Presensitization to HY antigens in female donors prior to transplant is not associated with male recipient post-transplant HY antibody development nor with clinical outcomes

Nakasone, Hideki; Sahaf, Bita; Tian, Lü; Wang, Tao; Haagenson, Michael; Schoenrock, Kelsi; Perloff, Spenser; Ryan, Christine E.; Wu, Fang; Spellman, Stephen R.; Lee, Stephanie J.; Ritz, Jérôme; Miklos, David B.

doi:10.3324/haematol.2015.134551

Cited by 5 publications

(7 citation statements)

References 15 publications

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“…Risk of chronic GVHD from allo-HCT is higher in male patients with female donors because of B-cell alloreactivity, 7,[65][66][67] which is detectable by antibody response that occurs after, 68 but not before, transplant. 69 Results presented here extend risk in this patient segment to the acute form of GVHD by implicating male-specific variants in four genes. Although definitive clinical recommendations require confirmatory analysis, it is possible to investigate the genetic basis for risk in this cohort.…”

Section: Y-chromosome-encoded Variants Associate With Acute Gvhdsupporting

confidence: 52%

Chromosome Y–encoded antigens associate with acute graft-versus-host disease in sex-mismatched stem cell transplant

Wang¹,

Huang

Halagan

et al. 2018

Blood Advances

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Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a curative option for blood cancers, but the coupled effects of graft-versus-tumor and graft-versus-host disease (GVHD) limit its broader application. Outcomes improve with matching at HLAs, but other factors are required to explain residual risk of GVHD. In an effort to identify genetic associations outside the major histocompatibility complex, we conducted a genome-wide clinical outcomes study on 205 acute myeloid leukemia patients and their fully HLA-A–, HLA-B–, HLA-C–, HLA-DRB1–, and HLA-DQB1–matched (10/10) unrelated donors. HLA-DPB1 T-cell epitope permissibility mismatches were observed in less than half (45%) of acute GVHD cases, motivating a broader search for genetic factors affecting clinical outcomes. A novel bioinformatics workflow adapted from neoantigen discovery found no associations between acute GVHD and known, HLA-restricted minor histocompatibility antigens (MiHAs). These results were confirmed with microarray data from an additional 988 samples. On the other hand, Y-chromosome–encoded single-nucleotide polymorphisms in 4 genes (PCDH11Y, USP9Y, UTY, and NLGN4Y) did associate with acute GVHD in male patients with female donors. Males in this category with acute GVHD had more Y-encoded variant peptides per patient with higher predicted HLA-binding affinity than males without GVHD who matched X-paralogous alleles in their female donors. Methods and results described here have an immediate impact for allo-HCT, warranting further development and larger genomic studies where MiHAs are clinically relevant, including cancer immunotherapy, solid organ transplant, and pregnancy.

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Section: Y-chromosome-encoded Variants Associate With Acute Gvhdsupporting

confidence: 52%

Chromosome Y–encoded antigens associate with acute graft-versus-host disease in sex-mismatched stem cell transplant

Wang¹,

Huang

Halagan

et al. 2018

Blood Advances

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“…In the transplant setting, these H-Y antibodies or adoptive B cells sensitized to H-Y antigens in female donors may be infused with the stem cell product and contribute to development of GVHD. However, in the adult setting Nakasone et al [33] recently reported that H-Y antibodies are not transferred from female donors to male recipients, although B cell transfer has not been studied.…”

Section: Discussionmentioning

confidence: 99%

“…Our results support the hypothesis that previous alloimmunization in adult female donors is important for male and perhaps female recipients and affects the incidence of cGVHD seen with donors over 12 years of age, but this hypothesis cannot be proved without evidence showing circulating H-Y antibodies and sensitized B cells are absent in young female donors and increase in incidence with age linked to sexual exposure. Nakasone et al's study [33] suggests H-Y antibody testing does not improve donor selection in adults, and it is de novo development of humoral H-Y immunity after F-M HSCT that predicts cGVHD. We hope this report serves as an impetus for both multiinstitutional studies and investigation of the underlying biology.…”

Section: Discussionmentioning

confidence: 99%

Young Female Donors Do Not Increase the Risk of Graft-versus-Host Disease or Impact Overall Outcomes in Pediatric HLA-Matched Sibling Hematopoietic Stem Cell Transplantation

Friedrich

Guerra-García

Stetson

et al. 2018

Biology of Blood and Marrow Transplantation

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Optimal donor selection is critical in hematopoietic stem cell transplantation (HSCT). Donor-recipient sex mismatch, donor age, and female donor-donor parity are known to impact graft-versus-host disease (GVHD) and outcomes in adults. Minor histocompatibility antigens encoded by the human Y chromosome can result in specific antibody formation in some female donors, may increase in frequency with increasing donor age, and may be contributory to the increased incidence of GVHD. To better understand the role of donor age/sex and sex matching in HSCT outcomes, we conducted a retrospective study of pediatric patients receiving their first myeloablative sibling donor HSCT (n = 244) from 1998 to 2012. Observed rates of GVHD were low: 17% of patients surviving past engraftment (n = 243) developed grades II to IV acute GVHD (aGVHD) and 14% surviving ≥ 100 days (n = 229) developed chronic GVHD (cGVHD). On multivariate analysis the risk of aGVHD, cGVHD, and death increased with patient age as expected. Female donor sex and sex mismatch (female donor-male recipient) had no impact on the development of aGVHD. cGVHD was increased with female donors only if the donor was ≥12 years old. No cGVHD was observed among 109 patients aged < 10 years who received a 6/6 HLA-matched marrow HSCT, regardless of donor age or sex. Survival was mostly driven by diagnosis. Results suggest that in pediatric HSCT, young HLA-matched siblings are equivalently good donors regardless of sex or donor-recipient sex mismatch.

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“…In patients who receive HLA-matched stem cells, the best-characterized antibodies are directed against minor histocompatibility antigens such as HY antigens in male recipients who receive stem cell grafts from female donors. 11,12,14,24,25 Antibodies to autosomal minor histocompatibility antigens have also been documented as well as antibodies against autoantigens commonly detected in patients with autoimmune diseases. 19,26 In almost all cases, these antibodies are directed against intracellular proteins and the role of these antibodies as mediators of tissue injury is not known.…”

Section: Discussionmentioning

confidence: 99%

“…In previous studies, it was shown that anti-HY antibodies are generated primarily de novo following sex-mismatched HSCT, and only the de novo development of HY antibodies after HSCT predicts cGVHD development. 24,25 Patients with cytomegalovirus reactivation after transplant were more likely to develop antibodies against multiple HY antigens. 14 These observations suggest that allogeneic immune Recent studies in animal models and patients have shown that B cells play an important role in the development of cGVHD.…”

Section: Discussionmentioning

confidence: 99%

Antibodies targeting surface membrane antigens in patients with chronic graft-versus-host disease

Wang¹,

Kim

Nikiforow³

et al. 2017

Blood

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Chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplant reflects a complex immune response resulting in chronic damage to multiple tissues. Previous studies indicated that donor B cells and the antibodies they produce play an important role in the development of cGVHD. To understand the pathogenic role of antibodies in cGVHD, we focused our studies on posttransplant production of immunoglobulin G antibodies targeting cell surface antigens expressed in multiple cGVHD affected tissues, due to their potential functional impact on living cells in vivo. Using plate-bound cell membrane proteins as targets, we detected a significantly higher level of antibodies reactive with these membrane antigens in patients who developed cGVHD, compared with those who did not and healthy donors. Plasma-reactive antibody levels increased significantly prior to the clinical diagnosis of cGVHD and were reduced following cGVHD therapies including prednisone, interleukin-2, or extracorporeal photophoresis. Using cell-based immunoprecipitation with plasma from cGVHD patients and mass spectrometry, we identified 43 membrane proteins targeted by these antibodies. The presence of antibodies in cGVHD patients' plasma that specifically target 6 of these proteins was validated. Antibodies reactive with these 6 antigens were more frequently detected in patients with cGVHD compared with patients without cGVHD and healthy donors. These results indicate that antibodies that target membrane antigens of living cells frequently develop in cGVHD patients and further support a role for B cells and antibodies in the development of cGVHD.

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Presensitization to HY antigens in female donors prior to transplant is not associated with male recipient post-transplant HY antibody development nor with clinical outcomes

Cited by 5 publications

References 15 publications

Chromosome Y–encoded antigens associate with acute graft-versus-host disease in sex-mismatched stem cell transplant

Chromosome Y–encoded antigens associate with acute graft-versus-host disease in sex-mismatched stem cell transplant

Young Female Donors Do Not Increase the Risk of Graft-versus-Host Disease or Impact Overall Outcomes in Pediatric HLA-Matched Sibling Hematopoietic Stem Cell Transplantation

Antibodies targeting surface membrane antigens in patients with chronic graft-versus-host disease

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