Anti-Donor HLA Antibody Response After Pancreatic Islet Grafting: Characteristics, Risk Factors, and Impact on Graft Function

Abstract

Pancreatic islet grafting restores endogenous insulin production in type 1 diabetic patients, but long-term outcomes remain disappointing as a result of immunological destruction of allogeneic islets. In solid organ transplantation, donor-specific anti-HLA antibodies (DSA) are the first cause of organ failure. This retrospective multicentric study aimed at providing in-depth characterization of DSA response after pancreatic islet grafting, identifying the risk factor for DSA generation and determining the impact of DSA on graft function. Forty-two pancreatic islet graft recipients from the Groupe Rhin-Rhône-Alpes-Genève pour la Greffe d'Ilots de Langerhans consortium were enrolled. Pre- and postgrafting sera were screened for the presence of DSA and their ability to activate complement. Prevalence of DSA was 25% at 3 years postgrafting. The risk of sensitization increased steeply after immunosuppressive drug withdrawal. DSA repertoire diversity correlated with the number of HLA and eplet mismatches. DSA titer was significantly lower from that observed in solid organ transplantation. No detected DSA bound the complement fraction C3d. Finally, in contrast with solid organ transplantation, DSA did not seem to negatively affect pancreatic islet graft survival. This might be due to the low DSA titers, specific features of IgG limiting their ability to activate the complement and/or the lack of allogenic endothelial targets in pancreatic islet grafts.

Donor-Specific Antibodies—The Devil Is in the Detail

“…We read with interest the study by Pouliquen et al for the GRAGIL network (1). This seeks to address the important question of the role of donor-directed HLA antibodies (DSAs) after pancreatic islet transplantation by examining samples from multiple centers.…”

Class II Human Leukocyte Antigen Epitope Mismatch Predicts De Novo Donor‐Specific Antibody Formation After Liver Transplantation

“…Epitope-based matching has already shown improvement of outcomes in other organs. (9)(10)(11)(12)(13)(14) Some studies have shown that HLA class I and class II MMs with low eplet loads are less likely to induce antibody responses. (15) Recently, Willicombe et al demonstrated that the epitope MM burden predicts the risk of dn-DSA formation in kidney transplantation.…”

Cum hoc sed non propter hoc

“…In our cohort, onethird of islet graft recipients developed alloantibodies directed against mismatched HLA molecules expressed by the graft. The diversity of the repertoire and the titer of donor-specific antibodies (DSAs) were highly variable, and maintenance immunosuppression appeared to protect against DSA generation (2). Interestingly, and in marked contrast with solid organ transplantation (where antibody-mediated rejection is widely considered the main cause of transplant failure [3]), the appearance of DSAs did not seem to accelerate the rate of islet graft attrition in our cohort (2).…”

“…The diversity of the repertoire and the titer of donor-specific antibodies (DSAs) were highly variable, and maintenance immunosuppression appeared to protect against DSA generation (2). Interestingly, and in marked contrast with solid organ transplantation (where antibody-mediated rejection is widely considered the main cause of transplant failure [3]), the appearance of DSAs did not seem to accelerate the rate of islet graft attrition in our cohort (2). While our conclusion has since been confirmed in an independent single-center study (4), it is in striking disagreement with a previous report, which found an absolute association between de novo DSA onset and graft loss in five islet recipients (5).…”