HLA Mismatch - Professor Richard Kirk 2023

Transplant Challenges
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HLA Mismatch

Sensitisation

Preformed HLA antibodies occurs through exposure to foreign DNA (Figure 1). This may be through blood products (especially platelets), homografts (used in the repair of congenital heart disease), pregnancy and of course a previous solid organ transplant. Sensitisation can also occur in the absence of known factors and it is postulated that this may be the result of some viral antigens being similar to HLA glycoproteins - a mechanism that has similarities with the development of ABO antibodies and E.coli colonisation of the gut. As a consequence up to 20% of individuals may have pre existing HLA antibodies - they therefore have memory B and plasma cells that are active, and also have memory T cells to the antigen too, as B cells require the T helper cells TCR to bind to the same antigen as the BCR to become activated and subsequently transform into plasma cells.

Figure 1. Sensitization Events

At the time of listing for transplant the HLA antibody status of the patient is assessed, for example by using Luminex technology. Individuals with preformed HLA antibodies may limit the suitability of potential donors, depending on their strength, as assessed by their mean fluorescent index (MFI). For example avoiding a strong (MFI>5,000) pre-existing HLA antibody directed at an HLA-A2 antigen would reduce the potential donor pool by 50% as half the population genotype is A2. On the other hand, a Cw15 antigen is only present in around 5% of the population and so if a patient has a Cw15 antibody then the likelihood of a potential donor being compatible is 95%.

This is known as the virtual crossmatch.

Desensitization

For those patients who have a very limited pool of potential donors then desensitization may be attempted. Desensitization is a loose term comprising methods to reduce or block the effect of antibodies (Figure 2). There are 4 main methods:

General immunosuppression - IVIG can reduce the HLA load - the possible mechanisms include neutralization of HLA antibodies and cytokines, inhibition of complement and down regulation of T and B cells. Steroids are also potent inhibitors of cytokines and T cell activation. The cytokine family of IL-6 has recently been recognised as a regulator of immune and physiologic processes including the innate and adaptive immunity. It plays a major role in the interaction between T & B cells and the differentiation into and control of plasma cells. Tocilizumab, a humanized monoclonal antibody, against IL-6R is the first such dug to be able to block IL-6 effects
Antibody removal using either plasmapheresis or more specific means such as immunoadsorption
Block the effect of antibodies - either through complement blockade (Eculizumab) or destroying the antibody by enzymatic cleavage (Imlifidase)
Reduce antibody production - Cytostatic drugs including mycophenolate prevent the production of antibody producing short lived plasma cells, daratumumab, an anti-CD38 antibody and proteosome inhibitors cause apoptosis of both short and long lived plasma cells.

Whilst the theory is clear the practicalities are more problematic:

Plasmapheresis requires cardiovascular stability and a reasonable blood pressure - in cardiac failure this therefore becomes challenging. In addition plasmapheresis removes many components of plasma unlike immunoadsorption, however the latter is not universally available. Additionally when the HLA antibody levels are very high (MFI 10,000 and above) then reducing them to a level where they will not cause rejection may prove impossible. Even if the HLA MFI can be reduced to an acceptable level, then pheresis needs to continue for a prolonged period
For a patient to have persistent high HLA levels then it is reasonable to assume they have active long lived plasma cells (LLPC). These LLPCs tend to reside in bone marrow niches which are relatively protected places since drug penetration is difficult. Proteosome inhibitors are effective for some, but not all LLPCs and there is some evidence that if LLPCs are reduced they are rapidly replaced from memory B cells. There is now some evidence that reducing the memory B cell population (CD20+) with a combination of rituximab and proteasome is more effective.
Blockade of cleavage of C5 with eculizumab is very effective but the blockade is not indefinite, lasting at most 3 weeks. It is thus able to buy time but unless it is given repeatedly, it is only a short-term measure. Likewise the cleavage of IgG is also effective, although short lived and generally not repeatable due to the rapid development of anti Imlifidase antibodies that negate the effect of additional doses.

In view of the limitations of desensitization and the uncertainties of the virtual crossmatch predicting rejection then protocols (e.g.CTOTc) have been developed to transplant, regardless of sensitization, which include most of the methods outlined above.

In summary desensitization can be accomplished in some, but by no means all and is least effective in highly sensitized patients. However it can increase the potential donor pool for some patients.

Figure 2. Desensitization Toolbox

Adapted from Janeway’s Immunobiology. Garland Science; 7th edition (2008). ISBN-13: 978-0815341239