H–Y antigen-binding B cells develop in male recipients of female hematopoietic cells and associate with chronic graft vs. host disease

Sahaf, Bita; Yang, Yang; Arai, Sally; Herzenberg, Leonard A.; Herzenberg, Leonore A.; Miklos, David B.

doi:10.1073/pnas.1222900110

Cited by 30 publications

(32 citation statements)

References 28 publications

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“…The correlative biological analysis of HY-Abs supports the allogeneic B-cell pathogenic role in independent prospective trials for cGVHD prophylaxis and treatment. 9,24,29,30 HY-Abs would serve as a prognostic biomarker for cGVHD and an immunologic indicator.…”

Section: Discussionmentioning

confidence: 99%

“…Our prior studies have demonstrated that HY-Abs were detected in F→M HCT patients, 8,9 but the temporal association between HY-Ab development and cGVHD has yet to be established. In addition, prior studies were limited by antibody detection technologies and by measurement of HY-Abs in blood samples collected $9 months after HCT.…”

Section: Introductionmentioning

confidence: 97%

“…Our group has previously shown that alloantibodies against H-Y antigens (HY-Abs) were detected in 39 F→M recipients using enzyme-linked immunosorbent assay and that H-Y antigen-specific B cells developed in F→M HCT patients. 8,9 Clinical manifestations of cGVHD are similar to those observed in connective tissue disease, including scleroderma and sicca syndrome, and autoreactive/alloreactive immune abnormalities have so far been proposed to play a pathogenic role in cGVHD. 10,11 B-cell activating factor has been associated with active cGVHD.…”

Section: Introductionmentioning

confidence: 99%

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

Nakasone¹,

Tian

Sahaf³

et al. 2015

Blood

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Key Points• Detection of multiple HY-Abs at 3 months post-F→M HCT predicts cGVHD incidence, severity, and nonrelapse mortality.• Patients with a high HY score may be good candidates for cGVHD prevention trials, especially those targeting allogeneic B cells.Allogeneic antibodies against minor histocompatibility antigens encoded on the Y chromosome (HY-Abs) develop after hematopoietic cell transplant (HCT) of male recipients with female donors (F→M). However, the temporal association between HY-Ab development and chronic graft-versus-host disease (cGVHD) has yet to be elucidated. We studied 136 adult F→M HCT patients, with plasma prospectively collected through 3 years posttransplant, and measured immunoglobulin G against 6 H-Y antigens. Multiple HY-Abs were frequently detected beginning at 3 months posttransplant: 78 (57%) of F→M patients were seropositive for at least 1 of the 6 HY-Abs, and 3-month seropositivity for each HYAb was associated with a persistent seropositive response throughout the posttransplant follow-up period (P < .001 in each). There were no associations between pretransplant features and 3-month overall HY-Ab development. Detection of multiple HY-Abs at 3 months (represented by HY score) was significantly associated with an increased risk of cGVHD (P < .0001) and nonrelapse mortality (P < .01). Compared to clinical factors alone, the addition of HY score to clinical factors improved the predictive potential of cGVHD (P < .01). Monitoring HY-Ab development thus stratifies cGVHD risk in F→M HCT patients and may support preemptive prophylaxis therapy for cGVHD beginning at 3 months posttransplant. (Blood. 2015;125(20):3193-3201)

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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

Nakasone¹,

Tian

Sahaf³

et al. 2015

Blood

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“…47,48,102,103 Autoantibodies are widely detected in patients with cGVHD. Although initial reports suggested that antibodies to the platelet-derived growth factor receptor may be pathogenic, 104 this finding has been debated.…”

Section: Org Frommentioning

confidence: 99%

Chronic graft-versus-host disease: biological insights from preclinical and clinical studies

MacDonald¹,

Hill

Blazar

2017

Blood

226

212

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With the increasing use of mismatched, unrelated, and granulocyte colony-stimulating factor–mobilized peripheral blood stem cell donor grafts and successful treatment of older recipients, chronic graft-versus-host disease (cGVHD) has emerged as the major cause of nonrelapse mortality and morbidity. cGVHD is characterized by lichenoid changes and fibrosis that affects a multitude of tissues, compromising organ function. Beyond steroids, effective treatment options are limited. Thus, new strategies to both prevent and treat disease are urgently required. Over the last 5 years, our understanding of cGVHD pathogenesis and basic biology, born out of a combination of mouse models and correlative clinical studies, has radically improved. We now understand that cGVHD is initiated by naive T cells, differentiating predominantly within highly inflammatory T-helper 17/T-cytotoxic 17 and T-follicular helper paradigms with consequent thymic damage and impaired donor antigen presentation in the periphery. This leads to aberrant T- and B-cell activation and differentiation, which cooperate to generate antibody-secreting cells that cause the deposition of antibodies to polymorphic recipient antigens (ie, alloantibody) or nonpolymorphic antigens common to both recipient and donor (ie, autoantibody). It is now clear that alloantibody can, in concert with colony-stimulating factor 1 (CSF-1)-dependent donor macrophages, induce a transforming growth factor β–high environment locally within target tissue that results in scleroderma and bronchiolitis obliterans, diagnostic features of cGVHD. These findings have yielded a raft of potential new therapeutics, centered on naive T-cell depletion, interleukin-17/21 inhibition, kinase inhibition, regulatory T-cell restoration, and CSF-1 inhibition. This new understanding of cGVHD finally gives hope that effective therapies are imminent for this devastating transplant complication.

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“…[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%

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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H–Y antigen-binding B cells develop in male recipients of female hematopoietic cells and associate with chronic graft vs. host disease

Cited by 30 publications

References 28 publications

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

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

Chronic graft-versus-host disease: biological insights from preclinical and clinical studies

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

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