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16 ASHI Quarterly Third Quarter 2015 C U R R E N T L I T E R A T U R E R E V I E W Ciurea et al 5 addressed the effect of pre-existing HLA DSA, as determined by solid-phase/single-antigen assay, in 28 patients who underwent haploidentical transplantation The mismatches ranged from two to five HLA alleles Five patients (21%) had DSA and 3 of 4 (75%) patients with DSA failed to engraft, compared to 1 of 20 (5%) without DSA (P=0 008) All four (3 DSA + and 1 DSA - ) patients with primary graft failure had second haploidentical transplants One patient with high DSA developed a second graft failure Three of the patients engrafted, two of them in the absence of DSA Although not all confounding factors were considered, this study favored the concept that donor-specific anti-HLA antibodies were associated with a high rate of graft rejection in patients undergoing haploidentical BMT/HSCT Yoshihara et al 6 investigated the role of donor-specific HLA antibodies (DSA) in 79 adult patients with graft failure after unmanipulated haploidentical SCT, by prospectively assessing HLA antibodies using a solid phase single antigen bead based assay Sixteen patients (20 2%) were HLA Ab-positive and 11 had no DSA toward their respective donors The authors report that the neutrophil recovery was significantly lower in patients with positive pre-transplant DSA than in DSA-negative patients (61 9% vs 94 4%, P=0 026) And most importantly, 3 of 5 patients with high levels of DSA had total engraftment failure Hence, this study also indicated that haploidentical donors should be selected with an evaluation of pre-existing HLA DSAs in the recipients Gladstone et al 7 retrospectively evaluated both the presence and relative strength of DSA in haploidentical and unrelated mismatched BMT/HSCT patients In the study, 296 allo-BMT candidates were studied of which 111 (37 5%) were female DSAs were detected in 43 (14 5%), mostly among female candidates (42 9%) compared to males (12 5%) Interestingly, moderate-to- strong DSA strength was more frequent against haploidentical donors compared with mismatched unrelated donors Of all these DSA-positive patients, nine, without any other available donors, underwent desensitization and eight patients who reduced their DSA to negative or weak levels proceeded to allo-BMT and achieved full donor engraftment Hence this study indicated that desensitization should be considered when mismatched BMT/ HSCT is the only option Prevalence of HLA Antibodies in BMT/HSCT Donors: Potential of the Sensitized B Cells of the SCT Donor to Turn into Plasma Cells and Produce Antibodies to the Mismatched Recipient HLA Antigens The frequency of the presence of HLA antibodies in BMT/ HSCT donors remains unknown Donor evaluation for anti-HLA antibodies is infrequent since no pre-formed antibodies are likely to be transferred during BMT/HSCT However, it is known that HLA antibodies are detected in about 30% of all multiparous blood donors for BMT/HSCT Taniguchi et al 8 investigated the presence of circulating HLA antibodies in 123 related donors using solid-phase single bead antigen assays Of these, 6/27 (22%) parous female and 1/57 (1 8%) male donors were HLA antibody- positive None of the non-parous female donors in this study had any detectable antibodies The authors then determined HLA antibody levels in seven patients who received BMT/HSCT from antibody positive donors Of these, four recipients became HLA antibody-positive after BMT/HSCT The authors report that the specificities of the antibodies that were detected in these patients post-transplant closely resembled those of the antibodies found in the donors, suggesting their production by donor-derived plasma cells Apparently, the kinetics of the HLA antibody levels were similar in all four recipients with levels of HLA antibodies increasing within one week of BMT/HSCT and peaking at days 10-21, followed by steady decline While the allotypes of these HLA antibodies were not characterized, the authors claimed that, based on the specificities and kinetics, they were most likely derived from the passenger B cells from the allograft donors Potential Clinical Implications of Recipient- Specific HLA Antibodies of the BMT/HSCT Donor-Derived Recipient Specific Antibodies (DRSA) While pre-existing DSA in the recipient could adversely affect engraftment, the role of DRSA is not very well studied Donor- derived CD4 + and CD8 + T lymphocytes have traditionally been implicated as the major players in GVHD pathogenesis However, because DRSA is directed against the host, GVHD might ensue While the RSA are not directly transferred through a stem cell allograft, it is possible that immunocompetent donor B lymphocytes could be passively transferred with the allograft Donor-derived recipient-specific HLA antibodies (DRSA) have been shown to be involved in GVHD 9 There is precedence for such passive transfer of sensitized B cells capable of maturing into blood group A/B antibody producing plasma cells causing hemolytic anemia in ABO/Rh mismatched BMT/HSCT 10-12 Hence, it is possible that such donor derived passenger B lymphocytes could differentiate into antibody-producing plasma cells targeting the mismatched recipient HLA antigens, provided the donor had been sensitized to the those antigens prior to transplant There is some compelling clinical evidence indicating the role of B cells in GVHD B cell depletion with rituximab (monoclonal antibodies against CD20) has been associated with favorable effects on GVHD outcome Kamble et al 13 treated patients having acute GVHD, unresponsive to multiple immunosuppressants, with rituximab resulting in full remission Other studies showed that rituximab, given as part of a myeloablative or nonmyeloablative conditioning regimen given before or after transplantation, led to lower-than-expected rates of GVHD 13-16 The treatment with rituximab, however, is not effective in patients with high risk for relapse of aggressive B-Cell non-Hodgkin lymphoma 17 And, on a positive note, studies so far indicate that rituximab administered just before or immediately after transplantation is safe and that the engraftment is unaffected, 18 but maybe delayed 19 Another line of evidence for a potential role for B cells in GVHD comes from the fact that apheresis products with high numbers of B cells result in a higher incidence of acute GVHD and increased treatment-related mortality 20 The exact mechanisms of B cell mediated GVHD is not yet understood