Belimumab to Mobilise Memory B-cells From Secondary Lymhoid Organs to Improve Memory B-cell HLA-specificity Profiling to Support Delisting for Transplant Access in Highly-sensitized

Kidney transplantation is the optimal treatment for patients with end-stage kidney disease, but access is limited by antibodies targeting non-self human leukocyte antigens (HLA). Antibody-mediated rejection (AMR) occurs when HLA molecules on the donor organ correspond to preformed antibodies in the transplant recipient, which may arise from sensitizing events such as prior organ transplantation, pregnancy, or blood transfusion. To prevent AMR, pre-transplant testing identifies the HLA specificities targeted by patient antibodies, and these specificities are listed as "unacceptable HLA specificities," thereby excluding donor kidneys with incompatible HLA molecules from allocation. Although registration of unacceptable HLA specificities reduces the probability of identifying a compatible donor, this strategy is generally accepted because it mitigates the risk of AMR. However, in highly sensitized transplant candidates, defined as those with HLA antibodies against ≥85% of the donor population, the probability of identifying a suitable donor becomes extremely low. Such patients often remain on transplant waiting lists for years and face a five-year mortality rate of approximately 50% associated with maintenance dialysis. Two approaches may subsequently be considered to improve allocation probability: delisting and desensitization.

Desensitization can be achieved using immunosuppressive agents targeting antibodies and antibody-producing cells. Current desensitization strategies are associated with a high risk of AMR and do not confer a survival benefit compared to remaining on the waiting list. Consequently, delisting should be considered as an initial strategy. Delisting enables transplantation despite the presence of preformed donor-specific antibodies (DSA) that confer a relatively low risk of AMR. Ideally, HLA specificities that occur frequently in the donor pool but pose minimal individual risk are selected for delisting.

Methods for defining low-risk HLA specificities remain imperfect, and no validated international delisting protocols are currently available. After exclusion of specificities associated with a positive complement-dependent cytotoxicity assay, clinicians frequently rely on semi-quantitative mean fluorescence intensity (MFI) values obtained from the Luminex single-antigen bead (SAB) assay. However, this assay is limited by non-standardized cut-off values, a weak correlation with HLA antibody titers, and a primary reflection of antibodies produced by plasma cells. Importantly, the assay does not account for memory B cells (mBC), which can rapidly regenerate antibody production after transplantation and contribute to "rebound" AMR. This limitation partially explains the variability in transplant outcomes associated with pre-transplant DSA exhibiting low MFI values. Direct assessment of HLA-specific mBC may therefore improve pre-transplant risk stratification.