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HLA-specific antibodies are back in fashion, although perhaps never too fashionable in orthotopic liver transplantation (OLT). Why the renewed interest? One of the main reasons is a recent technological advance that uses fast solid-phase assays and immobilized HLA to characterize HLA-specific antibodies. The most widely adopted form of this is the single antigen bead assay (SABA), which although not perfect, has distinct advantages over the complement-dependent lymphocytotoxicity assay with which it is compared. SABAs identify antibody specificities to individual HLA alleles and can separate reactivity against different HLA loci, which is difficult to achieve using assays based on whole cells expressing multiple HLA in set combinations due to linkage disequilibrium. SABA also make sequential testing of multiple samples much easier to do. In this edition of AJT O’Leary and colleagues used SABA to demonstrate that donor HLA-specific antibodies (DSA) are associated with chronic rejection of liver allografts (1). They documented unequivocally where HLA serological reactivity corresponded to donor HLA mismatches and tested successive samples over the life of the transplant. A recent paper by Musat et al. used the same assay to show an association between portal capillary and stromal C4d staining, indirect evidence of antibody mediated graft injury and DSA in patients with biopsy-proven rejection (2). Together these papers support a role for DSA in OLT as proposed by Donaldson et al. more than 20 years ago (3). However, the question of whether these antibodies are a cause or a consequence of the rejection process is unproven. O’Leary et al. found that preexisting donor HLA Class I specific antibodies were associated with subsequent rejection and that in general the appearance of posttransplant antibodies preceded the diagnosis of rejection. The fact that rejection was associated with Class I and not Class II specific antibodies further supports a functional role given the far more extensive Class I expression on bile ducts the principle targets in chronic liver rejection. However, many of their nonrejection cases had preexisting DSA or developed de novo DSA implying that DSA per se are not sufficient to cause rejection.

We therefore have a risk factor but no proven mechanism of DSA-mediated graft injury in OLT. Further work needs to be undertaken to investigate the circumstances under which DSA are pathogenic before these findings can be used to direct therapeutic intervention or transplant management (4). Pretransplant testing of liver recipients and donor HLA typing can therefore identify patients at risk of rejection and graft loss, and guidelines used in the United Kingdom (http://www.bts.org.uk/transplantation/standards-and-guidelines) recommend their routine testing to aid posttransplant management, such as changes in immunosuppression or antibody removal. The need for posttransplant antibody monitoring is less clear, not least because the appearance of DSA can precede the development of chronic rejection by years, or even decades in some cases and in many patients will never translate into graft dysfunction. Furthermore the current incidence of chronic rejection in most centers is very low. However, we now have clear evidence that DSA are associated with chronic rejection of liver grafts as they are in other organ transplants where posttransplant monitoring is recommended. At the very least this revelation should stimulate transplant units to prospectively collect posttransplant serum samples at regular intervals in order to confirm or refute these findings. As the evidence implicating DSA in the rejection process grows one could argue that testing for HLA-specific antibodies at the time of acute rejection might help determine prognosis and the likelihood of subsequent chronic rejection. If so, such cases could be targeted for more aggressive immunosuppression, although without understanding the underlying mechanisms effective therapy might be difficult to design. There is however a little nugget in the paper from O’Leary et al. that might point in the right direction (2). They found a markedly improved graft survival in patients with preformed DSA who received induction therapy with daclizumab or OKT3 suggesting that early T cell activation is important in the generation of antibody-mediated rejection. Consistent with this Musat et al. (3) found a significant association between DSA, C4d+ deposition and acute cellular rejection. There is evidence that T cell-specific agents are effective in acute antibody-associated rejection of other organs; in HLA incompatible renal transplantation OKT3 can reverse rejection even in the continuing presence of high levels of DSA (5).

Therapeutic targeting of B cells is also appealing although the most commonly used B-cell therapy rituximab targets CD20 which is absent from plasma cells and memory B cells that will already be primed in patients with preexisting DSA (6). However recent work in monkeys has shown that pretransplant depletion of B cells can prevent the subsequent development of chronic antibody-mediated rejection of heart transplants (7). The treatment of antibody-associated chronic rejection represents a more difficult problem because there can be a significant delay between the appearance of DSA and diagnosis of rejection; should one treat the antibody or the rejection? Until there are confirmatory data the answer is obviously the latter, but we now have the tools and reasons to undertake these further studies. We now know that donor HLA-specific antibodies develop after OLT so we need to keep knocking on the door of rejection [to continue the metaphor introduced by Knechtle (1)]. Of course we don't really know what's behind this door; antibody, T cells, something else or all of these?

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The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

References

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