Antibody-Incompatible
Transplantation
An ever-increasing number of patients on the transplant
waiting list and a static rate of DBD donation has forced the development of
DCD donor programmes and the increasing use of living donors. If a patient has
a potential living donor, one of the major barriers to successful transplantation
is donor–recipient immunological incompatibility, i.e. the presence of
circulating donor-specific ABO or HLA antibodies. In such cases,
transplantation in the absence of antibody removal would result in hyperacute
rejection and immediate loss of the graft (see Chapter 28). Even low levels of
antibody can cause acute antibody-mediated rejection (AMR), which has a poor
prognosis.
Antibody Specificity
ABO antibodies
ABO antigens are not only found on the surface of red blood
cells, but also on endothelial cells (see Chapter 10). ABO antigens are
carbohydrates (not protein antigens, in contrast to HLA). Carbo- hydrate
antigens are termed ‘T-independent’ antigens, i.e. B cells do not require
T cell help to make antibodies to such antigens. B cells in the marginal zone
of the spleen are important for T-independent antibody responses.
Group O individuals (who lack A and B antigens), develop
antibodies to both antigens. This is thought to be driven by cross- reactivity
with microbial antigens. In group A individuals, B anti- bodies are present,
while group B individuals have A antibodies. Thirty per cent of potential
living donor-recipients have ABO- incompatible (ABOi) donors (mainly group O
recipients with donors who are A, B or AB to whom they have antibodies).
HLA antibodies
One-third of patients on the transplant waiting list
have detectable antibodies to human leucocyte antigens (HLA). These patients
are termed ‘sensitised’. HLA molecules are highly polymorphic (see Chapter
10), so if the immune system encounters foreign cells expressing HLA molecules,
they will likely be different from self-HLA and will induce an immune response.
There are three common scenarios in which non-self HLA has been encountered by
patients awaiting transplantation, termed as ‘sensitising events’:
· blood transfusion
· pregnancy
· previous transplantation (including skin grafts).
These sensitising events may result in the formation of
antibodies to multiple HLA molecules, both MHC class I and class II.
Desensitisation procedure
A number of strategies are used to facilitate antibody
incompatible transplantation including:
· removal of donor-specific antibodies (DSA) to a ‘safe’ level prior
to transplantation
· prevention of the synthesis of further DSA, by inhibiting memory B
and T cells, and plasma cells
· inhibition of antibody-mediated complement activation.
Antibody removal
This involves filtration or plasma exchange; the
patient’s blood is passed through a special column that removes the antibody
component. Antibody removal may be more or less specific, for example there are
columns that bind only anti-A and anti-B anti-bodies, and do not deplete the
patient’s general pool of IgG (Gly-cosorb columns). Some systems return the
patient’s filtered plasma, while others require replacement with human albumin
solution (HAS) or fresh frozen plasma (FFP). Most centres will begin antibody
removal in the week prior to the planned transplantation, since the number of
sessions required varies, depending on the starting titre of DSA. Intravenous
immunoglobulin (pooled human IgG, IVIG) can also reduce DSA through blockade of
FcRn, the receptor responsible for recycling IgG.
Prevention of the formation of additional DSA
IgG is produced by plasma cells, which are generated
from B cells following the receipt of T cell help in the germinal centres of
lymph nodes and spleen. The emerging plasma cells migrate from these organs to
niches within bone marrow, where they reside for pro- longed periods.
Long-lived plasma cells do not proliferate (and are therefore difficult to
target therapeutically), but exist as ‘protein factories’ producing 95%
of serum IgG. Some post-germinal centre B cells become ‘memory’ B cells
(characterised by surface expres- sion of CD27). They continually circulate
through the secondary lymphoid organs and if the individual is re-challenged
with an antigen, these memory B cells can rapidly proliferate to produce large
quantities of low-affinity antibody. Thus, to prevent re-accu-mulation of DSA
post transplant, a strategy that targets B cells, T cells and plasma cells is
required.
Most centres will start immunosuppression some time
before antibody removal begins. This involves the administration of a
lymphocyte-depleting agent, the nature of which varies from centre to centre.
Some centres use panlymphocyte depletion with anti-thymocyte globulin (ATG) or
alemtuzumab (CamPath-1H), while others use B cell-targeted therapy, such as the
CD20 monoclonal antibody rituximab. Early attempts at antibody-incompatible
transplantation utilised splenectomy as a means of depleting B cells. Each of
the above agents has its own merits and disadvantages: ATG is a polyclonal
mixture of antibodies that targets both B and T cells. On the negative side it
is a profound immunosuppressant and is associated with an increased risk of
infection. Alemtuzumab, an anti-CD52 antibody, depletes B cells, T cells, DCs
and natural killer cells. It appears to have a relatively good safety profile
in terms of infection. Often the choice of agent will depend on the perceived
magnitude of the donor-specific immune response.
The proteosome inhibitor bortezomib has also been used
to target plasma cells in transplantation, but is currently an experimental
treatment only.
ABO-incompatible transplantation is more amenable to
desensitisation procedures, with patient and allograft survival nearing that of
ABO-compatible living donor transplants in experienced centres.
HLA-incompatible transplantation appears to pose a greater challenge, and even
with desensitisation, some patients’ DSA titres do not fall sufficiently to
allow safe transplantation.
Prevention of complement activation
IgG immune complexes activate complement via the
classical pathway. This generates the C3 convertase C4b2b, which catalyses the
conversion of C3 to C3a. This in turn activates C5 and initiates the formation
of the membrane attack complex (MAC) which disrupts cell membrane integrity,
leading to cell lysis. A monoclonal antibody, eculizumab, specifically binds to
C5a and inhibits its activity, preventing MAC formation. Early studies suggest
that this agent may well be of use post-transplant in preventing the
deleterious effects of antibody-mediated complement activation. IVIG may also
act to block FcγR-mediated activation of phagocytes.
Paired exchange kidney donation
Patients with a potential antibody-incompatible donor
can be placed into a national pool with other antibody-incompatible
donor–recipient pairs. Attempts are made to match one pair with another such
that an antibody-compatible transplant may occur, i.e. the donor from pair
A is compatible with the recipient from pair B and vice versa. More complex
exchanges between three or more pairs are possible. Such kidney exchanges allow
transplantation to proceed while avoiding the rigors of desensitisation.
