0%
20%
40%
60%
80%
100%
CPRA 100%(n=209)
99%(n=80)
95-98%(n=120)
80-94%(n=151)
0-79%(n=1159)
% of
cand
idates
Re-Tx candidates with total points >7 (n=1719)
32.6% (n=560)
Male
Female
Re-
tx1
st-t
x
55
0
20
40
60
80
100
DRB DPDQ
CA
DR53
DR51
DR52 DRB DPDQ
CA
DR53
DR51
DR52 DRB DPDQ
CA
DR53
DR51
DR52 DRB DPDQ
CA
DR53
DR51
DR52 DRB DPDQ
CA
DR53
DR51
DR52
Antibody profile of candidates with total points >7 (n=1719)
% of
cand
idates
CPRA 100%(n=209)
99%(n=80)
95-98%(n=120)
80-94%(n=151)
0-79%(n=1159)
56
85.4%(n=108)
14.6%(n=44)
FXM
VXM
Most transplants are preformed using VXM approach in new KAS era
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0
10
20
30
40
50
60
70
80
90
Pre-KAS (1/1/2014 to 12/3/2014) n=235Post-KAS (12/4/2014 to 7/31/2015) n=152
CPRA 100%99%95-98%80-94%0-79%
% of
Tran
splan
tsPre- vs. Post-KAS: Transplant rate
58
59
99%n=60
100%n=202
98%n=49
80-97%n=276
20-79%n=939
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
1 3 5 7 9 110%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
1 3 5 7 9 110%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
1 3 5 7 9 11
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
1 3 5 7 9 110%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
1 3 5 7 9 11
CPRA
% F
requ
ency
of C
andi
date
s
Frequency of CREG Antibodies in Kidney waitlist can didates with different CPRA Groups
60
Most 100% CPRA candidates are sensitized to large number of HLA antigens
HLA Antibodies and Risks of Antibody-Mediated Rejec tion
Accelerated Rejection
HyperacuteRejection
Chronic Rejection
63
45
179
21
16
367
136
Living Donor 147Deceased Donor 220
(Wait list=5198)
9
Adult=69Pediatric=67
15
Number of Transplants Performed in UCSF in 2015 (n= 779)
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Waiting List
University of California San Francisco (UCSF)Kidney Transplant Program (7/1/2014-6/30/2015)
Transplants
95.1% (n=105,743) 98% (n=17,425)
2.0% (n=359)4.9% (n=5,198) UCSF
All other
centers
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CIBMTR monitoring of 1-year Overall Survival for First Allogeneic HCT (performed 2011-2013) suggests that, based on the complexity of the HCTs performed at UCSF:
Our predicted OS rate should be 78.9% (95% CI: 71.5-86.6%)
Our actual OS was 85.4% (N = 103)
UCSF Tops North America in Pediatric Hematopoietic Stem Cell Transplant Outcome
Slide: Christopher C. Dvorak
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Immunogenetics and Transplantation LaboratoryDepartment of Surgery, University of California, San Francisco