Donor‐specific anti‐HLA antibodies and …recipient‐specific anti‐HLA antibodies? The conundrum on pregnancy in transplantation
Authors: Stefan O. Ciurea, Kai Cao, Jun Zou
Journal: American Journal of Hematology (2020)

The presence of Donor-Specific anti-HLA Antibodies (DSA) in recipients has been associated with increasing risk of graft failure in hematopoietic stem cell transplantation (HSCT) with HLA mismatched donors. While allosensitization can occur when a patient comes in contact with foreign antigens, this problem appears more common in female recipients of haploidentical stem cell transplants, due to the development of anti-HLA antibodies during pregnancy against offspring's HLA antigens. The incidence of DSAs in haploidentical transplants is approximately 15%-20%1; however, it can be as high as 42.9% in parous females.2 Until now, only allosensitization of the recipient against donor HLA antigens has been studied. Nevertheless, multiparous female donors are not uncommon in a haploidentical transplant setting, and may carry a similar risk of developing anti-HLA antibodies against recipient's HLA antigens on the unshared haplotype. This phenomenon, herein referred to as recipient-specific anti-HLA antibodies (RSA), has not yet been described, and its impact on transplant outcomes remains unknown. We recently identified a haploidentical donor who was a multiparous woman and had RSAs against recipient's HLA antigens. The patient carried numerous DSAs against all potential haploidentical donors (cPRA >99%), with mean fluorescence intensity (MFI) ranging from 1000 to 33 000. Several of those antibodies were capable of binding complement as suggested by a positive C1q test. Prior to transplantation, the patient was desensitized with our multimodality management to dimisish DSA levels.3 In addition to anti-HLA antibodies against donor's HLA antigens, the donor was found to have RSAs against recipient's HLA-Cw10 (17 266 MFI) and B8 (4682 MFI). Although the effects of passive transfer of RSAs to recipient with the graft are yet unknown, it is conceivably possible that damage to recipient's tissues of major organs can occur before these antibodies are eventually absorbed. Thus, we decided to proceed with removal of RSAs using plasma depletion of the donor's peripheral stem cell graft. Unfortunately, the patient had graft failure likely from the high DSAs despite the desensitization treatment. Regarding RSAs, with the plasma depletion procedure, these antibiodies were completely eliminated, as demonstrated by undetectable MFI levels of RSAs in recipient's serum after transplant (Figure 1). High levels of DSA may pose a significant threat to engraftment, and a multimodality approach has been proposed by our group to minimize the risk of primary graft failure in this setting.1 This extreme case of allosensitization with very high levels of complement-binding DSAs against multiple donor antigens, together with RSAs against recipient's HLA antigens reveals how important this problem can be. In addition to the critical aspect of DSAs, this case illustrates the existence of RSAs, which has never been described to date in transplantation. Previous studies identified an increased risk of graft-vs-host disease (GVHD) is associated with parous female donors in unrelated donor transplantation,4 and parity was identified as a risk factor for chronic GVHD in recipients of grafts from parous female sibling donors.5 Moreover, the role of these donor HLA antibodies against the recipient's HLA antigens has not been studied, and it remains unclear that transferred memory B cells from the donor are capable of producing antibodies upon further exposure to allogeneic antigen post-HSCT.6 In this case, it unlikely that RSAs contributed to the negative impact of DSAs on engraftment as these antibodies from donor's serum were likely eliminated prior to transplant (Figure 1). However, it is reasonable to assume that a proportion of haploidentical transplants were performed with unnoticed RSAs given the fact that HLA antibodies was observed in approximately 10%-40% of unselected platelet female donors who have ever been pregnant. While the potential effects of RSAs remain unclear, presumably these antibodies can bind to recipient tissue antigens and might cause end organ damage which may impact the development of GVHD and increase treatment-related mortality post-transplant. A prior report on 174 patients receiving HLA identical allogeneic HSCT studied the factors associated with acute GVHD. Comparing to ABO matched or major mismatched group, a significant higher risk of severe acute GVHD is associated with minor ABO mismatch, in which the donor antibody is against recipient ABO antigen.7 A similar study observed that the incidence of liver GVHD was higher in minor ABO mismatched HSCT. This group hypothesized that donor derived anti-ABO antibodies attack the antigen expressed on the epithelial cells of the large bile tract and therefore enhance the incidence and severity of liver GVHD.8 In conclusion, this complex case illustrates the importance of testing HLA antibodies in the setting of haploidentical HSCT, especially in multiparous women, who are likely to be allosensitized,3 some to the extreme, as seen in this case. In addition to measuring DSAs in the recipient's serum, antibodies against recipient HLA antigens (RSAs) should probably be tested in adult female donors considered for haploidentical transplantation as part of the routine pre-transplant work-up. However, it remains to be elucidated if the proactive treatment of such healthy donors with strong RSAs levels is necessary, as previous data indicated a higher non-relapse mortality is associated with female donors in AML patients who underwent transplant. Further studies with larger cohorts of patients are warranted to explore to role of RSA in haploidentical transplantation. The authors do not have any conflict of interest to declare for this work. S.O.C., K.C., J.Z. contributed with study design, data interpretation and manuscript writing.