Detection and Clinical Relevance of Donor Specific HLA Antibodies

Frans H.J. Claas, Leiden University Medical Center, Leiden, The Netherlands

For several decades complement dependent cytotoxicity (CDC) has been the standard assay for HLA antibody screening and the final crossmatch before transplantation. Life was easy as a positive crossmatch, due to donor specific HLA antibodies (DSA), was considered a contra-indication for transplantation.

In the meantime new and more sensitive assays have been introduced, mainly based on the reactivity of antibodies with isolated HLA molecules attached to a solid phase. The advantage of these techniques is the higher degree of reproducibility compared to CDC and the fact that also non-complement fixing antibodies can be detected.

Currently, these assays are widely used for the determination of HLA antibodies before transplantation and the definition of acceptable and unacceptable HLA mismatches facilitating virtual crossmatching. The outcome of these assays plays also a determinative factor in the decision to apply desensitization protocols for particular donor-recipient combinations. Furthermore, patients are monitored after transplantation for the presence of DSA as more and more data suggest that the formation of DSA after transplantation is associated with a higher risk of graft loss due to chronic rejection.

Since the introduction of these assays, the frequency of HLA antibody screening in (potential) transplant recipients has increased enormously. In contrast to the old situation, the clinical relevance of HLA antibodies , detectable in solid phase assays only, is not well established. The presence of DSA before transplantation is certainly not a contra-indication for transplantation but rather a risk factor. This risk may vary between no risk at all to a high risk to develop an acute humoral rejection. The same holds true for the development of DSA after transplantation. On the population level patients with DSA have a poorer prognosis than patients without DSA but quiet some patients with DSA have an excellent graft function for many years.

The challenge is to develop strategies by which these techniques can be used to determine the relevance of DSA in a specific donor-recipient combination.