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Clinical Science ( 1 990) 78,343-350
Editorial Review
Mechanisms of liver allograft rejection in man
DAVID ADAMS
Liver Unit, Queen Elizabeth Hospital, Birmingham, U.K.
INTRODUCTION
With increased experience of liver transplantation it has
become apparent that, contrary to earlier views, graft
rejection is a major problem. Approximately 70% of
patients experience at least one episode of acute, reversible rejection and between 10 and 15% develop chronic
rejection, which is usually irreversible and requires retransplantation [ 1-51.
Rejection can be defined as graft damage arising from
the response to the transplanted liver by the recipient
immune system and may take several forms resulting in
different clinical patterns [6]. The mechanisms underlying
rejection remain poorly understood.
Mechanisms shown to be important in animal transplant models are not always relevant to man [7] and until
recently there have been few studies addressed to analysing the mechanisms of human liver rejection.
This article will review the current understanding of the
mechanisms of liver allograft rejection in man and discuss
theories as to how the inflammatory response of rejection
may be generated.
CLINICAL PATTERNS OF LIVER ALLOGRAFT
REJECTION
There are two broad clinical presentations of rejection
after liver transplantation, conventionally termed acute
and chronic. Acute rejection may occur at any time after
grafting, and chronic rejection can present as early as the
first 2 weeks. This has led some authors to favour a division into reversible and irreversible rejection, or to refer
to chronic rejection according to its morphological
features, i.e. vanishing bile duct syndrome (VBDS)[8].
Within these two categories there may be several clinical patterns of rejection and it is unclear whether these
clinical forms reflect different presentations of the same
underlying process or if there are several distinct mechanisms that can lead to graft rejection.
Acute, reversible rejection
Acute rejection usually becomes clinically apparent
between 4 and 14 days after transplantation. Clinical
features are fever, malaise and jaundice. Liver biopsy
reveals the histological changes of acute rejection which
consist of (a)a mixed inflammatory cell infiltrate in portal
tracts, (b) infiltration and damage to biliary epithelium by
inflammatory cells and (c) inflammation of the venous
endothelium. T h e infiltrate is largely confined to portal
tracts and central venous endothelium with very little
inflammation of the liver parenchyma [9-141.
Acute rejection usually responds to treatment with
high-dose corticosteroids (e.g. 1 g of methylprednisolone/
day intravenously for 3 consecutive days) [ 151.
Chronic/irreversiblerejection (VBDS)
VBDS may present as early as 2 weeks after transplantation with clinical features similar to those of acute rejection, although in other cases the presentation may be
more insidious. VBDS, unlike acute rejection, does not
respond to high-dose corticosteroids and there is then a
relentless rise in serum bilirubin culminating in graft
failure [5,6,8]. The characteristic morphological features
are a loss of small bile ducts and arterial lesions. In the
initial stages there is active inflammation’ of both portal
tracts and medium-sized arteries. Although the inflammation subsides as the condition progresses, the bile duct
loss may approach 100% and arteries become occluded
by foamy macrophages [5, 8-10, 131. These changes
appear to be irreversible and re-transplantation is
required [5].
Other patterns of rejection
Correspondence: Dr David Adams, Liver Unit, Queen
Elizabeth Hospital, Edgbaston, Birmingham B 15 2TH, U.K.
Hyperacute rejection, which occurs with renal and
cardiac transplants within hours of transplantation, is due
344
D. A d a m
to humoral damage associated with preformed cytotoxic
antibodies [ 161. It has only recently been recorded after
human liver transplantation, despite many transplants
being carried out in the presence of positive lymphocytotoxic cross-matches, and must be considered an extremely
rare occurrence [ 17, 181.
Massive haemorrhagic necrosis is a rare syndrome of
fulminant graft failure occurring after several days of
normal function. The findings of increased human leucocyte antigen (HLA) expression and immunoglobulin
deposition in the graft favour an immunological mechanism, although whether this is due to rejection is unknown
since the pathogenesis remains obscure [ 191.
These syndromes are both rare and it is not known
whether they are genuinely forms of rejection or whether
other mechanisms may be involved in their pathogenesis.
For this reason they will not be‘discussed further.
MECHANISMS OF REJECTION
Graft antigens
Major histocompatibility antigens. The host immune
system must recognize an allograft as being ‘foreign’
before it can mount an immunological reaction against it.
Recognition depends on the presence of allogeneic histocompatibility determinants and the most important of
these are coded for by the major histocompatibility complex (MHC) [20-221. The function of MHC antigens is to
act as recognition signals in lymphocyte reactions, rather
than to prevent tissue transplantation. They are essential
for the development of both humoral and cell-mediated
responses and are involved in recognition of ‘self‘
[23-251. These antigens, termed HLA in man, are
encoded for by closely linked genes situated on the short
arm of chromosome 6. Class I genes (HLA-A, -B and -C)
encode cell-surface antigens that are expressed on the
majority of nucleated cells, whereas class I1 genes (HLAD, -DR) encode proteins that are expressed principally on
lymphocytes and macrophages but also on some other
tissues such as endothelium [26]. The loci within the class
I and I1 regions are highly polymorphic giving rise within
the population to a large number of different antigenic
variants which are unique to the individual. Expression of
the gene products is dynamic and can be regulated by
many different factors [27]. Rejection of an allograft by an
unmodified recipient is determined primarily by incompatibility for these major and, to a lesser extent, minor
histocompatibility antigens [28].
Class I antigens consist of a 4 3 kDa glycosylated, transmembrane polypeptide that is non-covalently bound to
&microglobulin (&M), a 12 kDa polypeptide encoded
for by a gene on chromosome 15 [20, 261. The class II
antigens are made up of two non-covalently bound, glycosylated transmembrane polypeptides of 33 kDa and 28
kDa, both encoded for by genes in the class I1 region and
are subdivided into families HLA-DP, HLA-DR, HLADQ. They are associated with an invariant, transmembrane polypeptide of 30 kDa encoded for on
chromosome 5 [29]. Class 1 and class I1 antigens act as
restriction elements for the interaction and recognition of
T-lymphocytes with their target cells. As a general rule
class I antigens serve as the primary targets for cytotoxic
T-lymphocytes and class I1 antigens as the primary targets
for helper T-lymphocytes [30-321.
The expression of MHC antigens varies between different tissues. In human liver HLA class I (ABC)and class I1
(DR, DP, DQ) are found on sinusoidal lining cells, usually
only class I on vascular endothelium, and class I and occasionally class I1 antigens on biliary epithelium. Hepatocytes are usually negative for both class I and class I1
expression [33-361. The presence of HLA antigens on
biliary epithelium and vascular endothelium may be
responsible for the histological distribution of the
inflammatory damage during rejection.
Antigen presentation. Transplant antigens must be
efficiently presented to the recipient immune system to
evoke a rejection response [32,37]. This may occur in one
of two ways: (i) donor antigen may be processed by host
antigen-presenting cells (APCs) and presented in
conjunction with host class I1 HLA; (ii) donor antigen can
be presented directly to alloantigen-specific host cells by
donor APCs without the need for processing by the host
or for host class I1 restriction. The second mode of
antigen presentation is probably most important in
vascularized organ grafts, since direct stimulation by
donor cells has been shown to present antigen more
strongly than host processing in experimental models [38].
Cells of the macrophage lineage are usually associated
with antigen presentation and dendritic cells have been
implicated in the pathogenesis of the obliterative
arteriopathy of chronic human liver allograft rejection
[39]. The cells lining liver sinusoids include macrophages
(Kupffer cells) which can present antigens efficiently [40].
It has recently been demonstrated that after human transplantation donor Kupffer cells are replaced by host cells
and that this may be increased during episodes of rejection [41, 421. This immigration of host Kupffer cells may
be important in determining the eventual acceptance of
the graft.
Animal studies have shown that both vascular endothelial cells and biliary epithelial cells (although not
hepatocytes) are also capable of presenting antigen, which
may be another reason for the involvement of these structures in liver rejection [43,44].
Targeted structures in liver allograft rejection. The
importance of the biliary epithelium and vascular endothelium as targets for rejection in man is suggested by
several studies. Immunohistochemical localization of
laminin has demonstrated severe disruption and damage
to the basement membrane of both biliary epithelium and
vascular endothelium during rejection [45]. Other studies
have demonstrated the presence of markers of biliary
epithelial damage in bile and of increased levels of hyaluronic acid, a marker of hepatic endothelial cell damage,
in serum during rejection episodes [46,47].
Evidence is also available which suggests that HLA are
the likely targets on these structures. Lymphocytes isolated from human liver grafts demonstrate alloreactivity
towards cells bearing donor HLA. Lymphocytes from
Mechanisms of liver allograft rejection
patients with intense but reversible infiltrates on liver
biopsy more commonly react to class I-bearing cells,
whereas class I1 reactivity is more common in patients
with severe biliary epithelial damage and VBDS [48,49].
The King’s College Hospital/Cambridge group have
shown that VBDS occurs more frequently in patients who
are matched for class I1 antigens but mismatched for class I.
Their hypothesis is that a class I1 match allows donor
cells to act as efficient APCs, thereby generating a
response to the foreign class I antigen which results in bile
duct damage [SO, 511. Further evidence implicating class I
antigens on the biliary epithelium comes from the finding
that &M, which is intimately linked to these antigens on
the cell surface, is shed into bile during episodes of acute
rejection [52]. Moreover, VBDS is associated with the
development of circulating antibodies to class I antigens
~ 1 .
The expression of HLA antigens on liver components
is increased during episodes of rejection. Hepatacytes display a membranous pattern of focal staining for both class
I and class I1 antigens and biliary epithelium and vascular
endothelium show intense staining for class I and I1
[53-571. This presumably occurs in response to locally
produced cytokines (particularly y-interferon) which are
known to be capable of increasing tissue expression of
MHC products [SS, 591. This will render the tissue more
susceptible to T-cell-mediated cytolytic damage [27]. Surprisingly, however, this increase in MHC expression is not
specific for rejection and identical patterns can be seen in
non-rejection complications after transplantation and in
patients in whom rejection has resolved. Other factors
must, therefore, be involved before a response to these
antigens can be generated.
Cellular response to graft antigens
The cellular events leading to the development of acute
rejection in liver transplantation are possibly as follows
(see Fig. 1).
(1) APCs (which may include biliary epithelial cells
and vascular endothelial cells) present transplant antigens
to C D 4 + T-helper cells in the presence of interleukin-1.
(2) These T-cells become activated and release
lymphokines (including interleukin-2) which lead to the
recruitment and proliferation of lymphocytes, some of
which have cytotoxic potential.
(3) The escalating immunological reaction results in
the production of cytokines which attract other cell types
such as eosinophils, macrophages and neutrophils.
(4) The combination of T-cell cytotoxicity and a more
generalized inflammatory response results in damage to
the graft and finally clinical rejection.
The role of lymphocytes. Results of studies using
animal models of transplantation suggest that T-lymphocytes play a central role in instigating the acute inflammatory response to the graft [60-621. Rejection does not
occur in animals depleted of helper T-cells but does
occur, though delayed and less vigorous, if only cytotoxic
T-cells are depleted [63,64].
345
1DonorMHC
I L j
A
h.\T-cel!-c IL-2R
I
I
I
(ii) T-cell activation
production
I
activation
1
1
1
I
(v) Effector mechanism
Proteolytic enzymes Cytotoxici,,,
+free,
/Yntibody
0
Graft
(vi) Graft damage
Fig. 1. The inflammatory ‘cascade’ of rejection. (i) Donor
MHC antigens are presented by APCs of either host or
donor origin to recipient helper T-cells (TH)which are
stimulated to produce interleukin-2 (IL-2). (ii)IL-2 results
in the activation and proliferation of other T-cells which
express activation markers, such as IL-2 receptors (IL2R). (iii) Activated lymphocytes secrete lymphokines
(IFN, interferon; NAF, neutrophil-activating factors; IL-4,
interleukin-4). (iv) These lymphokines are capable of
recruiting and activating other inflammatory cells (MO,
macrophages; PMN, neutrophils, T,, cytotoxic T-cells). (v)
The generalized inflammatory response results in several
effector mechanism capable of causing graft damage.
Information about the cell types involved in rejection of
human liver allografts has come from studies using monoclonal antibodies which recognize surface determinants
on leucocytes. Immunohistochemical analysis of liver
biopsies from patients with rejection shows that T-cells
are the most common infiltrating cell type but that substantial numbers of B-cells, monocytes, macrophages and
neutrophils are also present [53].
Both helper (CD4 + ) and suppressor (CD8 + )
T-lymphocytes accumulate in portal tracts and around
small bile ducts (the presumed site of antigen exposure),
during rejection [65]. Perkins et al. [66] suggested that the
presence of a predominantly C D 4 + T-cell infiltrate indicates that the rejection episode will respond to corticosteroids, whereas a predominantly CD8 + infiltrate is
associated with irreversible rejection. Since CD8 +
lymphocytes respond primarily to class I HLA antigens,
this is compatible with the King’s College Hospital/
346
D. Adams
Cambridge theory that class 1 mismatches may be important in the irreversible rejection of the VBDS [SO, 5 11.
So et al. [67] have demonstrated, using a murine mixed
lymphocyte/hepatocyte culture system, that cytolytic
lymphocytes can inhibit hepatocyte functions, such as
protein synthesis, without causing cell lysis. Accessory
cells were necessary to instigate the response, reflecting
the inability of hepatocytes to act as APCs. Although
hepatocyte damage tends to be a late event in vivo, this
work suggests that cytotoxic T-cells may be important in
causing liver damage during episodes of rejection.
Not all infiltrating lymphocytes respond to HLA
antigens [48, 491 and the function of these remaining
T-cells and of the other cell types is uncertain, as are the
mechanisms causing their recruitment to the graft.
Cellular recruitment to the graft. There are two ways
by which T-cells may accumulate at the site of rejection:
they may be either continually attracted to the site by
ctemotactic factors; or, after initial migration, they may
proliferate in sifcc in the presence of T-cell growth factors.
Circulating T-cell counts increase bcfore rejection of liver
allografts in man and there are increased numbers of
CD8 + and C D 4 + cells within the liver during rejection
[65, 68, 691. This is consistent with the hypothesis that
T-cells move preferentially from the periphery to accumulate within the graft. Proliferation of T-cells in sim has
been demonstrated in experimental models [60, 701,
although whether this occurs during graft rejection in man
is unknown.
Since the inflammatory infiltrate of liver rejection is
centred on small bile ducts, bile provides direct access to
the microenvironment of the rejection process and an
opportunity to investigate factors which are locally active
within portal tracts. The routine use of an externally
draining T-tube for the first 3 months after human liver
transplantation allows frequent bile sampling to be
carried out. The study of sequential bile samples from
patients after liver transplantation has revealed a dynamic
pattern of leucocyte chemotactic activity for different cell
types. Bile contains chemotactic factors for lymphocytes
before the onset of clinical rejection. The activity of these
factors subsequently decreases and is replaced, when
rejection becomes apparent clinically, by chemotactic
activity for monocytes and neutrophils [7 11. This suggests
that lymphocytes may be attracted to the graft early in the
rejection process and that the subsequent attraction of
other inflammatory cells could be responsible for the
onset of symptoms and the tissue destruction which is
characteristic of rejection.
The nature of thcse chemotactic factors is unknown.
Chemotaetic factors for T-lymphocytes include interleukin-1 and interleukin-2 and several T-lymphocytespecific lymphokines [72-741. There are many potential
chemotactic factors for monocytes and neutrophils,
including prostaglandins, leukotrienes and products of
mononuclear cells, such as neutrophil-activating factor
[75, 761. The neutrophil and monocyte chemotactic
activity in bile may be due to factors secreted by activated
lymphocytes within portal tracts, since thesc factors
appear in bile after the increase in lymphocyte chemo-
tactic activity. Lymphocyte activation markers have been
detected in bile during episodes of rejection in man and
activated lymphocytes have been isolated from the liver
by fine-needle aspiration cytology [77, 781. Activated
lymphocytes are capable of producing neutrophil chemotactic factors iw vifro [79] and, fwthermore, lymphocytes
cultured from patients with acute liver rejection have
recently been shown to produce a neutrophil chemotactic
factor [SO].
Effector mechanisms. The role of cytotoxic T-cells in
mediating graft damage is discussed above. Animal
studies have suggested that other leucocytes may be
involved, resulting in an inflammatory cascade and a
number of different effector mechanisms. This concept is
supported by morphological studies in human liver rejection. It has been recognized for several years that the
infiltrate of acute rejection contains, not only lymphocytes, but also large numbers of monocytes, neutrophils
and eosinophils. The presence of the latter two cell types
was recently shown to be a reliable predictor of rejection
P , 8 11.
Neutrophils. Recent work has demonstrated that
neutrophils isolated from patients after liver transplantation become activated shortly before the onset of clinical
rejection. This activation is suppressed in those patients
who respond to treatment with high-dose corticosteroids
[SO].The activated cells are capable of releasing increased
amounts of superoxide radicals and proteolytic enzymes,
both of which may cause tissue damage [S2,83]. Neutrophils may, therefore, play an important role in the pathogenesis of acute rejection.
Monocytes/macrophages. Delayed-type hypersensitivity, involving activation of macrophages or other cells
with surface receptors for the Fc portion of immunoglobulin G, has been implicated in animal studies,
although there is no direct evidence that such processes
play a role in human liver rejection [84,85].
Natural killer cells. Natural killer cells have been
detected in renal allografts in large numbers during rejection and are capable of causing tissue damage in a nonMHC restricted manner [86]. Their importance in liver
rejection in man is unknown.
Eosinophils. In man rejection of the liver is associated
with both graft and peripheral eosinophilia [87]. Eosinophils can inhibit some immunological reactions and can
release a toxic substance (eosinophil major basic protein)
which has cytotoxic properties [88].However, the role of
these cells during rejection is unknown.
Humoral mechanisms. Humoral mechanisms are
important in rejection of renal transplants and there is
increasing evidence that they may be important in human
liver rejection [S9]. TWOstudies have reported increased
levels of anti-class I cytotoxic antibodies in patients with
rejection [50, 901 and immunohistochemical studies have
reported the deposition of significant amounts of
immunoglobulin, particularly immunoglobulin M, in
arterial walls of rejected livers [91]. Recent studies suggest
that humoral mechanisms may be of particular importance in the rejection of ABO incompatible grafts [92].
Other factors. Soluble factors such as cytokines and
Mechanisms of liver allograft rejection
arachidonic acid metabolites may exacerbate graft
damage. Tumour necrosis factor, which is produced by
activated macrophages, has cytotoxic properties [93] and
prostaglandins and leukotrienes, the end-products of the
cyclo-oxygenase and lipoxygenase pathways of arachidonic metabolism, respectively, are powerful mediators of
inflammation [94]. Prostaglandins cause an increase in
vascular permeability, the recruitment of inflammatory
cells and alterations in leucocyte adherence to endothelium. Leukotrienes are chemotactic and also affect vascular permeability. Other leucocyte products, such as
platelet-activating factor and neutrophil-activating factor,
may be important in activating and recruiting inflammatory cells [95].
It has been suggested that coexistent viral infection may
lead to the induction or amplification of rejection [96,97,
5 11. An association has been reported between cytomegalovirus (CMV) infection and graft rejection in
human renal transplantation [96] and the King’s College
Hospital/Cambridge group have reported that CMV
infection is a risk factor for the development of the VBDS
variant of liver allograft rejection [5I]. These associations
may be related to some of the immunomodulating
properties of CMV. In murine experiments CMV infection was shown to augment the host’s ability to mount a
cytotoxic response against allogeneic histocompatibility
antigens [98]. In human renal transplantation CMV infection leads to an increase in expression of class 11 antigens
on renal tubular cells [96]. These effects may be mediated
by CMV-induced cytokines since y-interferon is capable
of inducing HLA expression in vifro [58, 591. Although
the concept of infections amplifying or initiating the rejection process is theoretically attractive, the mechanisms of
such interactions, and their clinical importance, remain
poorly understood.
IMMUNOSUPPRESSION
If several different effector mechanisms are involved in
rejection, immunosuppressive therapy may need to be
aimed at suppressing other immune processes as well as
lymphocyte function.
Most liver transplant centres use cyclosporin for maintenance immunosuppression, either alone or in conjunction with corticosteroids and azathioprine [ 151.
Cyclosporin produces suppression of T-lymphocyte function with little effect on other immune mechanisms [15],
whereas corticosteroids and azathioprine both have wider
effects on the immune system. Corticosteroids have been
shown to suppress neutrophil activation [99] and recent
work from our laboratory has demonstrated that azathioprine can inhibit neutrophil chemotaxis and block the
production of neutrophil-activating factors by cultured
lymphocytes (D. Adams & L. Wang, unpublished work).
Maintenance immunosuppression with all three drugs
may, therefore, offer advantages over cyclosporin monotherapy. Experience from renal transplantation suggests
that combination therapy is at least as effective as monotherapy in preventing rejection and that it is not asso-
347
ciated with an increase in opportunistic infections [ 1001.
However, the efficacy and safety of such treatment in
human liver transplantation is unknown.
Episodes of acute rejection do not usually respond to
cyclosporin but require treatment with high-dose
corticosteroids [6, 151. This may reflect the involvement
of effector mechanisms, such as neutrophil activation,
which are suppressed by corticosteroids but not by the
more specific cyclosporin. If neutrophils are important in
causing the tissue damage of acute rejection, other treatments capable of protecting tissues from neutrophilmediated damage may be useful adjuvants to
conventional immunosuppressive therapy. N-Acetylcysteine and dimethylthiourea are two such agents which
have the advantage of not suppressing the immune
response to infections [loll.
WHICH PATIENTS
REJECTION?
DEVELOP
IRREVERSIBLE
It is not known whether acute/reversible rejection and
irreversible/chronic rejection (VBDS) are part of the
same process or whether the pathogenesis of each is different. In most patients VBDS follows an earlier episode
of ‘acute rejection’ and attempts have been made to find
factors which may differentiate between reversible acute
rejection and the onset of VBDS. Since the lesions of endstage VBDS include arterial thickening and a loss of bile
ducts, studies have focused on damage to these structures.
There is evidence for increased endothelial damage
during the early inflammatory episodes in VBDS both
histologically [2] and from elevated levels of hyaluronic
acid, a marker of hepatic endothelial damage [46]. In
addition, it is claimed that increased levels of glutamyl
transpeptidase ( y-glutamyltransferase, E C 2.3.2.2) reflect
more severe bile duct damage [ 1021. However, endothelial
and bile duct damage are also features of acute reversible
rejection.
A different pathogenesis for VBDS is suggested by the
association with infection reported by the Cambridge/
King’s College Hospital Group [Sl]. This study also
showed VBDS to be independently associated with a class
I HLA mismatch and it is possible that CMV infection
promotes a continuing immune response to HLA antigens
on bile ducts. This may be related to an increase in the
expression of HLA antigens on biliary epithelium secondary to y-interferon production as discussed above [58,
591. Further studies examining the interaction of CMV
and liver cell components are awaited.
Although the early lesions of VBDS are characterized
by intense inflammation in portal tracts, serum markers of
lymphocyte activation decrease as the condition proceeds
and the end-stage liver often contains a minimal inflammatory infiltrate [77]. This may reflect diminishing antigen
challenge, since by this time there are few remaining bile
ducts and arteries demonstrate intimal thickening and
sclerosis. Future studies should therefore be concerned
with attempts to reduce or control the early intense
inflammatory reactions which precede this irreversible
damage.
348
D. Adams
CONCLUSIONS
Although lymphocytes probably instigate liver allograft
rejection, the tissue damage and clinical features may
result from the activation of several effector mechanisms.
Rather than viewing rejection as a mainly T-cell-mediated
process, it is perhaps more accurate to consider it a n
inflammatory cascade resulting in the activation of
neutrophils, macrophages and B-cells as well as cytotoxic
T-cells. This concept of rejection has implications for
treatment, since most treatment is aimed at suppressing
lymphocyte activity. Therapies which suppress other
inflammatory mechanisms may also have an important
role in reducing damage t o the graft during rejection.
However, any broadening of immunosuppression must
take into account the potential increased risks of opportunistic infection.
ACKNOWLEDGMENTS
I am grateful to Drs D. Burnett, E. Elias, J. Neuberger and
R. A. Stockley for their support and encouragement, and
to the Medical Research Council and the West Midlands
Regional Health Authority for financial support.
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