Allogeneic HY antibodies detected 3 months after female-to-male HCT predict chronic GVHD and nonrelapse mortality in humans

Nakasone, Hideki; Tian, Lu; Sahaf, Bita; Kawase, Takakazu; Schoenrock, Kelsi; Perloff, Spenser; Ryan, Christine E.; Paul, Jed; Popli, Rakesh; Wu, Fang; Otani, Joanne; Coller, John A.; Warren, Edus H.; Miklos, David B.

doi:10.1182/blood-2014-11-613323

Cited by 62 publications

(59 citation statements)

References 32 publications

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“…We used the female donormale recipient gender combination as marker for one group of minor histocompatbility antigens, the HY complex and ignored other minor antigens. 23,24 On the basis of these well-established markers, we postulated a donor type hierarchy and found it confirmed. We had no details on prevention and treatment or on onset and degree of acute and chronic graft-versus-host disease, and did not compare patients with or without graft-versus-host disease.…”

Section: Alloreactivity In Hsct a Gratwohl Et Almentioning

confidence: 98%

Alloreactivity: the Janus-face of hematopoietic stem cell transplantation

et al. 2017

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Differences in major and minor histocompatibility antigens between donor and recipient trigger powerful graft-versus-host reactions after allogeneic hematopoietic stem cell transplantation (HSCT). The clinical effects of alloreactivity present a Janus-face: detrimental graft-versus-host disease increases non-relapse mortality, beneficial graft-versus-malignancy may cure the recipient. The ultimate consequences on long-term outcome remain a matter of debate. We hypothesized that increasing donor-recipient antigen matching would decrease the negative effects, while preserving antitumor alloreactivity. We analyzed retrospectively a predefined cohort of 32 838 such patients and compared it to 59 692 patients with autologous HSCT as reference group. We found a significant and systematic decrease in non-relapse mortality with decreasing phenotypic and genotypic antigen disparity, paralleled by a stepwise increase in overall and relapse-free survival (Spearman correlation coefficients of cumulative excess event rates at 5 years 0.964; P o 0.00; respectively 0.976; P o0.00). We observed this systematic stepwise effect in all main disease and disease-stage categories. The results suggest that detrimental effects of alloreactivity are additive with each step of mismatching; the beneficial effects remain preserved. Hence, if there is a choice, the best match should be donor of choice. The data support an intensified search for predictive genomic and environmental factors of 'no-graft-versus-host disease'.

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Section: Alloreactivity In Hsct a Gratwohl Et Almentioning

confidence: 98%

Alloreactivity: the Janus-face of hematopoietic stem cell transplantation

et al. 2017

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“…We recently reported H-Y antibody-predicted development of chronic GVHD as an indicator of allo-immunity. 14 We, therefore, focused on the H-Y antibody response in Female→Male HCT and explored whether the detection of H-Y antibodies 3 months after HCT could predict reduced relapse in Female→Male HCT with TLI-ATG.…”

Section: Detection Of H-y Antibodies 3 Months After Hematopoietic Celmentioning

confidence: 99%

“…7,14 To relate sex-mismatched alloimmunity more directly with decreased relapse, we measured H-Y antibody development in Female→Male HCT 3 months after the transplant. About half of TLI-ATG patients had developed at least one H-Y antibody, and an association was observed between H-Y antibody development and chronic GVHD, as we previously reported.…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

“…[1][2][3][4][7][8][9][10] This adverse effects of Female→Male HCT are thought to result from allogeneic immune responses against minor histocompatibility antigens encoded on the Y-chromosome of a male recipient (H-Y antigens). 7,[11][12][13][14] To avoid these post-HCT complications or to reduce disease relapse, various conditioning types have developed. 15 Non-myeloablative conditioning regimens such as total lymphoid irradiation and anti-thymocyte globulin (TLI-ATG) conditioning have shown promise as a method to reduce GVHD incidence and non-relapse mortality.…”

Section: Introductionmentioning

confidence: 99%

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Risks and benefits of sex-mismatched hematopoietic cell transplantation differ according to conditioning strategy

et al. 2015

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Sex-mismatched hematopoietic cell transplantation is linked to increased graft-versus-host disease and mortality in myeloablative conditioning. Here we evaluated outcomes of 1,041 adult transplant recipients at two centers between 2006 and 2013 and investigated how the effect of sex-mismatching differed in myeloablative, reducedintensity, and non-myeloablative total lymphoid irradiation with anti-thymocyte globulin conditioning. Among patients who underwent myeloablative conditioning, male recipients with female donors had increased chronic graft-versus-host disease (hazard ratio 1.83, P<0.01), increased non-relapse mortality (hazard ratio 1.84, P=0.022) and inferior overall survival (hazard ratio 1.59, P=0.018). In contrast, among patients who received reduced-intensity conditioning, male recipients with female donors had increased acute graft-versus-host disease (hazard ratio 1.96, P<0.01) but no difference in non-relapse mortality or overall survival. Among the patients who underwent total lymphoid irradiation with anti-thymocyte globulin, male recipients with female donors showed no increase in graft-versus-host disease or non-relapse mortality. Notably, only in the cohort receiving total lymphoid irradiation with antithymocyte globulin were male recipients with female donors significantly associated with reduced relapse (hazard ratio 0.64, P<0.01), and allo-antibody responses against H-Y antigens were predictive of reduced relapse. In the cohort given total lymphoid irradiation with anti-thymocyte globulin, the graft-versus-leukemia effect resulted in superior overall survival in recipients of sex-mismatched grafts (HR 0.69, P=0.037). In addition, only in the cohort treated with total lymphoid irradiation with anti-thymocyte globulin were female recipients with male donors associated with reduced relapse (hazard ratio 0.59, P<0.01) and superior survival (hazard ratio 0.61, P=0.014) compared with sex-matched pairs. We conclude that the risks and benefits of sex-mismatched transplants appear to differ according to conditioning strategy and this could affect donor selection. Risks and benefits of sex-mismatched hematopoietic cell transplantation differ according to conditioning strategy ABSTRACT © F e r r a t a S t o r t i F o u n d a t i o nH. Nakasone et al. 1478haematologica | 2015; 100 (11) factors and disease status are among the major drivers determining the conditioning intensity for HLA-matched or single-allele mismatched transplantation. In general, after selection of conditioning, if multiple potential donors are available, other factors such as blood type and sex of the donor versus recipient are evaluated. To determine a potential effect of sex-mismatching within each conditioning type, we evaluated the outcomes of 1,041 adult recipients at two centers between 2006 and 2013. We found that the impact of sex-mismatched transplants differs according to conditioning strategy. Myeloablative conditioned, sex-mismatched Female→Male patients showed increased non-relapse mortality and reduced overall survi...

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“…7,8 Thus, Abs against mHags may represent early biomarkers of GvHD and could therefore possibly be of value in therapeutic decision making in GvHD. This encourages research toward identification of new mHags that are able to induce Ab responses after allo-SCT.…”

Section: The Role Of Minor Histocompatibility Ags In Gvt and Gvhdmentioning

confidence: 99%

Minor histocompatibility Ags: identification strategies, clinical results and translational perspectives

Oostvogels

Lokhorst

Mutis

2015

Bone Marrow Transplant

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Allogeneic stem cell transplantation (allo-SCT) and donor lymphocyte infusion are effective treatment modalities for various hematological malignancies. Their therapeutic effect, the graft-versus-tumor (GvT) effect, is based mainly on an alloimmune response of donor T cells directed at tumor cells, in which differences in the expression of minor histocompatibility Ags (mHags) on the cells of the patient and donor have a crucial role. However, these differences are also responsible for induction of sometimes detrimental GvHD. As relapse and development of GvHD pose major threats for a large proportion of allotransplanted patients, additional therapeutic strategies are required. To augment the GvT response without increasing the risk of GvHD, specific mHagdirected immunotherapeutic strategies have been developed. Over the past years, much effort has been put into the identification of therapeutically relevant mHags to enable these strategies for a substantial proportion of patients. Currently, the concept of mHag-directed immunotherapy is tested in clinical trials on feasibility, safety and efficacy. In this review, we will summarize the recent developments in mHag identification and the clinical data on mHag-specific immune responses and mHag-directed therapies in patients with hematological malignancies. Finally, we will outline the current challenges and future prospectives in the field.

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Allogeneic HY antibodies detected 3 months after female-to-male HCT predict chronic GVHD and nonrelapse mortality in humans

Cited by 62 publications

References 32 publications

Alloreactivity: the Janus-face of hematopoietic stem cell transplantation

Alloreactivity: the Janus-face of hematopoietic stem cell transplantation

Risks and benefits of sex-mismatched hematopoietic cell transplantation differ according to conditioning strategy

Minor histocompatibility Ags: identification strategies, clinical results and translational perspectives

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