Incidence and Role of Recipient-Specific Antibodies in Allogeneic Hematopoietic Cell Transplantation from Mismatched Related Donors

High titer of donor-specific antibodies (DSAs) increases the risk of graft rejection after mismatched related hematopoietic cell transplantation (HCT). There are no data regarding the incidence of anti-HLA recipient-specific antibodies (RSAs) and their role after transplantation. Here we aimed to identify the incidence of RSAs in a mismatched related hematopoietic cell donor population and their possible impact on immune-mediated complications, such as acute graft-versus-host disease (aGVHD), and complications resulting from endothelial injury, such as transplantation-associated thrombotic microangiopathy (TA-TMA) and veno-occlusive disease (VOD). We prospectively analyzed the incidence of anti-HLA antibodies in 28 mismatched related pairs of recipients and their donors who underwent HCT at our center between 2020 and 2022. In positive samples screened for anti-HLA class I and/or II antibodies, the specificity of the HLA antibodies was analyzed. All recipients had a hematologic malignancy and received a myeloablative conditioning regimen and immunosuppression consisting of post-transplantation cyclophosphamide, tacrolimus, and mycophenolate mofetil. Patients were tested for TA-TMA and aGVHD development during routine post-transplantation visits up to 100 days post-transplantation. We used modified Jodele criteria for TA-TMA diagnosis, and based aGVHD grading on the MAGIC criteria. VOD was assessed using the European Society for Blood and Marrow Transplantation. Anti-HLA antibodies were detected in 12 donors (43%) and in 9 recipients (32%). There were no significant differences between donors and recipients according to age (median, 42 years [range, 17 to 69 years] versus 39 years [range, 8 to 68 years]), sex, or pregnancy history. No transfusion history was noted in the donor group (P < .05). RSA antibodies were present more often than DSAs and were detected in 9 out of 12 (75%) anti-HLA-positive donors and in only 2 out of 9 (22%) recipients, respectively (P < .05). During the follow-up, 11 patients (39%) developed aGVHD, including grade I-II in 9 (32%) and grade III-IV in 2 (7%). Twelve patients (43%) met the criteria for TA-TMA, and only 1 patient (3.5%) was diagnosed with VOD by day 100 post-HCT. RSAs were detected significantly more often in the TA-TMA group; among 12 patients diagnosed with TA-TMA, 7 (58%) had RSAs (P < .05). We did not find a correlation between RSAs and aGVHD. The patient with VOD did not have an RSA-positive donor. There was no difference in membrane attack complex (MAC) concentration in the RSA-positive group on day 30 and day 60 post-HCT; however, there was a trend toward higher MAC concentration in the RSA-positive group on day 100 (median, 912 ng/mL [range, 788 to 1120 ng/mL] versus 616 ng/mL [range, 352 to 1244 ng/mL]; P = .055). Patients with RSA suffered more often from platelet and red blood cell decreases or transfusion refractoriness, and increased lactate dehydrogenase activity was observed in all RSA-positive cases. The donor immune status and the presence of RSA may be associated with higher rates of TA-TMA in mismatched HCT recipients. Antibody-mediated complement activation might be an additional factor influencing TA-TMA occurrence.