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1.
Haematologica ; 2020 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-32439725

RESUMO

Leukocytes that lack HLA allelic expression are frequently detected in patients with acquired aplastic anemia (AA) who respond to immunosuppressive therapy (IST), although the exact mechanisms underlying the HLA loss and HLA allele repertoire likely to acquire loss-of-function mutations are unknown. We identified a common nonsense mutation at position 19 (c.19C>T, p.R7X) in exon 1 (Exon1mut ) of different HLA-A and -B alleles in HLA-lacking granulocytes from AA patients. A droplet digital PCR (ddPCR) assay capable of detecting as few as 0.07% Exon1mut HLA alleles in total DNA revealed the mutation was present in 29% (101/353) of AA patients, with a median allele frequency of 0.42% (range, 0.071% to 21.3%). Exon1mut occurred in only 12 different HLA-A (n=4) and HLA-B (n=8) alleles, including B*40:02 (n=31) and A*02:06 (n=15), which correspond to 4 HLA supertypes (A02, A03, B07, and B44). The percentages of patients who possessed at least one of these 12 HLA alleles were significantly higher in the 353 AA patients (92%, P<0.001) and in 83 AA patients with copy number neutral loss of heterozygosity in chromosome 6p (6pLOH) (100%, P<0.001) than that (81%) in 18,604 Japanese healthy individuals. 82% (37/45) of AA patients with Exon1mut responded to IST. Small populations of leukocytes that lack particular HLA-A or B alleles due to Exon1mut are common in AA patients. The detection of Exon1mut using the ddPCR assay without the need for HLA typing may serve as a powerful tool for diagnosing the immune pathophysiology of patients with bone marrow failure.

2.
Br J Haematol ; 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32311088

RESUMO

Immune aplastic anaemia (AA) is caused by cytotoxic T lymphocytes (CTLs) that destroy haematopoietic stem and progenitor cells. Enhanced type 1 T helper (Th1) responses and reduced regulatory T cells (Tregs) are involved in the immune pathophysiology. CD24hi CD38hi regulatory B cells (Bregs) suppress CTLs and Th1 responses, and induce Tregs via interleukin 10 (IL-10). We investigated circulating B-cell subpopulations, including CD24hi CD38hi Bregs, as well as total B cells, CD4+ T cells, CD8+ T cells and natural killer cells in 104 untreated patients with severe and very severe AA, aged ≥18 years. All patients were treated with standard immunosuppressive therapy (IST) plus eltrombopag. CD24hi CD38hi Bregs were markedly reduced in patients with AA compared to healthy individuals, especially in very severe AA, but residual Bregs remained functional, capable of producing IL-10; total B-cell counts and the other B-cell subpopulations were similar to those of healthy individuals. CD24hi CD38hi Bregs did not correlate with responses to IST, and they recovered to levels present in healthy individuals after therapy. Mature naïve B-cell counts were unexpectedly associated with IST response. Markedly reduced CD24hi CD38hi Bregs, especially in very severe AA, with recovery after IST suggest Breg deficits may contribute to the pathophysiology of immune AA.

3.
Int J Hematol ; 110(6): 648-653, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31542851

RESUMO

A "biosimilar" is a biotechnological product with a lower cost profile and equivalent efficacy and safety to the originator, but post-marketing clinical evaluation of biosimilar products has not been adequately conducted. We prospectively investigated the utility of biosimilar filgrastim in 13 peripheral blood stem cell (PBSC) donors from June 2014 to January 2017. In addition, we retrospectively compared these to another 13 PBSC donors mobilized with the originator filgrastim in the same period. Donor characteristics were equivalent between the groups. The median number of CD34+ cells per donor body weight (BW) and blood volume processed (BV) were 4.87 × 106/kg and 25.5 × 103/mL in the biosimilar group and 4.93 × 106/kg and 16.6 × 103/mL in the originator group, respectively. There were no significant differences between the groups in the number of CD34+ cells per donor BW or BV. All adverse events associated with G-CSF were permissive. The total G-CSF cost was significantly lower in the biosimilar group than in the originator group. These findings suggest that biosimilar filgrastim has the same efficacy and short-term safety as originator filgrastim for PBSC mobilization in healthy donors, with economic superiority. Longer follow-up studies are needed to evaluate the incidence of long-term adverse events.


Assuntos
Medicamentos Biossimilares/normas , Filgrastim/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/análise , Mobilização de Células-Tronco Hematopoéticas/métodos , Doadores de Tecidos , Adulto , Antígenos CD34/sangue , Medicamentos Biossimilares/efeitos adversos , Medicamentos Biossimilares/economia , Feminino , Filgrastim/efeitos adversos , Filgrastim/economia , Filgrastim/normas , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Células-Tronco de Sangue Periférico , Estudos Prospectivos , Estudos Retrospectivos
5.
Blood Adv ; 2(9): 1000-1012, 2018 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-29720492

RESUMO

Clonal hematopoiesis by hematopoietic stem progenitor cells (HSPCs) that lack an HLA class I allele (HLA- HSPCs) is common in patients with acquired aplastic anemia (AA); however, it remains unknown whether the cytotoxic T lymphocyte (CTL) attack that allows for survival of HLA- HSPCs is directed at nonmutated HSPCs or HSPCs with somatic mutations or how escaped HLA- HSPC clones support sustained hematopoiesis. We investigated the presence of somatic mutations in HLA- granulocytes obtained from 15 AA patients in long-term remission (median, 13 years; range, 2-30 years). Targeted sequencing of HLA- granulocytes revealed somatic mutations (DNMT3A, n = 2; TET2, ZRSR2, and CBL, n = 1) in 3 elderly patients between 79 and 92 years of age, but not in 12 other patients aged 27 to 74 years (median, 51.5 years). The chronological and clonogenic analyses of the 3 cases revealed that ZRSR2 mutation in 1 case, which occurred in an HLA- HSPC with a DNMT3A mutation, was the only mutation associated with expansion of the HSPC clone. Whole-exome sequencing of the sorted HLA- granulocytes confirmed the absence of any driver mutations in 5 patients who had a particularly large loss of heterozygosity in chromosome 6p (6pLOH) clone size. Flow-fluorescence in situ hybridization analyses of sorted HLA+ and HLA- granulocytes showed no telomere attrition in HLA- granulocytes. The findings suggest that HLA- HSPC clones that escape CTL attack are essentially free from somatic mutations related to myeloid malignancies and are able to support long-term clonal hematopoiesis without developing driver mutations in AA patients unless HLA loss occurs in HSPCs with somatic mutations.


Assuntos
Anemia Aplástica/sangue , Anemia Aplástica/genética , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia Aplástica/patologia , Anemia Aplástica/terapia , Cromossomos Humanos Par 6/genética , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Feminino , Células-Tronco Hematopoéticas/patologia , Humanos , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Indução de Remissão
6.
Blood Adv ; 2(4): 390-400, 2018 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-29472446

RESUMO

Hematopoietic stem cells (HSCs) that lack HLA-class I alleles as a result of copy-number neutral loss of heterozygosity of the short arm of chromosome 6 (6pLOH) or HLA allelic mutations often constitute hematopoiesis in patients with acquired aplastic anemia (AA), but the precise mechanisms underlying clonal hematopoiesis induced by these HLA-lacking (HLA-) HSCs remain unknown. To address this issue, we generated induced pluripotent stem cells (iPSCs) from an AA patient who possessed HLA-B4002-lacking (B4002-) leukocytes. Three different iPSC clones (wild-type [WT], 6pLOH+, and B*40:02-mutant) were established from the patient's monocytes. Three-week cultures of the iPSCs in the presence of various growth factors produced hematopoietic cells that make up 50% to 70% of the CD34+ cells of each phenotype. When 106 iPSC-derived CD34+ (iCD34+) cells with the 3 different genotypes were injected into the femoral bone of C57BL/6.Rag2 mice, 2.1% to 7.3% human multilineage CD45+ cells of each HLA phenotype were detected in the bone marrow, spleen, and peripheral blood of the mice at 9 to 12 weeks after the injection, with no significant difference in the human:mouse chimerism ratio among the 3 groups. Stimulation of the patient's CD8+ T cells with the WT iCD34+ cells generated a cytotoxic T lymphocyte (CTL) line capable of killing WT iCD34+ cells but not B4002- iCD34+ cells. These data suggest that B4002- iCD34+ cells show a repopulating ability similar to that of WT iCD34+ cells when autologous T cells are absent and CTL precursors capable of selectively killing WT HSCs are present in the patient's peripheral blood.


Assuntos
Anemia Aplástica/patologia , Hematopoese , Células-Tronco Pluripotentes Induzidas/citologia , Linfócitos T Citotóxicos/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Células Cultivadas , Quimerismo , Genótipo , Células-Tronco Hematopoéticas/citologia , Humanos , Células-Tronco Pluripotentes Induzidas/transplante , Camundongos , Camundongos Endogâmicos C57BL
8.
Biol Blood Marrow Transplant ; 24(1): 43-49, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28860001

RESUMO

Late graft failure (LGF) without evidence of residual recipient cells is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-SCT) and often requires stem cell infusion from the same donor when the patient fails to respond to conventional therapies. We screened the peripheral blood (PB) of 14 patients who developed donor-type LGF at 2 to 132 months after allo-SCT for the presence of the markers for immune-mediated bone marrow (BM) failure. Increased glycosylphosphatidyl inositol-anchored protein-deficient (GPI-AP-) leukocytes, which accounted for .009% to 0.147% of the total granulocytes, were detected in 5 patients (severe aplastic anemia, n = 2; follicular lymphoma, n = 1; acute lymphoblastic leukemia, n = 1; myelodysplastic syndromes; n = 1) and 4.7% to 81.2% HLA-allele-lacking leukocytes (HLA-LLs) were detected in 2 patients (acute myelogenous leukemia, n = 1; and myelodysplastic syndromes, n = 1). Three of the 5 patients with increased GPI-AP- leukocytes were treated with antithymocyte globulin (ATG), and 2 patients achieved transfusion independence. These results suggest that immune mechanisms that are similar to acquired aplastic anemia underlie condition of approximately one-half of the patients with donor-type LGF, and that in patients with increased GPI-AP- cells, donor-derived hematopoiesis may be restored by ATG therapy alone without donor stem cell infusion.


Assuntos
Quimerismo , Rejeição de Enxerto/etiologia , Transplante Homólogo/efeitos adversos , Adulto , Soro Antilinfocitário/uso terapêutico , Feminino , Proteínas Ligadas por GPI/metabolismo , Rejeição de Enxerto/imunologia , Doenças Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucócitos/química , Masculino , Pessoa de Meia-Idade , Fatores de Tempo
9.
Blood ; 129(21): 2908-2916, 2017 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-28232583

RESUMO

To identify HLA alleles closely involved in the autoantigen presentation in acquired aplastic anemia (AA), we studied the HLA allelic loss frequencies of 312 AA patients, including 43 patients with loss of heterozygosity of 6p chromosome (6pLOH). An analysis of the HLA alleles contained in the lost haplotype revealed HLA-B*40:02 to be the most frequently lost allele. When we examined 28 AA (12 6pLOH[+] and 16 6pLOH[-]) patients with HLA-B*40:02 for the presence of leukocytes lacking HLA-B4002 (B4002-) using a new monoclonal antibody specific to this allele, B4002- granulocytes were detected not only in all 6pLOH(+) patients but also in 9 (56%) of the 16 6pLOH(-) patients. Furthermore, 10 (83%) of the 12 6pLOH(+) patients possessed 1.0% to 78% B4002- granulocytes that retained the HLA-A allele on the same haplotype (B4002-A+), suggesting the frequent coexistence of granulocytes that underwent mutations restricted to HLA-B*40:02 with 6pLOH(+) (B4002-A-) granulocytes. Deep sequencing of the HLA-B*40:02 of sorted B4002-A+ granulocytes revealed various somatic mutations, such as frameshift, nonsense, and splice site mutations, in all 15 patients studied. Surprisingly, missense mutations in the α-3 domain of HLA-B*40:02 that are not involved in the antigen presentation were detected exclusively in the B4002+ granulocytes of 3 patients possessing B4002- granulocytes. The markedly high prevalence of leukocytes lacking HLA-B4002 as a result of either 6pLOH or structural gene mutations, or both, suggests that antigen presentation by hematopoietic stem/progenitor cells to cytotoxic T cells via the HLA-B allele plays a critical role in the pathogenesis of AA.


Assuntos
Alelos , Anemia Aplástica , Apresentação do Antígeno/genética , Autoantígenos , Antígenos HLA-A , Antígeno HLA-B40 , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia Aplástica/genética , Anemia Aplástica/imunologia , Anemia Aplástica/patologia , Autoantígenos/genética , Autoantígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Feminino , Granulócitos/imunologia , Granulócitos/patologia , Antígenos HLA-A/genética , Antígenos HLA-A/imunologia , Antígeno HLA-B40/genética , Antígeno HLA-B40/imunologia , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/patologia , Humanos , Masculino , Pessoa de Meia-Idade
11.
Br J Haematol ; 175(2): 246-251, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27351867

RESUMO

Patients with mild hypomegakaryocytic thrombocytopenia (HMT) that does not meet the diagnostic criteria for a definite disease entity may potentially progress to aplastic anaemia (AA) that is refractory to therapy. To clarify the clinical picture of HMT, we prospectively followed 25 HMT patients with white blood cell count >3·0 × 109 /l, haemoglobin level >100 g/l and platelet count of <100·0 × 109 /l in the absence of morphological and karyotypic abnormalities in the bone marrow. Glycosylphosphatidylinositol-anchored protein-deficient blood cells [paroxysmal nocturnal haemoglobinuria (PNH)-type cells] were detected in 7 of the 25 (28%) patients and elevated plasma thrombopoietin (TPO, also termed THPO) levels (>320 pg/ml) were observed in 11 (44%) patients. Five (four PNH+ and one PNH-) of six TPOhigh patients who were treated with ciclosporin (CsA) showed improvement. Among the 21 patients who were followed without treatment, thrombocytopenia progressed in four of ten TPOlow patients and four of 11 TPOhigh patients. The 3-year failure-free survival rate of the CsA-treated TPOhigh patients (100%) was significantly higher than that of the untreated TPOhigh patients (20%). These results suggest that a significant population of HMT patients has an immune pathophysiology that is similar to AA and may be improved by early therapeutic intervention with CsA.


Assuntos
Megacariócitos/patologia , Trombocitopenia/diagnóstico , Trombocitopenia/etiologia , Adulto , Idoso , Anemia Aplástica/diagnóstico , Medula Óssea/imunologia , Medula Óssea/patologia , Feminino , Seguimentos , Hemoglobinúria Paroxística/diagnóstico , Humanos , Imunossupressores/uso terapêutico , Masculino , Megacariócitos/imunologia , Pessoa de Meia-Idade , Fenótipo , Trombocitopenia/tratamento farmacológico , Trombocitopenia/mortalidade , Trombopoetina/sangue , Resultado do Tratamento
12.
Exp Hematol ; 44(10): 931-939.e3, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27250585

RESUMO

To gain insight into the origin and clinical significance of leukocytes that lack human leukocyte antigen A (HLA-A) allele expression caused by a copy-number-neutral loss of heterozygosity in the short arm of chromosome 6 in patients with acquired aplastic anemia (AA), we used a high-sensitivity flow cytometry assay to investigate the presence of HLA-A allele-lacking leukocytes (HLA-LLs) in 144 AA patients. HLA-LLs, accounting for 0.2-99.8% of each leukocyte population, were detected in 18 of 71 (25.4%) newly diagnosed patients and in 25 of 73 (34.2%) previously treated patients. The lineage combination patterns of the HLA-LLs in the 43 HLA-LL(+) patients were granulocytes (Gs), monocytes (Ms), B cells (Bs), and T cells (Ts; GMBT) in 13 cases, GMB in 16 cases, GM in 11 cases, and B alone in three cases. The response rate to antithymocyte globulin plus cyclosporine therapy (100%) and the 2-year, failure-free survival rate (100%) in 8 newly diagnosed HLA-LL(+) patients were significantly higher than in 23 HLA-LL(-) patients (52.2% for both). These data suggest that HLA-LLs are a useful marker of the presence of immune pathophysiology in AA and that T-cell attacks against hematopoietic progenitor cells, rather than against hematopoietic stem cells, can trigger bone marrow failure in AA patients.


Assuntos
Alelos , Anemia Aplástica/diagnóstico , Anemia Aplástica/etiologia , Expressão Gênica , Antígenos HLA-A/genética , Leucócitos/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia Aplástica/tratamento farmacológico , Anemia Aplástica/mortalidade , Soro Antilinfocitário/uso terapêutico , Biomarcadores , Linhagem da Célula/genética , Criança , Pré-Escolar , Ciclosporina/uso terapêutico , Variações do Número de Cópias de DNA , Feminino , Citometria de Fluxo , Frequência do Gene , Estudos de Associação Genética , Genótipo , Humanos , Leucócitos/imunologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Prognóstico , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
13.
Ann Hematol ; 95(5): 771-81, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26968551

RESUMO

Most patients with acquired pure red cell aplasia (PRCA) and some with acquired aplastic anemia (AA) respond well to cyclosporine (CsA), but thereafter often show CsA dependency. The mechanism underlying this dependency remains unknown. We established a reliable method for measuring the regulatory T cell (Treg) count using FoxP3 and Helios expression as markers and determined the balance between Tregs and other helper T cell subsets in 16 PRCA and 29 AA patients. The ratios of interferon-γ-producing CD4(+) (Th1) T cells to Tregs in untreated patients and CsA-dependent patients were significantly higher (PRCA 5.77 ± 1.47 and 7.38 ± 2.58; AA 6.18 ± 2.35 and 8.94 ± 4.06) than in healthy volunteers (HVs; 3.33 ± 0.90) due to the profound decrease in the percentage of Tregs. In contrast, the ratios were comparable to HVs in convalescent CsA-treated AA patients (4.74 ± 2.10) and AA patients in remission after the cessation of CsA treatment (4.24 ± 1.67). Low-dose CsA (100 ng/ml) inhibited the proliferation of conventional T cells (Tconv) to a similar degree to the inhibition by Tregs in a co-culture with a 1:1 Treg/Tconv ratio. The data suggest that CsA may reverse the hematopoietic suppression in PRCA and AA patients by compensating for the inadequate immune regulatory function that occurs due to a profound decrease in the Treg count.


Assuntos
Anemia Aplástica/tratamento farmacológico , Ciclosporina/farmacologia , Hematopoese/efeitos dos fármacos , Imunossupressores/farmacologia , Aplasia Pura de Série Vermelha/tratamento farmacológico , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia Aplástica/imunologia , Antígenos de Diferenciação de Linfócitos T/análise , Ciclosporina/uso terapêutico , Feminino , Citometria de Fluxo , Hematopoese/imunologia , Humanos , Tolerância Imunológica , Imunofenotipagem , Imunossupressores/uso terapêutico , Testes de Liberação de Interferon-gama , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Aplasia Pura de Série Vermelha/imunologia , Indução de Remissão , Estudos Retrospectivos , Transtornos Relacionados ao Uso de Substâncias/etiologia , Transtornos Relacionados ao Uso de Substâncias/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/patologia
14.
Leuk Lymphoma ; 57(7): 1625-32, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26727336

RESUMO

Human herpesvirus-8-unrelated primary effusion lymphoma characterized by lymphomatous effusion without nodal lesions occasionally exhibits spontaneous remission. To elucidate the factors associated with a good prognosis, this study analyzed the clinical parameters of four patients treated in the department and 109 patients reported in case reports. The median age was 71 years and the median overall survival was 20 months. Patients possessing two independent favorable factors, an elderly status (≥ 70 years) and low serum lactate dehydrogenase (< 500 IU/L) showed a markedly higher 1-year survival than patients lacking either of the two factors in the absence of chemotherapy (94% vs 20%, p = 3 × 10(-5)), which was similarly observed in the chemotherapy group (94% vs 51%, p = 0.002). The use of rituximab was also a strong predictor of survival (89% vs 49%, p = 7 × 10(-6)). Elderly patients not exhibiting an increased lactate dehydrogenase may represent a benign sub-group of effusion lymphoma, which do not require chemotherapy to achieve remission.


Assuntos
Infecções por Herpesviridae/complicações , Herpesvirus Humano 8 , Lactato Desidrogenases/sangue , Linfoma de Efusão Primária/sangue , Linfoma de Efusão Primária/etiologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Biópsia , Aberrações Cromossômicas , Bandeamento Cromossômico , Coinfecção , Feminino , Infecções por Herpesviridae/virologia , Humanos , Imunofenotipagem , Linfoma de Efusão Primária/diagnóstico , Linfoma de Efusão Primária/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Fatores de Risco
15.
Int J Hematol ; 98(1): 96-101, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23661033

RESUMO

Passenger lymphocyte syndrome (PLS) presents as transient immune hemolysis due to anti-recipient ABO antibodies produced by donor B-lymphocytes accompanying minor or bidirectional ABO incompatible allogeneic hematopoietic stem cell transplantation (HSCT). We monitored both IgM and IgG type anti-recipient ABO antibodies in 18 consecutive HSCT recipients with hematological malignancies. Five of these patients (28%) developed transient immune hemolysis due to PLS after a median of 19 days post-HSCT. This response was associated with the detection of IgM and IgG anti-recipient ABO antibodies after a median of 16 and 22 days post-HSCT, respectively. All five patients subsequently developed acute graft-versus-host disease (GVHD) grades II-IV, and three died due to transplant-related mortality (TRM) within 1 year after HSCT, while in contrast, of the 13 patients without PLS, three (23%) developed grades II-IV acute GVHD (p < 0.01) and the 1-year TRM was 8% (p = 0.03). Thus, patients with PLS had a significantly lower 1-year overall survival than those without PLS (20 vs. 75%, p = 0.03). These findings suggest that the IgM anti-recipient ABO antibody may be an early predictor of acute GVHD and poor survival after minor or bidirectional ABO incompatible HSCT.


Assuntos
Sistema ABO de Grupos Sanguíneos/química , Anemia Hemolítica Autoimune/etiologia , Autoanticorpos/análise , Incompatibilidade de Grupos Sanguíneos/imunologia , Doença Enxerto-Hospedeiro/fisiopatologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunoglobulina M/análise , Adolescente , Adulto , Incompatibilidade de Grupos Sanguíneos/sangue , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/imunologia , Neoplasias Hematológicas/terapia , Humanos , Incidência , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Transplante Homólogo , Adulto Jovem
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