Graft
rejection
Allografts provoke a powerful immune response that results in rapid
graft rejection unless immunosuppressive therapy is given. The pioneering
studies of Medawar in the 1940s and 1950s firmly established that allograft
rejection was due to an immune response and not a nonspecific inflammatory
response.
Later studies demonstrated that T-lymphocytes play an essential role in
orchestrating the graft rejection response. The immunological effector
mechanisms responsible for graft rejection are those that have evolved to
provide protection from pathogens — in other words there are no unique
immunological
mechanisms causing graft rejection. Cytotoxic Tcells, delayed-type
hypersensitivity and antibody-dependent effector mechanisms all play a role.
The
allograft rejection response is directed against a group of cell-surface
molecules called the ‘human leucocyte antigens’ (HLAs) which were first
described by Dausset in 1958. HLAs are highly polymorphic (i.e. the amino
acid sequence is very variable between individuals) and play a special role in
immune recognition. Their normal physiological function is to display
antigenic peptides derived from foreign pathogens so that they can be recognised
by Tlymphocytes.
There
are two types of HLA molecule — HLA class I and HLA class II. HLA class I
molecules comprise a polymorphic alpha-chain which is associated with a smaller
nonpolymorphic chain known as a beta2-microglobulin. HLA class II
molecules comprise two polymorphic polypeptide chains designated alpha and beta The
tertiary structure of HLA class I and HLA class II is similar. In both classes
of HLA molecule, the extracellular domains form a cleft, the purpose of which is
to hind and display foreign peptides for surveillance by T-lymphocytes (Fig.
11.3). Each individual HLA molecule only binds one peptide at a time but can
bind a wide range of different
HLA
class I antigens are present on all nucleated cells, while HLA class II antigens
have a more restricted distribution and are expressed stongly on
antigen-presenting cells such as dendritic cells, macrophages and B-lymphocytes.
However, HLA class II expression is readily inducible on all cell types by
cytokines such as interferon-gamma. HLA molecules expressed on donor tissues trigger
a strong graft rejection response in the recipient by virtue of their special
role in Tcell recognition and the fact that they are so polymorphic. It is
rare for two unrelated individuals to have a completely identical set of HLA
molecules. The high degree of HLA polymorphism between individuals is clearly
unfortunate from the viewpoint of organ transplantation because it ensures
immunological incompatibility between unrelated individuals. However,
transplantation of organs is nonphysiological and it is reassuring to remember
that the existence of extensive HLA polymorphism provides a survival advantage
for the human species by maximising the chance that a given population will be
able to recognise and mount an effective immune response to new pathogens.
T-lymphocytes
recognise peptide antigens bound to HLA molecules through their T-cell receptor
(TCR), and each Tcell expresses a unique TCR that binds to a particular HLA—peptide complex. During their development, T-cells that recognise
self-derived peptides displayed by self HLA are normally deleted as they mature
in the thymus gland, thereby eliminating self-reactive T-cells and avoiding
autoimmunity.
The
TCR is a heterodimer comprising an alpha- and beta-chain. It associates at
the surface of the T-cell with the CD3 complex, which is involved in
intracellular signalling after the TCR is activated by engaging antigen. Mature
T-cells bear either CD4 or CD8 coreceptors and these bind to nonpolymorphic
regions of class II and class I HLA, respectively, on antigen-presenting cells.
Activation of a T-cell by an antigen-presenting cell requires the delivery of
two distinct signals (Fig. 11.4). The first signal (signal 1) is delivered after
ligation of the T-cell receptor with an HLA—antigen complex. The second
signal (signal 2) is delivered following the interaction of additional
nonpolymorphic ligand—receptor molecules or co stimulatory molecules on the
surface of the antigen-presenting cell and T-cell.
In
the context of organ transplantation, allogeneic HLA molecules are exceptionally
strong antigens because they are able to stimulate T-cells directly without the
need to be broken down into short peptides and presented in the cleft of an HLA
molecule. This pathway of antigen recognition is unique to transplantation and
is called direct allorecognition. All of the commonly transplanted organs
have large numbers of dendritic cells distributed throughout their parenchyma.
These professional antigen-presenting cells are richly endowed with class I and
class II antigens and possess all of the necessary costimulatory molecules to
trigger activation of recipient T-cells. Allogeneic molecules can also be
processed like other types of antigen and displayed as antigenic peptides
associated with HLA molecules on recipient antigen-presenting cells — this is
termed indirect allorecognition and makes an important contribution to
graft rejection.
After
encountering alloantigens, activated T-cells undergo a period of clonal
expansion which is dependent on IL-2 and other T-cell growth factors. CD4
T-cells, through release of cytokines, play a central role in orchestrating the
various effector mechanisms which are responsible for graft rejection ( Fig.
11.5). The cellular
effectors of graft rejection include cytotoxic CD8 I-cells that recognise donor HLA class T antigens
expressed by the graft and cause target cell death by releasing lytic molecules
such as perform and granzyme. Graft-infiltrating CD4 T-cells that recognise
donor HLA class II mediate direct target cell damage and are also able, by
releasing cytokines such as interferon-gamma, to recruit and activate macrophages
which act as nonspecific effector cells. Finally, CD4 T-cells provide essential
T-cell help for B-lymphocytes that produce alloantibodies which bind to graft
antigen and induce target-cell injury directly or through antibody-dependent
cell-mediated cytotoxicity.
Types
of allograft rejection
Allograft rejection can be divided into three distinct types on the
basis of timescale and underlying pathophysiology:
• hyper acute rejection (occurs immediately);
• acute rejection (occurs in the first 6 months);
• chronic rejection (occurs months and years after transplantation).
Hyper acute
rejection is avoidable and acute rejection, although common, can usually be
reversed by immunosuppressive therapy. Chronic rejection occurs after all
types of organ transplantation and, because it is largely resistant to currently
available immunosuppressive therapy, is a major cause of graft failure.
Allograft rejection manifests itself as functional failure of the transplant and
is confirmed by histological examination. Biopsy material is obtained from
renal and pancreas grafts by needle biopsy, and from hepatic grafts by
percutaneous or transjugular liver biopsy. Cardiac grafts are biopsied by
transjugular endomyocardial biopsy, and lung grafts by transbronchial biopsy.
After small intestinal transplantation, mucosal biopsies are obtained from the
graft stoma or more proximally by endoscopy. A standardised histological grading
system, termed the Banff classification (named after the Canadian town where the
initial scientific workshop was held) defines the presence and severity of
allograft rejection after solid organ transplantation.
Hyperacute
rejection is due to the presence in
the recipient of preformed cytotoxic antibodies against HLA class I antigens
expressed by the donor. These may arise from blood
Acute
allograft rejection usually occurs
during the first 6 months of transplantation but may occur later. It is mediated
predominantly byT-lymphocytes, but alloantibody may also play an important
role. Acute rejection is characterised by mononuclear cell infiltration of the
graft (Fig. 11.6). The mononuclear cell infiltrate is heterogeneous and includes
cytotoxic T-cells, B-cells, natural killer (NK) cells and activated macrophages.
Antibody deposition may also be present. All types of organ allograft are
susceptible to this form of rejection and it occurs in 25—50 per cent
of cases. Fortunately, the majority of acute rejection episodes can be reversed
by appropriate immunosuppressive therapy.
Chronic
allograft rejection occurs after the
first 6 months, and is due to antibody- and cell-mediated effector mechanisms
All types of transplant are susceptible to chronic rejection and it is the major
cause of allograft failure. Interestingly, however, the liver appears more
resistant than other solid organs to the
• previous episodes of acute rejection;
• degree of HLA mismatch;
• long cold ischaemia time;
•cytomegalovirus (CMV)
infection;
• raised blood lipids;
• inadequate immunosuppression (poor compliance).
The
single most important risk factor for chronic rejection is acute rejection.
After kidney transplantation, acute rejection with vascular inflammation and
recurrent episodes of acute rejection are strongly predictive of subsequent
graft failure from chronic rejection.
The
histological picture of chronic rejection is dominated by vascular changes with
arterial myointimal proliferation which results in ischaemia and fibrosis (Fig.
11.7). In addition to vasculopathy, there are organ-specific features of chronic
graft rejection. These are:
• kidney — glomerular sclerosis and tubular atrophy;
• pancreas — acinar loss and islet destruction;
• heart — accelerated coronary artery disease (cardiac allograft
vasculopathy);
• liver — vanishing bile duct syndrome;
• lungs — obliterative bronchiolitis.
Chronic
rejection causes functional deterioration in the graft resulting after months or
years in graft failure. Unfortunately, currently available immunosuppressive
therapy has had little effect in preventing chronic rejection.