Anti-HLA Antibodies and Graft Rejection In Hematopoietic Stem Cell Transplantation
Authors: Ciurea Stefan O. , Aung Fleur , de Lima Marcos , Thall Peter F. , Rondon Gabriela , Kebriaei Partow , Alousi Amin , Shpall Elizabeth J. , Hosing Chitra , Khouri Issa F , Champlin Richard E. , Fernandez-Vina Marcelo 
Published: October 2019

Abstract
Abstract 519
We have previously identified a high risk of primary graft failure (PGF) in patients with DSA in T-cell depleted haploidentical transplantation (HaploSCT); 3/4 patients with DSA had PGF compared with 1/20 patients without DSA. All patients with DSA against anti-HLA A, B and DRB1 developed PGF, while 1 patient with anti-DP DSA did not. We now hypothesize that anti-DP antibodies may have a significant but less deleterious impact on engraftment.

Methods:
We evaluated the occurrence of PGF in 592 patients who received matched unrelated donor transplants at our institution after 1/2005. 88 % of the transplants were matched in 8/8 alleles of HLA-A,B,C,DRB1 in the HvG vector; approximately 75% of the transplants were mismatched in either DRB 3/4/5, DQB1 or DPB1. The presence of DSA was determined by testing the patients' sera with a panel of fluorescent beads coated with single HLA antigen preparations using a Luminex™ platform; results were interpreted as fluorescence intensity (FI) against DSA mismatch. All HLA loci were typed by high resolution methods.

Results:
19/592 patients (3%) had either PGF (N=9) or died early without engraftment (ED) (N=10). The only DSA identified were against the DP molecule in 8 patients matched in 8/8 HLA alleles with no apparent specificity. 3/8 (37.5%) patients had PGF/ED compared with 16/584 (2.7%) who did not have DSA (p=0.001, RR=23.3). One patient with PGF in the presence of anti-DP DSA had a second transplant in the absence of antibodies and engrafted cells from the same donor. In spite of common HLA sensitization (116/592, 19.6%) only 8 patients (1.4%) presented DSA in their pre-transplant specimens, mostly females (N=7) with a median age 49 years. DSA ranged from 1558 to 9845 FI, similar in patients with and without engraftment. Overall there was a 3% risk of PGF/ED without HLA antibodies, 6% risk in the presence of antibodies but not DSA, and 37.5% risk in the presence of DSA. Multivariate analysis revealed that DSA (p=0.0001) and ABO mismatch (p=0.04) were the only variables associated with graft failure. There was a significant association between female gender and allosensitization, 30.8% of females had anti HLA antibodies vs. 12.1% males (p<0.0001). While no difference in the incidence of HLA antibodies was observed between females with no prior pregnancies and males (p=0.24), this became apparent when allosensitization was evaluated in males vs. females with one pregnancy (p=0.008) and females with 2 or more pregnancies (p=0.0003).

Conclusions:
These results, combined with our previous findings in HaploSCT, suggest that DSA are associated with graft rejection in hematopoietic stem cell transplantation. Graft failure occurs less often with anti-DP DSA (3/9) compared with DSA against high expression HLA molecules (3/3, HLA-A, B or DRB1) and may confer a lower risk for graft rejection. The differences may reside in the lower levels of DP molecules expressed on cell surface. DSA screening is warranted when considering donors with HLA mismatches as strategies for donor selection and/or antibody level reduction may be needed to decrease the risk of PGF in allogeneic HSCT from partially HLA-matched donors.

Disclosures:
No relevant conflicts of interest to declare.