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Review Article
E
From the Paris Translational Research nd-stage organ diseases are responsible for millions of deaths
Center for Organ Transplantation, INSERM, worldwide each year. Organ transplantation has become the treatment of
Unité Mixte de Recherche S970 (A.L.,
C.L.), the Kidney Transplant Department, choice, but despite the 120,000 new organ transplantations performed each
Necker Hospital, Assistance Publique– year, only 1 million persons worldwide have functioning solid-organ transplants1
Hôpitaux de Paris (AP-HP) (A.L.), and because of the lack of improvement in long-term allograft survival over the past
the Kidney Transplant Department,
Saint-Louis Hospital, AP-HP (C.L.) — all few decades and the limited organ supply.2
in Paris. Address reprint requests to Dr. HLA incompatibility between donors and recipients who are not genetically
Loupy at the Paris Translational Research identical has been identified as the main barrier to successful transplantation,
Center for Organ Transplantation, Insti-
tut National de la Santé et de la Recher- mostly because of antibody-mediated rejection, a form of allograft rejection trig-
che Médicale, Unité Mixte de Recherche gered by the production of antibodies directed mainly toward donor (nonself) HLA
S970, 56 Rue Leblanc, 75015 Paris, France, molecules. This review focuses on current standards for the management of anti-
or at alexandre.loupy@inserm.fr.
body-mediated rejection in transplant recipients and identifies future directions
N Engl J Med 2018;379:1150-60. for improving diagnostics and moving toward tailored therapeutics. Such advances
DOI: 10.1056/NEJMra1802677
Copyright © 2018 Massachusetts Medical Society. require the development of pathogenesis-based approaches that combine precise
characterization of the biologic properties of antibodies, noninvasive biomarkers,
and allograft gene-expression profiling, which will set the stage for bringing
antibody-mediated rejection into the era of precision medicine.
A
Kidney *
B
Heart *
*
The
C
Lung
Histologic features of antibody-mediated rejection are shown for recipients of kidney transplants (Panel A), heart transplants (Panel B), and lung transplants (Panel C). For each
type of transplant, the histologic images show ongoing antibody interaction with vascular endothelium, acute tissue injury, and chronic tissue injury. Panel A1 shows linear comple-
ment split-product C4d labeling in peritubular capillaries. Panel A2 (Masson’s trichrome) shows glomerulitis, characterized by microvascular inflammation in glomerular capillaries
(arrow). Panel A3 (Masson’s trichrome) shows microvascular inflammation in the peritubular capillaries, with capillaries that are filled with inflammatory cells (arrow). Panel A4
(hematoxylin and eosin) shows endarteritis, with prominent intimal inflammation in an interlobular artery (arrow). Panel A5 (methenamine silver) shows transplant glomerulopa-
mission electron microscopy. Panel A7 (Masson’s trichrome) shows arteriosclerosis in an interlobular artery with intimal thickening. Panel B1 shows linear complement split-product
C4d labeling in interstitial capillaries. Panels B2 and B3 (hematoxylin and eosin) show microvascular inflammation in myocardial interstitial capillaries (arrow in each panel). Panel
B4 (hematoxylin and eosin) shows endarteritis in a medium-size epicardial coronary artery (arrow). Panels B5 and B6 show chronic antibody-mediated rejection with multilayering
of the endothelial basement membrane in myocardial capillaries (asterisk in each panel) as observed on transmission electron microscopy. Panel B7 (hematoxylin and eosin) shows
vasculopathy, characterized by intimal thickening and chronic inflammation of the wall in a medium-size epicardial coronary artery. Panel C1 shows linear complement split-product
C4d labeling in alveolar-wall capillaries. Panel C2 (hematoxylin and eosin) shows interstitial lung-tissue inflammation with evidence of capillaritis (circle). Panel C3 (hematoxylin
and eosin) shows alveolar fibrin deposits, reflecting alveolar damage. Panel C4 (hematoxylin and eosin) shows arteritis in a pulmonary artery; vascular-wall infiltration with mono-
nuclear cells is evident (arrow). Panel C5 (hematoxylin and eosin) shows microvascular lesions in an explanted lung with the restrictive allograft syndrome (RAS) and ectatic septal
capillaries. Panel C6 shows microvascular lesions in an explanted lung with RAS and rarefaction of capillaries in fibrotic areas (CD34 endothelial labeling). Panel C7 (hematoxylin
and eosin) shows intimal thickening (arrows) adjacent to an area of bronchiolitis obliterans in an explanted lung allograft from a patient with the bronchiolitis obliterans syndrome.
Downloaded from nejm.org at KAOHSIUNG MEDICAL UNIVERSITY on September 19, 2018. For personal use only. No other uses without permission.
Antibody-Mediated Rejection of Solid-Organ Allogr afts
rejection has been observed in recipients of kid- specific anti-HLA antibodies that bind comple-
ney,22 heart,23 liver,24 and lung5 transplants. This ment in organ-transplant recipients, using single-
approach to the natural history of antibody- antigen bead assays that detect C1q-binding32 or
mediated rejection is supported by studies in C3d-binding33 donor-specific anti-HLA antibod-
animals, such as the nonhuman primate model ies or C4d deposition onto the bead surface.34
of chronic antibody-mediated kidney-allograft There is still debate regarding the role that as-
rejection developed by Smith et al.,25 as well as sessment of complement-activating, donor-spe-
by longitudinal analyses of protocol biopsies cific anti-HLA antibodies should play in clinical
performed in human kidney and heart recipi- practice, although the deleterious effect of these
ents, which reveals substantial oscillations in antibodies on allograft outcomes appears to be
disease activity levels.26 Antibody-mediated rejec- consistent across populations of patients who
tion is now considered to be a disease process have received transplants (kidney, heart, lung,
with a continuum of severity, beginning at any and liver) and across the types of tests used for
time after transplantation and continuing at their detection.35 Studies have shown that organ
varying levels of intensity, progressively leading recipients with complement-activating, donor-
to the development of chronic allograft damage, specific anti-HLA antibodies have an increased
dysfunction, and loss. An improved understand- risk of antibody-mediated rejection, more severe
ing of the natural history of antibody-mediated antibody-mediated injury, and overexpression of
rejection has led to a more complex interpreta- allograft genes associated with natural killer
tion of the various clinical scenarios encoun- cells, macrophages, and endothelial activation.36
tered in clinical practice, given the heterogeneity, The evaluation of complement activation by donor-
diverse polymorphism, and temporal dependency specific anti-HLA antibodies may allow more
of the clinical and histologic manifestations of rational and pathogenesis-based use of comple-
antibody-mediated rejection. ment-targeting agents.36
Besides complement activation, the relevance
of complement-independent mechanisms of anti-
C ompl emen t Ac t i vat ion in
A n t ibody-Medi ated R ejec t ion body-mediated allograft injury, which has been
primarily shown in animal models,37 is now in-
Converging evidence from basic and clinical sci- creasingly reported in human studies (Fig. S1 in
ence supports the concept that the complement the Supplementary Appendix). This is illustrated
cascade plays a crucial role as a pathogenic me- by the clinical recognition of C4d-negative anti-
diator of transplant rejection in animals and body-mediated rejection, the observation that
humans.27 Classical-pathway activation of the the rate of graft survival is lower among patients
complement cascade by antibodies is responsible with non–complement-binding, donor-specific
for allograft endothelial injury through the pro- anti-HLA antibodies than among patients without
duction of several biologically active fragments such antibodies,32 and the failure of complement-
(Fig. 2).28 The extent of complement activation inhibition therapies to prevent antibody-mediated
depends on the antibody isotype, the abundance rejection in patients with non–complement-
of the target antigen and density of immuno- binding anti-HLA antibodies.36
globulins, the local concentration of comple-
ment regulatory proteins, and the influence of Di agnos t ic Use of Gene-
antibody-targeting therapies and is determined E x pr e ssion Profil ing
mainly by the subclass composition of the IgG
isotype, which is the most common immuno- The complexity of antibody-mediated rejection
globulin isotype in antibody-mediated rejection.29 and the recognized limitations of standard his-
Emerging data have linked the IgG subclass com- tologic assessment have led to the development
position of donor-specific anti-HLA antibodies of new approaches for improving assessment.
to the phenotype and outcomes of allograft in- Following the example of the field of oncology,
jury, with a strong association between the pres- in which the measurement of multigene-expres-
ence of the complement-fixing IgG3 subclass sion profiles in tissue has been implemented in
and loss of kidney and liver allografts.30,31 routine clinical practice, transplantation investiga-
Today, we are able to detect circulating donor- tors have scrutinized transcriptome-wide micro-
A Complement-activating
DSA targeting HLA DRB1*03:01
Mean Fluorescence Intensity
20,000
15,000
L U ME N
10,000
0
G
G1
3
4
C1
G
G
G
Ig
Ig
Ig
Ig
Ig
n
Pa
NK-cell recruitment
B CCL4, CCL3
CXCL9, CXCL10 C5
IFNG, TNF, convertase
CSF2 Classical complement
KLRF1 SH2D1B GNLY, cascade
Up-regulation of C3 C5a
PRF1, GZMA, Monocyte C1
adhesion molecules convertase
NK cell GZMB complex C5
(SELE, VCAM1,
Soluble mediators ICAM1) C3a
proinflammatory C5b
cytokines IgG C4
CX3CR1 CD16a ADCC CD32-CD64, C3
Antigen (TNF, interleukin-1, FCGR
FCGR IgG interleukin-6) IgG C5b–C9 MAC
HLA CX3CL1 C4b C4d
HLA C3d
C3b
E NDOT HE L I A L C E L L
array data since 200338 and have found associa- mon tissue-based measurements of specific patho-
tions with discrete phenotypes and lesions. More genesis-based transcripts (Fig. S2 in the Supple-
recently, molecular signatures with evident spec- mentary Appendix). These data suggest that
ificity for antibody-mediated rejection have been antibody-mediated rejection involves the presence
identified and are similar in kidney-transplant and activation of natural killer cells, endothelial
and heart-transplant recipients,39 supporting the cells, and macrophages.
hypothesis that common mechanisms promote The information provided by allograft molecu-
rejection in solid-organ transplants of multiple lar assessment has led to an improved under-
types. Data from various centers in Europe and standing of the biologic processes that govern
North America are consonant, providing com- antibody-mediated rejection and that have the
Plasma exchange
Immunoadsorption Dendritic
cell
Interleukin-6 Macrophage
IgG-degrading enzyme of
Streptococcus pyogenes Effector
Clazakizumab CD52 NK Cell
CD52
IgG
Glucocorticoids
Intravenous
Antithymocyte globulin
immune globulin
Ca2+
Belimumab
Tabalumab
Classical
Interleukin-6R complement C5
convertase Eculizumab
cascade
Clazakizumab Interleukin-6 C1 TNT009 C5a
Tocilizumab complex C5
C3
convertase
Berinert C3a C5b
Cinryze
C4
C5b–C9 MAC IgG C3 C5b–C9 MAC
E NDO T H E L IA L C E L L S
velopment and testing of new drugs. The poten- allograft survival in patients with antibody-
tial role of the anti-CD20 monoclonal antibody mediated rejection was recently evaluated in two
rituximab and the proteasome inhibitor bortezo- randomized, controlled trials (RITUX ERAH58 and
mib in decreasing the production of donor-spe- BORTEJECT61), but neither trial showed clinical
cific anti-HLA antibodies (by targeting B cells benefits.
and plasma cells, respectively) and improving There is growing interest in the potential for
targeting the complement system to prevent and lighted. Inhibition of interleukin-6 with the use
treat antibody-mediated rejection. The anti-C5 of tocilizumab, an anti–interleukin-6 receptor
monoclonal antibody eculizumab, which inhibits monoclonal antibody, may be associated with
terminal complement activation, was reported to good outcomes,62 suggesting that future clinical
decrease the incidence of early antibody-mediated trials of interleukin-6 and interleukin-6 receptor
rejection in HLA-sensitized renal-transplant re- inhibitors may be indicated in patients with
cipients,69 although it failed to prevent chronic chronic antibody-mediated rejection.
antibody-mediated rejection in recipients with Finally, in small studies, use of the IgG-
persistently high levels of donor-specific anti-HLA degrading enzyme of Streptococcus pyogenes (IdeS)
antibodies.70 Two phase 2, unpublished trials — reduced or eliminated donor-specific anti-HLA
a randomized, open-label, multicenter trial and a antibodies before kidney transplantation in pa-
single-group, multicenter trial — investigated the tients who were HLA-incompatible with their
efficacy of eculizumab in preventing antibody- donors.60 However, IdeS has not yet been evaluated
mediated rejection in HLA-incompatible kidney- in patients with antibody-mediated rejection.
transplant recipients, with no definitive conclu-
sions (ClinicalTrials.gov numbers, NCT01399593 Sum m a r y
and NCT01567085, respectively). Proximal com-
plement inhibition has also been studied as a Antibody-mediated rejection has been recognized
therapeutic target. Two pilot studies showed that as a major cause of organ-transplant failure dur-
the plasma C1 esterase inhibitors Berinert (CSL ing the past two decades. Through better in-
Behring)71 and Cinryze (Shire ViroPharma)59 may sights into the pathogenesis of antibody-mediated
improve allograft function in kidney recipients rejection and an emphasis on anti-HLA antibody
with antibody-mediated rejection. Two additional characterization and gene-expression profiling
clinical trials evaluating a C1 esterase inhibitor in the allograft, precision diagnostics are now
added to plasma exchange and intravenous im- possible. The merging of organ-specific approach-
mune globulin for the treatment of antibody- es to antibody-mediated rejection offers the op-
mediated rejection (NCT02547220) and for the portunity to both elucidate the scope of this
treatment of antibody-mediated rejection that is problem and identify specific pathogenic mech-
resistant to plasma exchange and intravenous anisms in the various types of organ trans-
immune globulin (NCT03221842) in renal-trans- plants. However, much work remains to be done
plant recipients are currently recruiting patients. in the area of therapeutics to translate our im-
Data are even more limited for patients with proved understanding of pathophysiological pro-
chronic antibody-mediated rejection, in whom a cesses into effective personalized treatment for
poor response to the above-mentioned therapies antibody-mediated rejection.
is generally expected. Thus, there is an unmet
Disclosure forms provided by the authors are available with
need for the development of new therapeutic the full text of this article at NEJM.org.
strategies for this patient population. The poten- We thank Drs. Duong Van Huyen, Michael Mengel, Patrick
tial of proinflammatory cytokine blockade in Bruneval, Dylan Miller, Antoine Roux, Leila Zemoura, Elisabeth
Longchampt, Stijn Verleden, and Jan von der Thüsen for provid-
kidney-transplant recipients with chronic anti- ing the histologic images, and Dr. Luis Hidalgo for help in build-
body-mediated rejection has recently been high- ing the figure on prototypical immune responses.
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