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.
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).
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
· 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.
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.
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.