This document discusses transplant immunogenicity and summarizes several studies on predicting immunogenicity of HLA mismatches. It finds that: 1) Not all HLA antigen mismatches are equally immunogenic, and some provoke stronger rejection responses than others. Some donor-recipient HLA combinations are considered "taboo" as they are highly immunogenic. 2) Studies have identified a potential hierarchy of HLA antigens in terms of immunogenicity, with some like DR5/A2 mismatches associated with worse outcomes. 3) Newer methods using epitope-level analysis like HLAMatchmaker and PIRCHE II can better predict immunogenicity and risk of de novo donor-specific antibodies than serological HLA typing alone

1. 2020 Transplant
Immunogenicity calculator
Fiction or Reality
Ahmed Shoker

2. Tx Immunogenicity
•AIM
•Highlight the
hierarchy of HLA
Mismatches to
provoke allograft
rejection

3. Tx immunogenicity
Williams, Transplant direct,2017

4. Tx immunogenicity
Williams, Transplant direct,2017
AHR for 1 MM= 1.79 (CI = .86- 3.76)
AHR for 6 MM = 2.57 (CI= 1.43- 4.61)

5. Tx Immunogenicity
•Introduction
•Current HLA Report presents
• 1)HLA antigens ( D/R, serological/ Molecular)
•2) cPRA/ XM ( CDC/FLOW)
•3) DSA with MFI from SPA( Lumenix)

6. Tx Immunogenicity
•Introduction
• Current HLA Report presents
• 1)HLA antigens ( D/R, serological/ Molecular)
• 2) cPRA/ XM ( CD/FLOW)
• 3) DSA with MFI
•Is this enough to measure the likelihood
of D/R HLA MM to provoke vigorous
rejection?

7. Tx immunogenicity Antigen Vs immunogen
•Antigens are structural differences
•Donor HLA antigens may or may not not activate
recipients
•Donor Antigens that elicit an immunological injury
are immunogenic antigens
•All immunogens are antigens, while not all antigens
are immunogenic
•HLA Immunogenicity is limited only to the
mismatching antigens that elicit vigorous rejection

8. Tx immunogenicity
•HLA Immunogenicity is limited only to the MM
antigens that can elicit a vigorous host rejection (
Unacceptable MM)
•Acceptable (Permissible) MM = HLA antigens that do
not elicit vigorous rejection
•Unacceptable MM = HLA antigens that elicit
vigorous rejection = are immunogenic

9. Tx immunogenicity
•Goal is to transplant patients with a minimum HLA
immunogenic MM “ Immunogenicity load”
•BIG Questions
• What is the best clinical read out outcome of HLA
Immunogenicity ( alloreactivity)?
•Can we calculate immunogenic load of
HLA MM as part of outcome measure?

10. Tx Immunogenicity
•Immunogenic
HLA MM is
more likely to
produce HLA
Abs (DSA)

12. Tx immunogenicity
•HLA- Abs
• can be non-DSA and DSA
•Present before or after Tx (dn DSA)
• DSA is the best clinical outcome
measure of Immunogenicity so far
• Wiebe, AJT,2012,2015,2017
• DeVos, transplant,2014
• Auber JASN,2017
• KI, 2018

15. differences in immunogenicity of
HLA antigens ?
 1003 pts with DSA ng?
 Willicombe M, Transplant,2018

16. Tx Immunogenicity
16

17. Tx Immunogenicity
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. 17

18. Tx immunogenicity
•Dn DSA
•dn DSA develop in 10- 20% at 1yr
•2-5% annual increments
•25% will fail by three yrs after onset of DSA
•Associate with Bx finding of rejection/ fibrosis
• Wiebe, AJT,2012,2015,2017
• DeVos, transplant,2014
• Auber JASN,2017
• KI, 2018

19. Inflammation
DSA
Vascular
Injury
Endothelial
Injury Fibrosis
T-cell Reactivity
Suboptimum Immunosuppression

20. Tx Immunogenicity
•Is there a hierarchy of HLA types to
provoke dn DSA?
•Studies were done to identify D/R HLA
combos that associated with
significantly higher incidence of dn
DSA, graft and pt. survivals?
•Two types of studies

21. HLA antigen mismatches with highest
immunogenicity are called “Taboo”
mismatches
 Doxiadis II, lancet,1996;348
 Rene J. Duquesnoy
 Geneugelijk
 J Immunol Res,201
 Slavcev,A
 International J Immunogenetics,2013

22.  Tx Immunogenicity
 Examples of Taboo Donor/ Recipient
combinations
 A2/B44
 A3/DR6
 B7/A1
 B60/DR2
 B60/DR2
 DR5/A2 ( worst)
 B44:02/B44:03

23.  Tx immunogenicity
Frequencies of Ab to mismatched
HLA-A,B,DR and DQ determined in
703 Tx pts after Tx
 Lucas D , Zachary A
 Transplant, vol 99,2015
 Wiebe C,JASN 2015

24. Measure differences in
immunogenicity of HLA antigens ?
 Response to individual antigens= 15%- 76.2%
 Lower when there is cross reactivity
cellular HLA typing?
 Lucas D , Zachary A
 Transplant, vol 99,2015
 Wiebe C,JASN 2015

25.  Frequency of Ab when No XR Ag / XR Ag is present to
mismatched HLA
A31 = 46% to 14%
A23 = 66% to 69%
A24 = 86% to 58%
A26 = 60% to 90%
A1 = 76% to 54%
A2 = 78% to 55%

26.  Frequency of Ab when No XR Ag/XR Ag is present to mismatched
Recipient HLA
B7 = 52% to 47%
B27 = 55% to 53%
B53 = 67% to 29%
B72 = 46% to 23%

27.  Frequency of Ab when No XR Ag/XR Ag is
present to mismatched HLA
DR1 = 61% to 27%
DR4 = 64% to 45%
DR13 = 77% to 38%
DR53 = 82% to 61%

28. Frequency of Ab when No XR Ag/XR Ag
is present to mismatched
DQ 5 = 60% to 52%
DQ 8 = 90% to 43%
DQ 9 = 82% to 29%

29. Can we measure differences in
immunogenicity of HLA antigens ?
 308 pts waiting for 2nd Tx, immunized by the
lost allograft
 D.D Gae, Human Immunol, 2018

30.  Can we measure differences in immunogenicity of HLA antigens ?
 308 pts waiting for 2nd Tx, immunized by the lost allograft
Most aggressive and most frequent:
DQ3> DR53 group and A2
 followed by B7> A10> B5> DR52
Weakest : B46ng?
 D.D Gae, Human Immunol, 2018

31. OUR WORK
 Differential association between responders HLA-DR phenotypes and
HLA DR antibody production
 UNOS Data , 2249 pts awaiting for Tx
 J Clin Exp transplant, 2016

35. Tx Immunogenicity
• Which of the following better predicts the immunogenicity of kidney transplant recipients ?
• cPRA of 99% with a negative DSA
• Number and types of HLA
•Is there a hierarchy of HLA types to
provoke dn DSA?
•A: YES

36. Tx Immunogenicity
•Refined methods to predict
alloreactivity at the epitope
level
•HLAMatchmaker program
•Terasaki (TerEP)
•PIRCHE II
• Lim W, KI,2018
• Willicombe M, Transplant,2018

37. HLAMatchmaker Computerized
program Estimate the eplet
mismatches between R/D HLA
 0-2 eplet MM VS > 20 MM= HR for rejection
of 2.16
 Nguyen,Transplant direct,2016

38. Tx Immunogenicity
• Should epitope-based HLA compatibility be
used in the kidney allocation system?
Rene J.Duquesnoy(Professor Emeritus of
Pathology)

39. Tx Immunogenicity
• PIRCHE II Risk profile
• Calculated between a patient and donor at time of
allocation
• Does not change overtime
• Forecasts T cell related immune response against HLA
derived peptides after Tx based on the indirect
allorecognition
• PIRCH II correlates with the immunogenicity of HLA-
Abs
• H. G. Otten, Human Immunol,2013

41. Tx Immunogenicity
• HLAMatchmaker vs PIRCHE II
• Compared predictive to observed dn DSA in
2787 consecutive Tx without preformed DSA
• Dn DSA at 10 yrs= 20.9%
• PIRCHE II and HLAMatchmaker scores
Independently predicted significantly dn DSA
and allograft survival and patient survival at ten
yrs.
• N. Lachmann,AJT,2017

42. Tx Immunogenicity
•Conclusions
•Not all HLA antigens are immunogens
•Some DSA are worse than others
• dn DSA relates to Mismatching immunogenic HLA
peptides and can be predicted from Serological HLA
typing ( Fewer sharing of public epitopes, CREG
analysis)
•Hierarchy of HLA immunogens is better predicted at
the epitope level matchmaker program

43. 2020 Transplant
Immunogenicity calculator
Fiction or Reality
Ahmed Shoker

44. • A Kidney Graft
Survival Calculator
that Accounts for
Mismatches in Age,
Sex, HLA, and Body
Size. JASN, 2017
Ashby VB1, Leichtman AB2, Rees MA3, Song PX1, Bray
M1, Wang W1, Kalbfleisch JD4.
Tx Immunogenicity
• An adjustable predictive
score of graft survival in
kidney transplant
patients and the levels
of risk linked to de novo
donor-specific anti-HLA
antibodies. PLOS
one,2017
Prémaud A1,2, Filloux M3,4, Gatault P5, Thierry
A6, Büchler M5, Munteanu E7, Marquet P1,2,8, Essig
M1,2,7, Rousseau A1,2.

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48. Tx Immunogenicity
•Thanks
•Questions