Identification of risk epitope mismatches associated with de novo donor-specific HLA antibody development in cardiothoracic transplantation.

The development of de novo donor-specific HLA antibodies (dnDSA) after transplantation is associated with graft failure, mortality, and cost. There is no effective therapeutic intervention to prevent dnDSA or ameliorate associated injury. The aims of this study were to identify specific HLA factors associated with dnDSA development and to propose primary prevention strategies that could reduce the incidence of dnDSA without prohibitively limiting access to transplant. The investigation cohort included heart transplant recipients from 2008 to 2015 (n = 265). HLA typing was performed and HLA antibody testing was undertaken before and after transplantation. HLAMatchmaker analysis was performed for persistent dnDSA to identify potentially more immunogenic eplet differences. Validation was performed in recipients of lung transplants from 2008 to 2013 (n = 433). The majority of recipients with dnDSA had antibodies to identical eplet positions on DQ2 and DQ7. A high-risk epitope mismatch (found in DQA1*05 +  DQB1*02/DQB1*03:01(7)) was associated with a 4.2- and 4.9-fold increased risk of dnDSA in heart and lung recipients respectively. HLA electrostatic potential modeling provided a plausible explanation for this observed immunogenicity. A theoretical allocation algorithm avoiding high-risk epitope mismatches was generated and predicted to reduce dnDSA by up to 72% without additional testing, eplet analysis, or cost.

Allosensitization Following Bone Graft.

It is recognized that patients may become sensitized to donor-specific HLA antigens as a result of previous antigenic exposures, classically through previous transplantation, pregnancy, or blood transfusion. We present an unusual case of a patient who unexpectedly developed a range of anti-HLA antibodies following orthopedic surgery where a bone graft was deployed intraoperatively. We describe the case of a 52-year-old man awaiting a renal transplantation, undergoing elective orthopedic surgery requiring a small-volume bone graft. His postoperative antibody profile was found to be substantially changed compared to his previous negative samples, with the presence of HLA-DR, DQ, and DP specificities, at levels that would be likely to give a positive flow cytometry crossmatch and therefore according to local procedures required listing as unacceptable antigens for organ allocation. We perform a literature review of all previous cases of allosensitization following bone graft. This case is the first to demonstrate allosensitization following minor surgery with ;low-volume bone graft. Previous evidence is very limited and pertains only to massive osteochondral surgery for trauma or malignancy, and is confounded by potential concomitant blood transfusion. Clinicians should be aware of the risk of allosensitization where bone grafts are used.