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De novo Donor-Specific HLA Antibody (DSA)
Actualités Néphrologiques
Jean Hamburger
Hôpital Necker
Paris, April 2014
Peter Nickerson, MD, FRCPC, FCAHS
Flynn Family Chair in Renal Transplantation
Professor of Internal Medicine and Immunology
2008 Routine screen de novo Class II DSA (DQ4)
Tacrolimus, MMF, Prednisone
Creatinine 108 umol/L
2006 Deceased Donor Kidney Transplant
cPRA 0%
Flow crossmatch negative
HLA mismatch 0A 2B 1DR 2DQ
Tacrolimus, MMF, Prednisone
Creatinine 100-120 umol/L
What do we tell him? What should we do next?
Could we have prevented it from occuring?
35 yr male
Overview
De novo DSA leading to acute and chronic ABMR
1. Prevalence of de novo DSA
2. Risk factors associated with de novo DSA
3. Clinical impact associated with de novo DSA
4. Therapeutic options to treat late ABMR
315 patients without pre-transplant DSA (1999-2008)
De Novo DSA Prevalence over Time
Wiebe et al AJT 2012; 12: 1157-1167
De novo DSA leading to acute and chronic ABMR
1. Prevalence of de novo DSA
2. Risk factors associated with de novo DSA
3. Clinical impact associated with de novo DSA
4. Therapeutic options to treat late ABMR
Variation in time of de novo DSA onset
Definition or Depletion related?
Wiebe et al, Current Opinion Organ Transplant (2013) 18:470
0
50
100
150
200
250
300
350
400
450
500
0 1 2 3
Preferential repopulation T-effector memory subsets following Alemtuzumab/Thymoglobulin induction
TN
TEM
Tcm
Treg Tram
Pearl, et al. Am J Transplant 2005; 5:465-474
Induction to Prevent T-cell Mediated Rejection Alemtuzumab induction associated with early memory and
switched memory B-cell repopulation
Todeschini et al, JI (2013)
191:2818
Non-Adherence major risk factor
Adherent
20% at 10 years
Non-Adherent
60% at 10 years
Wiebe et al AJT 2012; 12: 1157-1167
Am J Transplant 2012; 12:1192-1198
Patients switched from CsA to Everolimus at 3.0 to 4.5 months post-
transplant have an increased incidence of de novo DSA and AMR.
Everolimus
CsA
Everolimus
CsA
Non-Adherence
Clinical Rejection
(0-6 months)
Subclinical Rejection
(0-6 months)
No dnDSA
(n=268)
8%
13%
15%
dnDSA
Total
(n=47)
49%
28% (p<0.05)
29% (p=0.09)
Early TCMR precedes the development of de novo
DSA
Wiebe et al AJT 2012; 12: 1157-1167
dnDSA
Adherent
(n=24)
0%
29%
30%
dnDSA
Non-Adherent
(n=23)
100%
26%
22%
Surveillance
biopsy
6 Mt 2 Y 4 Y 6 Y 8 Y 10 Y 12 Y
Indication
biopsy
Moreso et al, Transplantation (2012) 93: 41-46
Subclinical
tubulointerstitial
inflammation
Chronic Antibody-Mediated Rejection (TG, PTC BM multi-layering; C4d+; DSA)
associated
with
Linking early clinical TCMR and development of de novo DSA / ABMR
Hourmant et al. JASN (2005) 16: 2804-2812
Wiebe et al. AJT (2012) 12: 1157-1167
Liefeldt et al. AJT (2012) 12: 1192-1198
El Ters et al. AJT (2013) 13:2334-2341
Gibson et al, Am J Transplant 8:819,
2008
PTC 2
Patients with de novo DSA have early (0-6 month)
TCMR with more intense PTC inflammation
TCMR PTC score
de novo DSA
No DSA
2.0
1.0 p <0.05
Shed MHC II
B
IgG
Lymph Node
TFH
Plasma Cell
Wiebe et al AJT 2012; 12: 1157-1167
MHC II
IFN g
Muczynski et al, J Am Soc Nephro 14:1336,
2003
DR induction by IFN g
Th
Univariate Predictors of de novo DSA
Wiebe et al, Current Opinion Organ Transplant (2013) 18:470
Jean Dausset Nobel Prize (1980) for
Physiology of Medicine
“Genetically determined
structures on the cell
surface that regulate
immunological
reactions”
HLA
Jean Hamburger
Predicted tissue
compatibility proteins,
prior to HLA discovery,
play key role in organ
graft survival
Polymorphic Epitopes
on donor HLA-B51
Epitopes “seen” by
A2, A68
B27, B44
Epitopes “seen”
by
A2, A24
B7, B8
What can the recipient immune system “see”?
1 DR MM
1 DQ MM
# of Epitope MM
Single HLA Antigen MM Range of Epitope MM
Wiebe et al AJT 2013; 13: 3114-3122
Wiebe et al AJT 2013; 13: 3114-3122
High Epitope MM Load in Patients with de novo DSA
Wiebe et al AJT 2013; 13: 3114-3122
Multivariate Model of de novo DSA Risk Factors
p<0.000
1
0-16
17-69
Follow-up (years)
HLA-DQ Epitope Mismatches
p<0.0001
Follow-up (years)
0-9
10-57
HLA-DR Epitope Mismatches
Wiebe et al AJT 2013; 13: 3114-3122
Epitope MM Load
thresholds associated with
de novo DR or DQ DSA
Wiebe et al AJT 2013; 13: 3114-3122
Recurring DQ epitopes
associated with de novo DSA
Case for Immunodominance?
De novo DSA leading to acute and chronic ABMR
1. Prevalence of de novo DSA
2. Risk factors associated with de novo DSA
3. Clinical impact associated with de novo DSA
4. Therapeutic options to treat late ABMR
10 year
Median Survival
No DSA 96.4%
dnDSA 56.9%
De Novo DSA and Graft Survival Adult and Pediatric Kidney Transplants (1999 to 2008)
Wiebe et al AJT 2012; 12: 1157-1167
Pre-transplant HLA Ab and
de novo HLA Ab
do not predict graft survival
De Novo DSA and Graft Survival Adult and Pediatric Kidney Transplants (1999 to 2008)
Wiebe et al AJT 2012; 12: 1157-1167
de novo DSA
De Novo DSA and Graft Survival Adult and Pediatric Kidney Transplants (1999 to 2008)
Wiebe et al AJT 2012; 12: 1157-1167
Mean time to graft failure from time
de novo DSA first detected is ~ 5 to 6
years
Consecutive
Transplants
Jan. 1999 - Dec. 2008
(n=392)
(n=30)
(n=11)
(n=14)
(n=22)
DSA pre transplant
Primary non-function
Moved
Death with function
Excluded (n=77)
Study Patients
(n=315)
de novo DSA
(n=47)
No DSA
(n=268)
Dysfunction
No DSA
(n=55)
Stable
Function
No DSA
(n=213)
Acute
Dysfunction
de novo DSA
(n=14)
Indolent
Dysfunction
de novo DSA
(n=15)
Stable
Function
de novo DSA
(n=18)
Wiebe et al AJT 2012; 12: 1157-1167
Acute Dysfunction dnDSA (n=14) Indolent Dysfunction dnDSA (n=15) Stable Function dnDSA (n=18)
Class I Class II Class I Class II Class I Class II
A2 DQ2 A31* DR13, DR52, DQ6* B58 DR8, DR12, DQ4,
DQ7
B44 DR8*, DQ5 A2*, A11* DR9*, DQ9 A1 DQ6
A30, B61 DR17, DR52, DQ2 A68, B65 DQ7 DR15*, DR51, DQ6
A34 DR15, DR51, DQ5 B62 DR17, DR53*, DQ2 DR53, DQ8, DQ9
A24 DR9 DQ6 DR13, DR52*
A24 DQ4 DR53 DR11
DR17, DQ5 DQ5 DR16, DR51*
DQ2 DQ5 DQ7
DQ7 DQ5 DQ5
DP13 DR13 DQ5
DQ5 DR53*, DQ2 DQ2
DR53, DQ2 DQ7 DQ8
DR15, DR51* DR13, DR52,
DR53, DQ2 DQ7
DQ6 DR53 DQ7
A1 DQ9
DQ4
A30
A1
Class II are the dominant de novo DSA for all
Clinical Phenotypes
Wiebe et al AJT 2012; 12: 1157-1167
Wiebe et al AJT 2012; 12: 1157-1167
Clinical
Phenotypes
• 10/14 patients biopsied had pathologic features of AMR (PTC, C4d, g, v)
• 7 / 10 “subclinical” AMR re-biopsied:
o 1 persistent subclinical AMR
o 3 subclinical AMR + cAMR
o 3 clinical AMR + cAMR
Evidence suggesting that Stable
de novo DSA patients will progress
Wiebe et al AJT 2012; 12: 1157-1167
(updated Dec 2013)
What could explain the lack of
dysfunction in this group?
• de novo DSA titer affecting rate
of progression
• Differences in C1q binding or IgG
subclass
• Differences in epitope
immunogenicity or expression
• Regulation of antibody
responses
Th1
7
Th1 Treg
Bre
g
Early Inflammatory
Event(s)
Graft LossTransplant
De Novo Class II (I?) DSA
Peritubular Capillaritis
+/- C4d
Glomerulitis
IFTA +/- TG
Rising Cr /Proteinuria
Time
NormalHistology
SubclinicalInjury
ClinicalDysfunction
+/- Cellular Rejection
Proposed Natural History of dnDSA*
De Novo DSA
TCMR
with capillaritis
IFN g
Th
MHC II B TFH
Model linking TCMR, de novo DSA, ABMR with Graft Loss
Wiebe et al AJT (2012) 12: 1157-1167
(modified from Smith et al AJT (2008) 8:1662-1672)
Plasma Cell
Donor-Specific
Anti-Class II Ab
De Novo DSA Treatment Options?
Donor HLA II
B
TFh
+
Costimuli
APC
Allo-peptide
Donor HLA II
REGIONAL LYMPH NODE/SPLEEN
Bm
Tacrolimus / MMF ± Prednisone
IVIG ± Pheresis [FDA ~Std of Care, AJT 2011]
Rituximab (anti-CD20)
Bortezomib (Proteosome Inhibitor)
Eculizumab (C5a Inhibitor)
GRAFT
MICROCIRCULATION
Donor HLA II
FcgRIII
NK
C1q
MØ
C3a/C5a R
C3a C5a
MAC
2008 Routine screen de novo Class II DSA (DQ4)
Tacrolimus, MMF, Prednisone
Creatinine 108 umol/L
2006 Deceased Donor Kidney Transplant
cPRA 0%
Flow crossmatch negative
HLA mismatch 0A 2B 1DR 2DQ
Tacrolimus, MMF, Prednisone
Creatinine 100-120 umol/L
35 yr male
Biopsy
Mild Tx glomerulitis (g1,cg0)
with mononuclear cells
(circled)
C4d
Peritubular capillaritis (ptc2):
• Diffuse moderate mononuclear inflammatory cell accumulation
PTCs diffuse C4d +
De novo DSA related Subclinical AMR
Can we shut off the process?
Tac/MMF + IVIG (2g/kg)/mo x 3
Optimizing Tac/MMF, Pulse Steroids and IVIG appears to be insufficient
DSA
Banff Acute
Banff Chronic
Banff Acute
Banff Chronic
G I T V PTC C4d G I T V G I T V PTC C4d G I T V
DR12 DQ4,7 0 2 2 0 2 Pos 0 0 1 1 2 2 1 0 2 Neg 2 2 2 0
DQ4 1 1 1 0 2 Pos 0 0 1 0 2 2 1 0 2 Pos 0 1 0 0
DQ9 0 0 0 3 0 Neg 0 0 0 1 1 1 1 1 2 Pos 0 1 1 2
DQ7 0 1 1 0 2 Pos 0 0 1 0 0 1 1 0 2 Pos 0 0 1 0
Wiebe et al AJT 2012; 12: 1157-1167
6
mo
De novo DSA related Subclinical AMR
Evidence of concommitant TCMR
Optimizing Tac/MMF, Pulse Steroids and IVIG appears to be insufficient
DSA
Banff Acute
Banff Chronic
Banff Acute
Banff Chronic
G I T V PTC C4d G I T V G I T V PTC C4d G I T V
DR12 DQ4,7 0 2 2 0 2 Pos 0 0 1 1 2 2 1 0 2 Neg 2 2 2 0
DQ4 1 1 1 0 2 Pos 0 0 1 0 2 2 1 0 2 Pos 0 1 0 0
DQ9 0 0 0 3 0 Neg 0 0 0 1 1 1 1 1 2 Pos 0 1 1 2
DQ7 0 1 1 0 2 Pos 0 0 1 0 0 1 1 0 2 Pos 0 0 1 0
6
mo
Tac/MMF + IVIG (2g/kg)/mo x 3
Nickerson et al AJT 2013; 13: 2239-2240
Bx: g1, i1t1, ptc2, C4d+, cg0
Rx: Tac/MMF, monthly Pred + IVIG 2g/kg x3
de novo DQ4 DSA
Bx: g0, i2t1, ptc2, C4d-, cg3, ci3ct3, cv2, ptc bml 8
Rx: conservative
Bx: g2, i2t1, ptc2, C4d+, cg0
Subclinical ABMR Early Graft Failure
month
Subclinical 33 months
< 6mo
77%
88%
40±17
66±31
> 6mo
35%
54%
27±12
37±25
Walsh et al, Transplantation (2011) 91:1218
Immunologic Response
% of patients with >50% decline in DSA MFI D14 post-treat
Histologic Response
% patients resolved or resolving with repeat bx
Allograft Function Response
Mean pre-treatment eGFR (ml/min/1.73m2)
Mean post-treatment eGFR (ml/min/1.73m2)
De novo DSA associated ABMR
Prevention is Key:
• HLA DR and DQ matching (avoid high epitope load/immunodominant)
• Optimize immunosuppression to avoid sensitization (Tacrolimus/MMF)
• Non-adherence recognize and intervene early
• Avoid minimization in at risk individuals (epitope load, early TCMR)
Novel Therapeutics and Clinical Trials are needed to:
• Optimize induction to avoid early TCMR and/or ABMR
Avoid/control repopulation with effector memory T and B cells
• Augment T reg cells post-transplant
• Early recognition and treatment of de novo DSA associated ABMR
“Are there not human tissue groups allowing acceptable
compatibility?”
“Is it possible to prevent incompatible graft death
through pharmacodynamic properties of some drugs?”
J. Hamburger, J. d’Urologie (1947) 53:563-567
Acknowledgements
Transplant Manitoba
Adult and Pediatric Kidney Programs
David Rush
Chris Wiebe
Julie Ho
Martin Karpinski
Leroy Storsley
Patricia Birk
Tom Blydt-Hansen
Aviva Goldberg
Transplant Immunology
Laboratory (DSM)
Denise Pochinco Dawn Kelm
Kendra Hacking Iga Dembinski Willy Laidlaw
Cathy Krasnianski Brenda Schultz
Manitoba Centre for
Proteomics & Systems Biology
John Wilkins
Ang Gao
Oleg Krokhin
Department of Pathology
Ian Gibson
Department of Immunology
Kent HayGlass
Universität Basel
Stefan Schaub
Patricia Hirt-Minkowski
Gideon Hönger
Jürg Steiger