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1.
J Clin Invest ; 134(5)2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38426503

RESUMEN

Tissue-intrinsic mechanisms that regulate severity of systemic pathogenic immune-mediated diseases, such as acute graft-versus-host disease (GVHD), remain poorly understood. Following allogeneic hematopoietic stem cell transplantation, autophagy, a cellular stress protective response, is induced in host nonhematopoietic cells. To systematically address the role of autophagy in various host nonhematopoietic tissues, both specific classical target organs of acute GVHD (intestines, liver, and skin) and organs conventionally not known to be targets of GVHD (kidneys and heart), we generated mice with organ-specific knockout of autophagy related 5 (ATG5) to specifically and exclusively inhibit autophagy in the specific organs. When compared with wild-type recipients, animals that lacked ATG5 in the gastrointestinal tract or liver showed significantly greater tissue injury and mortality, while autophagy deficiency in the skin, kidneys, or heart did not affect mortality. Treatment with the systemic autophagy inducer sirolimus only partially mitigated GVHD mortality in intestine-specific autophagy-deficient hosts. Deficiency of autophagy increased MHC class I on the target intestinal epithelial cells, resulting in greater susceptibility to damage by alloreactive T cells. Thus, autophagy is a critical cell-intrinsic protective response that promotes tissue tolerance and regulates GVHD severity.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Animales , Ratones , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/patología , Intestinos/patología , Linfocitos T/patología , Células Epiteliales/patología
2.
Zhonghua Yi Xue Za Zhi ; 104(11): 850-856, 2024 Mar 19.
Artículo en Chino | MEDLINE | ID: mdl-38462361

RESUMEN

Objective: To evaluate the risk prediction and assessment function of HLA-DPB1 T-cell epitope (TCE) model and expression model in human leukocyte antigen (HLA)-matched unrelated hematopoietic stem cell transplantation (MUD-HSCT) with HLA-DPB1 mismatching. Methods: A total of 364 (182 pairs) potential MUD-HSCT donors and recipients confirmed by HLA high-resolution typing in Shaanxi Blood Center from 2016 to 2019 were analyzed retrospectively. Of the 182 recipients, there were 121 males and 61 females with an average age of (26.3±14.2) years. Of the 182 donors, there were 148 males and 34 females with an average age of (33.7±7.5) years. Polymerase chain reaction-sequence-based typing (PCR-SBT), next-generation sequencing (NGS) and polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSO) based on LABScan®3D platform were used for high-resolution typing of HLA-A, B, C, DRB1, DQB1, DPB1 gene, and PCR-SBT was used for single nucleotide polymorphism (SNP) typing. TCE model and expression model were used to predict and evaluate the HLA-DPB1 mismatch pattern and acute graft-versus-host-disease (aGVHD) risk. Results: A total of 26 HLA-DPB1 alleles and their 3'-UTR rs9277534 SNP genotypes were detected in this study population, and two new alleles HLA-DPB1*1052∶01 and HLA-DPB1*1119∶01 were found and officially named. The overall mismatch rate of HLA-DPB1 in MUD-HSCT donors and recipients was 90.66% (165/182). In TCE model, the HLA-DPB1 mismatch rates of permissible mismatch (PM) and non-permissible mismatch (non-PM) were 47.80% (87/182) and 42.86% (78/182), respectively. The non-PM in GvH direction was 13.73% (25/182), and which in HvG direction was 29.12% (53/182). A total of 73 pairs of donors and recipients in TCE model met the evaluation criteria of expression model. Among of TCE PM group, recipient DP5 mismatches accounted for 34.25% (25/73) were predicted as aGVHD high risk according to expression model. For the TCE non-PM group, both the recipient DP2 mismatches of 6.85% (5/73) and recipient DP5 mismatches of 10.86% (8/73) were predicted to be at high risk for aGVHD. Risk prediction by TCE model and expression model was 27.27% concordant and 16.97% unconcordant. Conclusions: TCE model and expression model are effective tools to predict aGVHD risk of MUD-HSCT. Comprehensive application of the two models is helpful to the hierarchical assessment of HSCT risk.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Masculino , Femenino , Humanos , Niño , Adolescente , Adulto Joven , Adulto , Epítopos de Linfocito T/genética , Estudios Retrospectivos , Cadenas beta de HLA-DP/genética , Donante no Emparentado , Enfermedad Injerto contra Huésped/genética
3.
Br J Haematol ; 204(5): 1920-1934, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38380743

RESUMEN

Pocket motifs and their amino acid positions of HLA molecules are known to govern antigen presentation to effector cells. Our objective was to analyse their influence on the risk of graft-versus-host disease (GVHD) and relapse after umbilical cord blood transplant (UCBT). The transplant characteristics of 849 patients with acute leukaemia were obtained from the Eurocord/EBMT database. Higher acute (a) GVHD was associated with homozygosity of UCB HLA-C amino acid positions 77 and 80 (NN/KK) (p = 0.008). Severe aGVHD was associated with HLA-A pocket B YSAVMENVHY motif (p = 0.002) and NN and RR genotypes of the HLA-C amino acid positions 77 and 156 (p = 0.006 and p = 0.002). Such risk was also increased in case of recipient and UCB mismatches in P4 (p < 0.0001) and P9 (p = 0.003) pockets of HLA-DQB1 alleles. For chronic GVHD, the pocket B YYAVMEISNY motif of the HLA-B*15:01 allele and the absence of mismatch between recipient and UCB in the P6 pocket of HLA-DRB1 were associated with a lower risk (p = 0.0007 and p = 0.0004). In relapse, both UCB pocket B YFAVMENVHY belonging to HLA-A*32:01 and recipient pocket B YDSVGENYQY motif of the HLA-C*07:01 allele were associated with higher risk (p = 0.0026 and p = 0.015). We provide clues on HLA-mediated cellular interactions and their role in the development of GVHD and relapse.


Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical , Enfermedad Injerto contra Huésped , Humanos , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/inmunología , Trasplante de Células Madre de Sangre del Cordón Umbilical/efectos adversos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Adolescente , Niño , Preescolar , Adulto Joven , Anciano , Antígenos HLA/genética , Antígenos HLA/inmunología , Lactante , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/inmunología , Leucemia/terapia , Leucemia/inmunología , Antígenos HLA-C/genética , Recurrencia , Sitios de Unión
4.
Front Immunol ; 15: 1280876, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38384455

RESUMEN

Introduction: Data on genomic susceptibility for adverse outcomes after hematopoietic stem cell transplantation (HSCT) for recipients are scarce. Methods: We performed a genome wide association study (GWAS) to identify genes associated with survival/mortality, relapse, and severe graft-versus-host disease (sGvHD), fitting proportional hazard and subdistributional models to data of n=1,392 recipients of European ancestry from three centres. Results: The single nucleotide polymorphism (SNP) rs17154454, intronic to the neuronal growth guidant semaphorin 3C gene (SEMA3C), was genome-wide significantly associated with event-free survival (p=7.0x10-8) and sGvHD (p=7.5x10-8). Further associations were detected for SNPs in the Paxillin gene (PXN) with death without prior relapse or sGvHD, as well as for SNPs of the Plasmacytoma Variant Translocation 1 gene (PVT1, a long non-coding RNA gene), the Melanocortin 5 Receptor (MC5R) gene and the WW Domain Containing Oxidoreductase gene (WWOX), all associated with the occurrence of sGvHD. Functional considerations support the observed associations. Discussion: Thus, new genes were identified, potentially influencing the outcome of HSCT.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Estudio de Asociación del Genoma Completo , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/genética , Genómica , Recurrencia
5.
Int J Hematol ; 119(5): 583-591, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38418747

RESUMEN

The impact of FOXP3 single-nucleotide polymorphisms (SNP) on clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains poorly understood. We investigated the relationship between a FOXP3 SNP (rs3761548) and clinical outcomes in 91 patients with hematological malignancies after allo-HSCT. Multivariate analysis showed that risk of severe chronic graft-versus-host disease (cGVHD) was significantly higher in patients with the FOXP3-3279C/A or FOXP3-3279A/A genotype than those with the FOXP3-3279C/C genotype [hazard ratio (HR), 2.69; 95% confidence interval (CI) 1.14-6.31; p = 0.023]. Therefore, FOXP3 at SNP rs3761548 can be a useful marker for predicting the occurrence of severe cGVHD.


Asunto(s)
Factores de Transcripción Forkhead , Enfermedad Injerto contra Huésped , Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Polimorfismo de Nucleótido Simple , Trasplante Homólogo , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Factores de Transcripción Forkhead/genética , Genotipo , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/genética , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/genética , Anciano
6.
Sci Transl Med ; 16(735): eadi1501, 2024 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-38381845

RESUMEN

Acute graft-versus-host disease (aGVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT), for which therapeutic options are limited. Strategies to promote intestinal tissue tolerance during aGVHD may improve patient outcomes. Using single-cell RNA sequencing, we identified a lipocalin-2 (LCN2)-expressing neutrophil population in mice with intestinal aGVHD. Transfer of LCN2-overexpressing neutrophils or treatment with recombinant LCN2 reduced aGVHD severity, whereas the lack of epithelial or hematopoietic LCN2 enhanced aGVHD severity and caused microbiome alterations. Mechanistically, LCN2 induced insulin-like growth factor 1 receptor (IGF-1R) signaling in macrophages through the LCN2 receptor SLC22A17, which increased interleukin-10 (IL-10) production and reduced major histocompatibility complex class II (MHCII) expression. Transfer of LCN2-pretreated macrophages reduced aGVHD severity but did not reduce graft-versus-leukemia effects. Furthermore, LCN2 expression correlated with IL-10 expression in intestinal biopsies in multiple cohorts of patients with aGVHD, and LCN2 induced IGF-1R signaling in human macrophages. Collectively, we identified a LCN2-expressing intestinal neutrophil population that reduced aGVHD severity by decreasing MHCII expression and increasing IL-10 production in macrophages. This work provides the foundation for administration of LCN2 as a therapeutic approach for aGVHD.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Animales , Ratones , Neutrófilos/patología , Interleucina-10 , Lipocalina 2/genética , Enfermedad Injerto contra Huésped/genética , Macrófagos/patología , Enfermedad Aguda
7.
Int J Immunogenet ; 51(2): 63-71, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38183417

RESUMEN

The patient-donor human leukocyte antigen (HLA) match remains the most important prognostic factor for successful unrelated donor haematopoietic stem cell transplantation (UD-HSCT). This single-centre study comprised 125 adult patients with malignant haematological diseases undergoing their first UD-HSCT. The primary goal of this study was to validate the impact of HLA matching on HSCT outcomes, specifically at the HLA-DPB1 and HLA-DRB3/4/5 loci. A multivariable Cox regression analysis with a backward selection algorithm was employed to assess the associations of selected prognostic factors with outcomes after UD-HSCT. Any HLA locus mismatch was found to be associated with an increased incidence of grade II-IV acute graft versus host disease (aGvHD) at 100 days (p = .031; hazard ratio [HR] 1.935) and 6 months (p = .004; HR 2.284) after HSCT. The results of the following analyses also confirmed the strong impact of HLA-DPB1-only mismatch on the incidence of grade II-IV aGvHD at 100-day (p = .006; HR 2.642) as well as at 6-month (p = .007; HR 2.401) time periods. The HLA-DPB1-only mismatch was also shown to be statistically significantly associated with lower relapse incidence (p = .034; HR 0.333). The impact of the HLA-DRB3/4/5 mismatch on outcomes was inconclusive, though the two and more HLA-DPB1 + DRB3/4/5-only mismatches showed a trend towards worse outcomes than a single mismatch. Based on our findings and those of more comprehensive studies, the extended HLA loci typing of patients and donors is suggested to avoid unexpected HLA mismatches during the UD selection.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Adulto , Humanos , Donante no Emparentado , Cadenas HLA-DRB3 , Prueba de Histocompatibilidad , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Enfermedad Injerto contra Huésped/genética , Estudios Retrospectivos
8.
Oncoimmunology ; 13(1): 2296712, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38170159

RESUMEN

Interferon regulatory factor 4 (IRF4) is a master transcription factor that regulates T helper cell (Th) differentiation. It interacts with the Basic leucine zipper transcription factor, ATF-like (BATF), depletion of which in CD4+ T cells abrogates acute graft-versus-host disease (aGVHD)-induced colitis. Here, we investigated the immune-regulatory role of Irf4 in a mouse model of MHC-mismatched bone marrow transplantation. We found that recipients of allogenic Irf4-/- CD4+ T cells developed less GVHD-related symptoms. Transcriptome analysis of re-isolated donor Irf4-/- CD4+ T helper (Th) cells, revealed gene expression profiles consistent with loss of effector T helper cell signatures and enrichment of a regulatory T cell (Treg) gene expression signature. In line with these findings, we observed a high expression of the transcription factor BTB and CNC homolog 2; (BACH2) in Irf4-/- T cells, which is associated with the formation of Treg cells and suppression of Th subset differentiation. We also found an association between BACH2 expression and Treg differentiation in patients with intestinal GVHD. Finally, our results indicate that IRF4 and BACH2 act as counterparts in Th cell polarization and immune homeostasis during GVHD. In conclusion, targeting the BACH2/IRF4-axis could help to develop novel therapeutic approaches against GVHD.


Asunto(s)
Colitis , Enfermedad Injerto contra Huésped , Ratones , Animales , Humanos , Colitis/inducido químicamente , Colitis/genética , Linfocitos T Reguladores/metabolismo , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/metabolismo
9.
Pharmacogenomics ; 25(1): 29-40, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38189154

RESUMEN

Aim: Successful treatment with tacrolimus to prevent graft versus host disease (GVHD) and minimize tacrolimus-related toxicities among allogeneic hematopoietic cell transplantation (alloHCT) recipients is contingent upon quickly achieving and maintaining concentrations within a narrow therapeutic range. The primary objective was to investigate associations between CYP3A4, CYP3A5 or ABCB1 genotype and the proportion of patients that attained an initial tacrolimus goal concentration following initiation of intravenous (iv.) and conversion to oral administration. Materials & methods: We retrospectively evaluated 86 patients who underwent HLA-matched (8/8) related donor alloHCT and were prescribed a tacrolimus-based regimen for GVHD prophylaxis. Results & conclusion: The findings of the present study suggests that CYP3A5 genotype may impact attainment of initial therapeutic tacrolimus concentrations with oral administration in alloHCT recipients.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Tacrolimus , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Inmunosupresores , Estudios Retrospectivos , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/prevención & control , Resultado del Tratamiento , Genotipo , Trasplante de Células Madre Hematopoyéticas/métodos , Subfamilia B de Transportador de Casetes de Unión a ATP/genética
10.
HLA ; 103(1): e15320, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38081622

RESUMEN

Hematopoietic stem cell transplantation (HSCT) offers the highest curative potential for patients with hematological malignancies. Complications including infection, graft-versus-host disease (GVHD), and relapse reflect delayed or dysregulated immune reconstitution. After transplantation, NK cells rapidly reconstitute and are crucial for immune surveillance and immune tolerance. NK cell function is tightly regulated by killer immunoglobin-like receptors (KIRs). Previous studies have revealed that donor KIRs, especially some activated KIRs (aKIRs) are closely related to transplant outcomes. Here, we performed a retrospective study, including 323 patients who received haploidentical (haplo) HSCT in our center. In univariate analysis, donor KIR2DS1, KIR2DS3 and KIR3DS1 gene protected patients with lymphoid disease from Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivation, while donor KIR2DS1, KIR2DS5 and KIR3DS1 gene conferred a higher risk of CMV reactivation for patients with myeloid disease. Multivariate analysis confirmed that donor telomeric (Tel) B/x and KIR2DS3 gene best protected patients with lymphoid disease from EBV (p = 0.017) and CMV reactivation (p = 0.004). In myeloid disease, grafts lacking Tel B/x and KIR2DS5 gene correlated with the lowest risk of CMV reactivation (p = 0.018). Besides, donor aKIR genes did not influence the rates of GVHD, relapse, non-relapse mortality (NRM) and overall survival (OS) in this study. The reactivation of EBV and CMV was associated with poor prognosis of haplo-HSCT. In conclusion, we found that donor aKIR genes might have a synergistic effect on CMV and EBV reactivation after haplo-HSCT. Whether the influence of donor aKIR genes varies with disease types remained to be studied.


Asunto(s)
Infecciones por Citomegalovirus , Infecciones por Virus de Epstein-Barr , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Herpesvirus Humano 4/genética , Suero Antilinfocítico/uso terapéutico , Estudios Retrospectivos , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/genética , Alelos , Recurrencia Local de Neoplasia/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/genética , Recurrencia
11.
J Invest Dermatol ; 144(3): 563-572.e9, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37742913

RESUMEN

Sclerotic-type cutaneous chronic graft-versus-host disease is a severe complication of allogeneic hematopoietic stem cell transplantation, with profound morbidity. A dearth of effective, targeted treatment options necessitates further investigation into the molecular mechanisms underlying this T-cell-mediated disease. In this study, we compared the transcriptome in skin biopsies from pediatric and young adult (aged <25 years) patients with sclerotic-type cutaneous chronic graft-versus-host disease (n = 7) with that in demographically matched healthy controls (n = 8) and patients with atopic dermatitis (n = 10) using RNA sequencing with RT-PCR and immunohistochemistry validation. Differential expression was defined as fold change > 1.5 and false discovery rate < 0.05. Sclerotic-type cutaneous chronic graft-versus-host disease exhibited strong and significant T helper (Th)1 skewing through key related cytokines and chemokines (CXCL9/10/11, IFNG/IFN-γ, STAT1/signal transducer and activator of transcription 1). Several markers related to the TSLP-OX40 axis were significantly upregulated relative to those in both controls and lesional atopic dermatitis, including TNFSF4/OX40L, TSLP, and IL33, as well as fibroinflammatory signatures characterized in a prior study in systemic sclerosis. Gene set variation analysis reflected marker-level findings, showing the greatest enrichment of the Th1 and fibroinflammatory pathways, with no global activation identified in Th2 or Th17/Th22. Cell-type deconvolution revealed a significant representation of macrophages and vascular endothelial cells. Sclerotic-type cutaneous chronic graft-versus-host disease in young patients may therefore be characterized by strong Th1-related upregulation with a unique TSLP-OX40 signature, suggesting new therapeutic avenues for this devastating disease.


Asunto(s)
Síndrome de Bronquiolitis Obliterante , Dermatitis Atópica , Enfermedad Injerto contra Huésped , Enfermedades de la Piel , Adulto Joven , Humanos , Niño , Citocinas/metabolismo , Dermatitis Atópica/genética , Dermatitis Atópica/patología , Células Endoteliales/metabolismo , Células Th2/metabolismo , Enfermedad Injerto contra Huésped/genética , Ligando OX40
12.
HLA ; 103(1): e15214, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37712429

RESUMEN

Relapse is a major cause of treatment failure in haploidentical haematopoietic progenitor cell transplant (HPCT) with PTCy. Natural killer cells suppress graft versus host disease and mediate the graft versus leukaemia effect, driven by killer cell immunoglobulin-like receptors (KIRs). Emerging research suggests that donor KIR genotype may influence graft outcome in haploidentical transplants with varying impacts between patient cohorts. This study investigates whether donors with greater KIR B motifs associate with outcomes such as greater relapse-free survival (RFS), overall survival (OS), nonrelapse mortality (NRM), acute graft versus host disease (GvHD) and infection. The study cohort included 98 haploidentical donor-recipient (D/R) pairs (myeloablative n = 37, RIC n = 61) with various haematological malignancies, receiving primary T-cell replete haploidentical HSCT with PTCγ. Following KIR SSO genotyping, donors are categorised into neutral (n = 63) or better and best (n = 35), based on KIR B motif content. Kaplan-Meier and Cox regression survival functions are performed to investigate associations with outcomes. Our results show that the better and best category has significantly poorer RFS (p = 0.013; hazard ratio [HR] 3.16, 95% CI 1.21-8.24: p = 0.018). The greater risk of relapse associated with poorer OS (p = 0.011; HR 2.24, 95% CI 1.18-4.24: p = 0.01) in the better and best category. The competing KIR receptor-ligand and missing licensing proof models failed to predict transplant outcomes. Here, we show neutral donors associate with favourable outcomes in T-cell replete haplo-HPCT with PTCγ after categorisation using the KIR B content model, due to the increased risk of relapse associated with the use of better and best donors.


Asunto(s)
Enfermedad Injerto contra Huésped , Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Humanos , Estudios Retrospectivos , Haplotipos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante Haploidéntico/efectos adversos , Alelos , Recurrencia Local de Neoplasia/etiología , Receptores KIR/genética , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/complicaciones , Enfermedad Crónica , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/prevención & control
14.
Int J Hematol ; 119(1): 80-87, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37980303

RESUMEN

A 55-year-old man in first complete remission of acute myeloid leukemia with a normal karyotype underwent allogeneic hematopoietic stem cell transplantation from a human-leukocyte-antigen-matched sibling. Bone marrow examination on day 28 confirmed complete remission, but G-banding analysis revealed a novel chromosomal abnormality, including dic(18;20)(p11.2;q11.2). The patient developed moderate chronic graft-versus-host disease on day 174, and the abnormal clones identified by dic(18;20) significantly increased after that point. Chimerism testing repeatedly confirmed complete donor type. Although next-generation sequencing showed no clonal hematopoiesis-related gene mutations, copy number analysis of the donor and the recipient revealed copy number deletion of 18p, 18q, and 20q. The patient has maintained remission for more than 2 years to date without developing a hematologic neoplasm or cytopenia. The distinctive clonal hematopoiesis with a dicentric chromosome seemed to have undergone the breakage-fusion-bridge cycle, which could cause the complex events of deletion, amplification, and inversion. These copy number alterations might have increased the number of clones with growth advantage, and the highly inflammatory environment in the recipient due to graft-versus-host disease might have contributed to the clonal selection.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Masculino , Humanos , Persona de Mediana Edad , Hematopoyesis Clonal , Trasplante Homólogo , Enfermedad Injerto contra Huésped/genética , Células Clonales , Hematopoyesis/genética
15.
Cancer Med ; 12(24): 21567-21578, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-38053512

RESUMEN

AIM: The gut microbiota has been reported to be associated with acute graft-versus-host disease (aGvHD) in hematopoietic stem cell transplantation (HSCT). Dynamic surveillance of the microbiota is required to understand the detailed pathogenesis involved in the process of aGvHD. METHODS: Fecal samples were collected prospectively at four timepoints, including pre-HSCT (T1), graft infusion (T2), neutrophil engraftment (T3), and 30 days after transplantation (T4). Fecal samples were profiled by 16S ribosomal RNA gene sequencing to assess the microbiota composition. RESULTS: From the T1 to T4 timepoint, the diversity of the gut microbiota decreased, and the dominant species also changed, with a decrease in the obligate anaerobic bacteria and a shift toward a "pathogenic community". Compared with non-aGvHD patients, aGvHD patients had a lower abundance of Roseburia at T1 and a higher abundance of Acinetobacter johnsonii at T2. Furthermore, Acinetobacter johnsonii was negatively correlated with the secretion of IL-4 and TNF-α. At T3, Rothia mucilaginos was demonstrated to be linked with a decreased risk of aGvHD, which was accompanied by decreased secretion of IL-8. At T4, higher abundances of Lactobacillus paracasei and Acinetobacter johnsonii were identified to be related with aGvHD. Lactobacillus paracasei was associated with the downregulation of IL-10, and Acinetobacter johnsonii was associated with the downregulation of IL-2 and TNF-α. CONCLUSIONS: Dynamic changes in gut microbiota composition and related cytokines were found to be related to aGvHD, including pathogenic or protective changes. These findings suggested that manipulation of gut microbiota at different timepoints might be a promising avenue for preventing or treating this common complication.


Asunto(s)
Microbioma Gastrointestinal , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Factor de Necrosis Tumoral alfa , Trasplante Homólogo/efectos adversos , Enfermedad Injerto contra Huésped/genética , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Aguda
16.
Front Immunol ; 14: 1227897, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37901227

RESUMEN

Transplantation of hematopoietic stem cells (HSCT) is a procedure commonly used in treatment of various haematological disorders which is associated with significantly improved survival rates. However, one of its drawbacks is the possibility of development of post-transplant complications, including acute and chronic graft-versus-host disease (GvHD) or CMV infection. Various studies suggested that NK cells and their receptors may affect the transplant outcome. In the present study, patients and donors were found to significantly differ in the distribution of the NKG2A rs7301582 genetic variants - recipients carried the C allele more often than their donors (0.975 vs 0.865, p<0.0001). Increased soluble HLA-E (sHLA-E) levels detected in recipients' serum 30 days after transplantation seemed to play a prognostic and protective role. It was observed that recipients with higher sHLA-E levels were less prone to chronic GvHD (11.65 vs 6.33 pg/mL, p=0.033) or more severe acute GvHD grades II-IV (11.07 vs 8.04 pg/mL, p=0.081). Our results also showed an unfavourable role of HLA-E donor-recipient genetic incompatibility in CMV infection development after transplantation (OR=5.92, p=0.014). Frequencies of NK cells (both CD56dim and CD56bright) expressing NKG2C were elevated in recipients who developed CMV, especially 30 and 90 days post-transplantation (p<0.03). Percentages of NKG2C+ NK cells lacking NKG2A expression were also increased in these patients. Moreover, recipients carrying a NKG2C deletion characterized with decreased frequency of NKG2C+ NK cells (p<0.05). Our study confirms the importance of NK cells in the development of post-transplant complications and highlights the effect of HLA-E and NKG2C genetic variants, sHLA-E serum concentration, as well as NKG2C surface expression on transplant outcome.


Asunto(s)
Infecciones por Citomegalovirus , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Antígenos de Histocompatibilidad Clase I , Subfamília C de Receptores Similares a Lectina de Células NK , Humanos , Infecciones por Citomegalovirus/metabolismo , Enfermedad Injerto contra Huésped/genética , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Células Madre Hematopoyéticas/metabolismo , Trasplante Homólogo/efectos adversos , Antígenos de Histocompatibilidad Clase I/genética , Subfamília C de Receptores Similares a Lectina de Células NK/genética , Antígenos HLA-E
17.
Hum Genet ; 142(12): 1677-1703, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37878144

RESUMEN

Beta-thalassemia (ß-thalassemia) is an autosomal recessive disorder caused by point mutations, insertions, and deletions in the HBB gene cluster, resulting in the underproduction of ß-globin chains. The most severe type may demonstrate complications including massive hepatosplenomegaly, bone deformities, and severe growth retardation in children. Treatments for ß-thalassemia include blood transfusion, splenectomy, and allogeneic hematopoietic stem cell transplantation (HSCT). However, long-term blood transfusions require regular iron removal therapy. For allogeneic HSCT, human lymphocyte antigen (HLA)-matched donors are rarely available, and acute graft-versus-host disease (GVHD) may occur after the transplantation. Thus, these conventional treatments are facing significant challenges. In recent years, with the advent and advancement of CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein 9) gene editing technology, precise genome editing has achieved encouraging successes in basic and clinical studies for treating various genetic disorders, including ß-thalassemia. Target gene-edited autogeneic HSCT helps patients avoid graft rejection and GVHD, making it a promising curative therapy for transfusion-dependent ß-thalassemia (TDT). In this review, we introduce the development and mechanisms of CRISPR/Cas9. Recent advances on feasible strategies of CRISPR/Cas9 targeting three globin genes (HBB, HBG, and HBA) and targeting cell selections for ß-thalassemia therapy are highlighted. Current CRISPR-based clinical trials in the treatment of ß-thalassemia are summarized, which are focused on γ-globin reactivation and fetal hemoglobin reproduction in hematopoietic stem cells. Lastly, the applications of other promising CRISPR-based technologies, such as base editing and prime editing, in treating ß-thalassemia and the limitations of the CRISPR/Cas system in therapeutic applications are discussed.


Asunto(s)
Enfermedad Injerto contra Huésped , Talasemia beta , Niño , Humanos , Edición Génica/métodos , Sistemas CRISPR-Cas/genética , Talasemia beta/genética , Talasemia beta/terapia , Talasemia beta/metabolismo , Enfermedad Injerto contra Huésped/genética
18.
Genes (Basel) ; 14(9)2023 09 13.
Artículo en Inglés | MEDLINE | ID: mdl-37761936

RESUMEN

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a clinically challenging modality for the treatment of many hematologic diseases such as leukemia, lymphoma, and myeloma. Graft-versus-host disease (GVHD) is a common complication after allo-HSCT and remains a major cause of morbidity and mortality, limiting the success of a potentially curative transplant. Several microRNAs (miRNAs) have recently been shown to impact the biology of GVHD. They are molecular regulators involved in numerous processes during T-cell development, homeostasis, and activation, and contribute to the pathological function of T-cells during GvHD. Here, we review the key role of miRNAs contributing to the GvHD; their detection might be an interesting possibility in the early diagnosis and monitoring of disease.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Linfoma , MicroARNs , Humanos , MicroARNs/genética , Trasplante Homólogo/efectos adversos , Enfermedad Injerto contra Huésped/genética , Trasplante de Células Madre Hematopoyéticas/efectos adversos
19.
Front Immunol ; 14: 1229266, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37731501

RESUMEN

Background: Methotrexate (MTX), utilized as a graft-versus-host disease (GvHD) prophylactic agent in allogeneic hematopoietic stem cell transplantation (allo-HSCT), has been proven to effectively decrease the occurrence of the peri-engraftment syndrome (Peri-ES) and acute GvHD (aGvHD). Changes in the pharmacodynamics of MTX are closely associated with gene polymorphisms in genes encoding drug-metabolizing enzymes and transporters. Nevertheless, the current studies mainly concentrate on leukemia or autoimmune diseases, and limited studies on allo-HSCT were reported. Methods: Here, we retrospectively assessed the relationship between MTX-related transporter and metabolizing enzyme gene polymorphisms, clinical characteristics, and outcomes in 57 pediatric patients who received haploid HSCT (haplo-HSCT) with malignant tumors at a single center. Results: We discovered all gene polymorphisms were in the Hardy-Weinberg equilibrium in our cohort. We discovered a significant correlation between platelet recovery time and ABCB1 (1236C>T) (p = 0.042). Compared with patients with SLCO1B1 (1865+4846T>C) TT, patients with SLCO1B1 (1865+4846T>C) TC/CC had an increased incidence of Peri-ES (p = 0.030). Based on the multivariate Cox analysis, we discovered that SLCO1B1 (1865+4846T>C) TT genotype was an independent protective factor for Peri-ES morbidity (hazard ratio (HR) = 0.464, p = 0.031), and the dose of mononuclear cells reinfused was significantly correlated with II-IV aGvHD (HR = 2.604, p = 0.039). Conclusion: In summary, our findings prove that the host's genotypes might modify the risk of developing Peri-ES, contribute to a better understanding of the inter-individual difference in efficacy, and facilitate the development of individualized approaches to GvHD prophylaxis.


Asunto(s)
Enfermedad Injerto contra Huésped , Enfermedades Hematológicas , Trasplante de Células Madre Hematopoyéticas , Enfermedades del Sistema Inmune , Humanos , Niño , Metotrexato/uso terapéutico , Estudios Retrospectivos , Enfermedades Hematológicas/genética , Enfermedades Hematológicas/terapia , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Proteínas de Transporte de Membrana , Transportador 1 de Anión Orgánico Específico del Hígado
20.
Blood ; 142(21): 1831-1844, 2023 11 23.
Artículo en Inglés | MEDLINE | ID: mdl-37699201

RESUMEN

Severe acute graft-versus-host disease (aGVHD) is associated with significant mortality and morbidity, especially in steroid-resistant (SR) cases. Spatial transcriptomic technology can elucidate tissue-based interactions in vivo and possibly identify predictors of treatment response. Tissue sections from 32 treatment-naïve patients with biopsy-confirmed lower gastrointestinal (GI) aGVHD were obtained. The GeoMx digital spatial profiler was used to capture transcriptome profiles of >18 000 genes from different foci of immune infiltrates, colonic epithelium, and vascular endothelium. Each tissue compartment sampled showed 2 distinct clusters that were analyzed for differential expression and spatially resolved correlation of gene signatures. Classic cell-mediated immunity signatures, normal differentiated epithelial cells, and inflamed vasculature dominated foci sampled from steroid-sensitive cases. In contrast, a neutrophil predominant noncanonical inflammation with regenerative epithelial cells and some indication of angiogenic endothelial response was overrepresented in areas from SR cases. Evaluation of potential prognostic biomarkers identified ubiquitin specific peptidase 17-like (USP17L) family of genes as being differentially expressed in immune cells from patients with worsened survival. In summary, we demonstrate distinct tissue niches with unique gene expression signatures within lower GI tissue from patients with aGVHD and provide evidence of a potential prognostic biomarker.


Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Transcriptoma , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/genética , Inmunidad Celular , Esteroides/uso terapéutico , Mucosa Intestinal , Enfermedad Aguda
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