The incidence and role of recipient-specific antibodies (RSA) in allogeneic hematopoietic cell transplantation from mismatched related donors

: High titer of donor-specific antibodies (DSA) increases the risk of graft rejection after mismatched related hematopoietic cell transplantation (HCT). There is no data regarding the incidence of anti-HLA recipient-specific antibodies (RSA) and their role after transplantation. : To identify the incidence of RSA in a mismatched related hematopoietic cell donor population and their possible impact on immune-mediated complications such as acute graft-versus-host (aGvHD) disease and complications resulting from endothelial injury such as transplant-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 transplanted in our center between 2020 and 2022. In positive samples screened for anti-HLA class I and/or II antibodies, identification of the specificity of the HLA antibodies was performed. All recipients suffered from hematological malignancies and received a myeloablative conditioning regimen and immunosuppression consisting of post-transplant cyclophosphamide, tacrolimus, and mycophenolate mofetil. Patients were tested for TA-TMA and GvHD development during routine post-transplant visits up to 100 days post-transplant. We used modified Jodele criteria for TA-TMA diagnosis, and GvHD grading was done based on MAGIC criteria. VOD was assessed using the EBMT revised criteria. : Anti-HLA antibodies were detected in 12 (43%) donors and 9 (32%) recipients. No significant differences between donors and recipients according to age (median 42 [17-69] vs 39 [18-68]), gender, and pregnancy history were observed. No transfusion history was noted in the donor group (p<0.05). RSA antibodies were present more often than DSAs and were detected in 9 out of 12 (75%) anti-HLA positive donors and only 2 out of 9 (22%) recipients, respectively (p<0.05). During the follow-up, 11 patients (39%) developed acute GvHD, grades I-II and III-IV in 9 (32%) and 2 (7%) cases, respectively. Twelve (43%) patients met TA-TMA criteria, and only 1 (3.5%) patient was diagnosed with VOD by day 100 post-HCT. RSA were detected significantly more often in the TA-TMA group: among 12 cases that met TA-TMA diagnosis, in 7 (58%) RSA were present (p<0.05). We did not find a correlation between RSAs and acute GvHD. Patient with VOD did not have RSA-positive donor. There was no difference in membrane attack complex (MAC) concentration in the RSA(+) group on day 30 and 60 post HCT, however, there was a trend toward higher MAC concentration in the RSA(+) group on day 100 – 912 ng/ml (788-1120) vs 616 ng/ml (352-1244) p=0.055. Patients with RSA suffered more often from platelet and red blood cell decrease or transfusion refractoriness, and increased lactate dehydrogenase activity was observed in all RSA (+) cases. : Donor`s 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.