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Highly sensitized patients
• Highly sensitized patients: antibodies against the HLA antigens of more than 85% of the panel.
• Difficult to transplant because cross-match with most donors is positive.
• Obvious solution: HLA identical or compatible donor but only available for a small proportion of the patients.
How to find a suitable donor for these patients?
3
Approaches to enhance transplantation of highly sensitized patients
• Do not accept that the patient is sensitized and try to remove the antibodies by:
* plasmapheresis * intravenous immunoglobulins (IVIg) * anti-CD20 antibodies
• Accept that the patient is sensitized and try to stimulate the allocation of cross-match negative donor kidneys to these patients.
4
Eurotransplant Kidney Allocation System.
Point system based on different parameters:
• HLA match
• Match prognostic index (extra points for sensitized patients)
• Waiting time
• Regional donor (cold ischemia time)
• Country balance.
Still a low chance for a higly sensitized patient to be transplanted.
0102030405060708090
100
0 3 6 9 12 15 18 21 24
ET-KAS
% patients transplanted
Waiting time (months)
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Need for an acceptable mismatch program
• Policy in Eurotransplant is the registration of the non-
acceptable HLA mismatches for sensitized patients to
prevent selection of donors with HLA mismatches
towards which the patient has preformed antibodies.
• Problem: it is impossible to determine all antibody
specificities in highly sensitized patients
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Acceptable Mismatch Program
• Basis: definition of those HLA antigens toward which the
patient did never form antibodies and use this knowledge
for donor selection.
• Original method: look at HLA type of negative panel
donors in screening and extensive antibody screening
against a patient specific panel (donors with a single HLA-A
or –B mismatch), taking advantage of a pool of 20,000 HLA
typed blood donors.
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Antibody screening
• Serum of patient (HLA: A1, A2, B7, B8) is tested against a panel of
HLA typed blood donors.
positive
negative
PRA is 92%
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Antibody screening
• Serum of patient (HLA: A1, A2, B7, B8) is tested against a panel of
HLA typed blood donors.
positive
negative
PRA is 92%
HLA type: A1, A24, B7, B8 acceptable mismatch is A24
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Non-inherited maternal HLA antigens are often acceptable mismatches.
NIMA NIPA
Antibodies 46 72
A.M 43 6
P< 0.001
Analysis of sera from highly sensitized patients
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Very difficult patients
• AM are difficult to determine for highly immunized
patients with rare HLA phenotypes.
• For these patients no suitable blood donors are available
to determine acceptable mismatches or cross-matches
with the few available donors are positive.
• Main problem: most target cells express several
mismatched HLA antigens.
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A1
A2
B7
B8
Cw3
Cw6
Difficult to identify acceptable mismatches
Is HLA-A2 an acceptable mismatch?
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SALs validated and shown to be useful for determination of acceptable mismatches.
HLA-A HLA-B HLA-C
A*0101 B*0702 B*4403 Cw*0102
A*0201 B*1402 B*4501 Cw*0303
A*0301 B* 1501 B*4601 Cw*0304
A*1101 B*2705 B*4901 Cw*0401
A*2402 B*3501 B*5501 Cw*0602
A*2601 B*3801 Cw*0801
A*3101 B*3901 Cw*1202
A*3201 B*4001 Cw*1402
A*3303 B*4002 Cw*1502
A*6901 B*4402
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Alternative approach
• Commercial assays including the use of single antigen beads
(Luminex) although the conformation of these molecules may be
different than that of membrane bound HLA molecules.
HLA-A1
HLA-A2
HLA-A3
HLA-B7
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Definition of acceptable mismatches is difficult and is often based on trial and error because our interpretation of the humoral immune
response to HLA is too simple.
HLA-A1 HLA-A2
anti-HLA-A2
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HLA-A2
HLA-B44HLA-B51HLA-B35
HLA-A68 HLA-B27
Many polymorphic sites, some of them shared between HLA alleles.
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Polymorphic Residues on B51
Structural Immunogenicity of HLA-B51
This polymorphism should be considered in the context of self HLA
epitopes of the antibody producer
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ForA2,A68;B27,B44
ForA2,A68;B35,B44
Polymorphic Residues on B51
Structural Immunogenicity of HLA-B51
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ForA2,A68;B27,B44
ForA2,A24;B7,B8
ForA2,A68;B35,B44
Polymorphic Residues on B51
Structural Immunogenicity of HLA-B51
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HLAMatchmaker is based on this principle a computer algorithm developed by Rena computer algorithm developed by René Duquesnoyé Duquesnoy
Donor HLA-A,B mismatches are defined byDonor HLA-A,B mismatches are defined by triplets of amino acid residues (epitopes) on antibodytriplets of amino acid residues (epitopes) on antibody
accessible sites of HLA moleculesaccessible sites of HLA molecules
HLA-A1
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HLA matching at the triplet level
Donor m.m B18
Patient: B7
Immune system of the recipient recognizes:
A single HLA mismatch or 11 triplet mismatches
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HLA matching at the triplet level
Donor m.m
B18
Patient: B7
B52
A33
.
Immune system of the recipient recognizes:
No triplet mismatches!
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No foreign antibody epitopes on HLA-B18 mismatch for patient, with HLA type HLA-A33, B51, B7.
2M
1
23
2
1
peptide
Top view Side view
27
The number of triplet mismatches predicts HLA antibody production after renal allograft rejection
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708090
100
0 1 2 3 4 5 6 7 8 9 10 11 12 triplet mismatches
% of patients with donor specific HLA antibodies
Dankers et al. 2005
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Validation of HLA matchmaker for the identification of acceptable mismatches in highly sensitized patients.
Mismatch HLA-A HLA-B
tested AM tested AM
zero-triplet 18 18 54 54
CDC cross-matches confirm theoretical approach
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Additional value of HLAMatchmaker
Also HLA antigens with triplet differences can be identified as
acceptable mismatches. This information can be used for
identification of additional acceptable mismatches.
Self-triplet mismatches on basis of own HLA type
A1
A2
B7
B8
30
Additional value of HLAMatchmaker
Also HLA antigens with triplet differences can be identified as
acceptable mismatches. This information can be used for
identification of additional acceptable mismatches.
More self-triplet mismatches on basis of combination of acceptable mismatches and own HLA type:
Consequence: more acceptable mismatches can be found
A1
A2
B7
B8
AM: A3
AM: B14
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Donor selection on basis of acceptable mismatches.
Patient: A24, A31, B27, B51, DR4 (highly sensitized)
AM: A25, A26, B44
Suitable donors: A25, A31; B27, B51; DR4A26, A31; B27, B51; DR4A24, A25; B27, B51; DR4
A24, A26; B27, B51; DR4A24, A31; B44, B51; DR4A24, A31; B27, B44; DR4A25, A31; B44, B51; DR4A26, A31; B44, B51; DR4A25, A31; B27, B44; DR4A26, A31; B27, B44; DR4A24, A25; B44, B51; DR4A24, A26; B44, B51; DR4 etc.
If such donor becomes available within Eurotransplant: mandatory shipment of the kidney to this highly sensitized patient
32
Conclusions:
0102030405060708090
100
0 3 6 9 12 15 18 21 24
AM
ET-KAS
HLAMatchmaker is of benefit for the identification of acceptable
mismatches for highly sensitized patients.
• Increased chance to be transplanted:
• Excellent graft survival:
50
60
70
80
90
100
0 6 12 18 24
AM
<5% PRA
5-85% PRA
>85% PRA
% patients transplanted