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1.
Blood ; 139(2): 287-299, 2022 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-34534280

RESUMO

Chronic graft-versus-host disease (cGVHD) is the most common cause for non-relapse mortality postallogeneic hematopoietic stem cell transplant (HSCT). However, there are no well-defined biomarkers for cGVHD or late acute GVHD (aGVHD). This study is a longitudinal evaluation of metabolomic patterns of cGVHD and late aGVHD in pediatric HSCT recipients. A quantitative analysis of plasma metabolites was performed on 222 evaluable pediatric subjects from the ABLE/PBMTC1202 study. We performed a risk-assignment analysis at day + 100 (D100) on subjects who later developed either cGVHD or late aGVHD after day 114 to non-cGVHD controls. A second analysis at diagnosis used fixed and mixed multiple regression to compare cGVHD at onset to time-matched non-cGVHD controls. A metabolomic biomarker was considered biologically relevant only if it met all 3 selection criteria: (1) P ≤ .05; (2) effect ratio of ≥1.3 or ≤0.75; and (3) receiver operator characteristic AUC ≥0.60. We found a consistent elevation in plasma α-ketoglutaric acid before (D100) and at the onset of cGVHD, not impacted by cGVHD severity, pubertal status, or previous aGVHD. In addition, late aGVHD had a unique metabolomic pattern at D100 compared with cGVHD. Additional metabolomic correlation patterns were seen with the clinical presentation of pulmonary, de novo, and progressive cGVHD. α-ketoglutaric acid emerged as the single most significant metabolite associated with cGVHD, both in the D100 risk-assignment and later diagnostic onset analysis. These distinctive metabolic patterns may lead to improved subclassification of cGVHD. Future validation of these exploratory results is needed. This trial was registered at www.clinicaltrials.gov as #NCT02067832.


Assuntos
Doença Enxerto-Hospedeiro/metabolismo , Ácidos Cetoglutáricos/metabolismo , Adolescente , Biomarcadores/sangue , Biomarcadores/metabolismo , Criança , Pré-Escolar , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/sangue , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Lactente , Ácidos Cetoglutáricos/sangue , Masculino , Metaboloma , Medição de Risco
2.
Blood ; 137(7): 983-993, 2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33206937

RESUMO

A disease risk index (DRI) that was developed for adults with hematologic malignancy who were undergoing hematopoietic cell transplantation is also being used to stratify children and adolescents by disease risk. Therefore, to develop and validate a DRI that can be used to stratify those with AML and ALL by their disease risk, we analyzed 2569 patients aged <18 years with acute myeloid (AML; n = 1224) or lymphoblastic (ALL; n = 1345) leukemia who underwent hematopoietic cell transplantation. Training and validation subsets for each disease were generated randomly with 1:1 assignment to the subsets, and separate prognostic models were derived for each disease. For AML, 4 risk groups were identified based on age, cytogenetic risk, and disease status, including minimal residual disease status at transplantation. The 5-year leukemia-free survival for low (0 points), intermediate (2, 3, 5), high (7, 8), and very high (>8) risk groups was 78%, 53%, 40%, and 25%, respectively (P < .0001). For ALL, 3 risk groups were identified based on age and disease status, including minimal residual disease status at transplantation. The 5-year leukemia-free survival for low (0 points), intermediate (2-4), and high (≥5) risk groups was 68%, 51%, and 33%, respectively (P < .0001). We confirmed that the risk groups could be applied to overall survival, with 5-year survival ranging from 80% to 33% and 73% to 42% for AML and ALL, respectively (P < .0001). This validated pediatric DRI, which includes age and residual disease status, can be used to facilitate prognostication and stratification of children with AML and ALL for allogeneic transplantation.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Índice de Gravidade de Doença , Adolescente , Fatores Etários , Aloenxertos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Estudos de Coortes , Terapia Combinada , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Distribuição Aleatória , Medição de Risco , Fatores de Risco
3.
Pediatr Blood Cancer ; 70 Suppl 6: e30577, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37480158

RESUMO

Since the publication of the last Cellular Therapy and Stem Cell Transplant blueprint in 2013, Children's Oncology Group cellular therapy-based trials advanced the field and created new standards of care across a wide spectrum of pediatric cancer diagnoses. Key findings include that tandem autologous transplant improved survival for patients with neuroblastoma and atypical teratoid/rhabdoid brain tumors, one umbilical cord blood (UCB) donor was safer than two UCB donors, killer immunoglobulin receptor (KIR) mismatched donors did not improve survival for pediatric acute myeloid leukemia when in vivo T-cell depletion is used, and the depth of remission as measured by next-generation sequencing-based minimal residual disease assessment pretransplant was the best predictor of relapse for acute lymphoblastic leukemia. Plans for the next decade include optimizing donor selection for transplants for acute leukemia/myelodysplastic syndrome, using novel engineered cellular therapies to target a wide array of malignancies, and developing better treatments for cellular therapy toxicities such as viral infections and graft-vs-host disease.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Criança , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Doadores não Relacionados
4.
Blood ; 135(15): 1287-1298, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32047896

RESUMO

Human graft-versus-host disease (GVHD) biology beyond 3 months after hematopoietic stem cell transplantation (HSCT) is complex. The Applied Biomarker in Late Effects of Childhood Cancer study (ABLE/PBMTC1202, NCT02067832) evaluated the immune profiles in chronic GVHD (cGVHD) and late acute GVHD (L-aGVHD). Peripheral blood immune cell and plasma markers were analyzed at day 100 post-HSCT and correlated with GVHD diagnosed according to the National Institutes of Health consensus criteria (NIH-CC) for cGVHD. Of 302 children enrolled, 241 were evaluable as L-aGVHD, cGVHD, active L-aGVHD or cGVHD, and no cGVHD/L-aGVHD. Significant marker differences, adjusted for major clinical factors, were defined as meeting all 3 criteria: receiver-operating characteristic area under the curve ≥0.60, P ≤ .05, and effect ratio ≥1.3 or ≤0.75. Patients with only distinctive features but determined as cGVHD by the adjudication committee (non-NIH-CC) had immune profiles similar to NIH-CC. Both cGVHD and L-aGVHD had decreased transitional B cells and increased cytolytic natural killer (NK) cells. cGVHD had additional abnormalities, with increased activated T cells, naive helper T (Th) and cytotoxic T cells, loss of CD56bright regulatory NK cells, and increased ST2 and soluble CD13. Active L-aGVHD before day 114 had additional abnormalities in naive Th, naive regulatory T (Treg) cell populations, and cytokines, and active cGVHD had an increase in PD-1- and a decrease in PD-1+ memory Treg cells. Unsupervised analysis appeared to show a progression of immune abnormalities from no cGVHD/L-aGVHD to L-aGVHD, with the most complex pattern in cGVHD. Comprehensive immune profiling will allow us to better understand how to minimize L-aGVHD and cGVHD. Further confirmation in adult and pediatric cohorts is needed.


Assuntos
Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Aguda , Antígenos CD/análise , Antígenos CD/imunologia , Linfócitos B/imunologia , Linfócitos B/patologia , Biomarcadores/sangue , Criança , Doença Crônica , Citocinas/sangue , Citocinas/imunologia , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/patologia , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Linfócitos T/imunologia , Linfócitos T/patologia
5.
J Pediatr Hematol Oncol ; 44(2): e343-e348, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-35200220

RESUMO

Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) posthematopoietic stem cell transplantation (HSCT) is often diagnosed using the modified Seattle (MS) or European Society for Blood and Marrow Transplantation (EBMT) criteria. We hypothesized that strict application of these criteria could affect the timing of diagnosis and incidence of SOS/VOD. We collected data on 215 transplants performed in 184 patients at a single pediatric hematopoietic stem cell transplantation center, which were divided into 3 cohorts. Clinical diagnosis and treatment of SOS/VOD was documented in 13% of transplants (cohort 1). On retrospective review, 49% of transplant events met either MS and/or EBMT criteria, however, were not diagnosed with SOS/VOD (cohort 2); remaining 38% of transplant events did not meet MS or EBMT criteria and were not diagnosed with SOS/VOD (cohort 3). Day+100 overall survival was significantly inferior for cohort 1 (78%) compared with cohorts 2 or 3 (92% and 95%, P=0.01) with no difference between cohorts 2 and 3 (P=0.5). Patients diagnosed with SOS/VOD >day+13 had worse day+100 overall survival when compared with those diagnosed ≤day13 (64.3% and 100%, respectively, P=0.02). This study highlights the value of careful clinical assessment to guide diagnosis and the need to refine diagnostic criteria for SOS/VOD in children.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Hepatopatia Veno-Oclusiva , Criança , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatopatia Veno-Oclusiva/diagnóstico , Hepatopatia Veno-Oclusiva/tratamento farmacológico , Hepatopatia Veno-Oclusiva/etiologia , Humanos , Incidência , Polidesoxirribonucleotídeos/uso terapêutico , Estudos Retrospectivos , Transplante de Células-Tronco/efeitos adversos , Síndrome
6.
Blood ; 134(3): 304-316, 2019 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-31043425

RESUMO

Chronic graft-versus-host disease (cGVHD) and late acute graft-versus-host disease (L-aGVHD) are understudied complications of allogeneic hematopoietic stem cell transplantation in children. The National Institutes of Health Consensus Criteria (NIH-CC) were designed to improve the diagnostic accuracy of cGVHD and to better classify graft-versus-host disease (GVHD) syndromes but have not been validated in patients <18 years of age. The objectives of this prospective multi-institution study were to determine: (1) whether the NIH-CC could be used to diagnose pediatric cGVHD and whether the criteria operationalize well in a multi-institution study; (2) the frequency of cGVHD and L-aGVHD in children using the NIH-CC; and (3) the clinical features and risk factors for cGVHD and L-aGVHD using the NIH-CC. Twenty-seven transplant centers enrolled 302 patients <18 years of age before conditioning and prospectively followed them for 1 year posttransplant for development of cGVHD. Centers justified their cGVHD diagnosis according to the NIH-CC using central review and a study adjudication committee. A total of 28.2% of reported cGVHD cases was reclassified, usually as L-aGVHD, following study committee review. Similar incidence of cGVHD and L-aGVHD was found (21% and 24.7%, respectively). The most common organs involved with diagnostic or distinctive manifestations of cGVHD in children include the mouth, skin, eyes, and lungs. Importantly, the 2014 NIH-CC for bronchiolitis obliterans syndrome perform poorly in children. Past acute GVHD and peripheral blood grafts are major risk factors for cGVHD and L-aGVHD, with recipients ≥12 years of age being at risk for cGVHD. Applying the NIH-CC in pediatrics is feasible and reliable; however, further refinement of the criteria specifically for children is needed.


Assuntos
Doença Enxerto-Hospedeiro/diagnóstico , Doença Aguda , Adolescente , Fatores Etários , Criança , Pré-Escolar , Doença Crônica , Conferências para Desenvolvimento de Consenso de NIH como Assunto , Feminino , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Guias de Prática Clínica como Assunto , Fatores de Risco , Índice de Gravidade de Doença , Avaliação de Sintomas , Fatores de Tempo , Transplante Homólogo , Estados Unidos , Fluxo de Trabalho
7.
Haematologica ; 106(7): 1839-1845, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32554562

RESUMO

With limited data comparing hematopoietic cell transplant outcomes between myeloablative total body irradiation (TBI) containing and non-TBI regimens in children with de novo acute myeloid leukemia, the aim of this study was to compare transplant-outcomes between these regimens. Cox regression models were used to compare transplant-outcomes after TBI and non-TBI regimens in 624 children transplanted between 2008 and 2016. Thirty two percent (n=199) received TBI regimens whereas 68% (n=425) received non-TBI regimens. Five-year non-relapse mortality was higher with TBI regimens (22% vs. 11%, p<0.0001) but relapse was lower (23% vs. 37%, p<0.0001) compared to non-TBI regimens. Consequently, overall (62% vs. 60%, p=1.00) and leukemia-free survival (55% vs. 52%, p=0.42) did not differ between treatment groups. Grade II-IV acute GVHD was higher with TBI regimens (56% vs. 27%, p<0.0001) but not chronic GVHD. The 3-year incidence of gonadal or growth hormone deficiency was higher with TBI regimens (24% vs. 8%, p<0.001) but there were no differences in late pulmonary, cardiac or renal impairment. In the absence of a survival advantage, the choice of TBI or non-TBI regimen merits careful consideration with the data favoring non-TBI regimens to limit the burden of morbidity associated with endocrine dysfunction.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Bussulfano , Criança , Ciclofosfamida , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Estudos Retrospectivos , Condicionamento Pré-Transplante , Irradiação Corporal Total
8.
Pediatr Transplant ; 24(8): e13821, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32844543

RESUMO

No standardized guidelines exist for infectious prophylaxis following pediatric auto-HSCT. We hypothesized significant variation in clinical practice. Thirty-three Pediatric Transplant and Cell Therapy Consortium centers completed a survey to assess institutional management. The majority utilize viral (91%) and fungal prophylaxis (94%), but duration varies. Bacterial prophylaxis during neutropenia is instituted by 42%. Our study demonstrates marked practice variability in infectious prophylaxis across centers. Additional research is needed to address patterns of infectious complications and to develop meaningful clinical practice guidelines for pediatric auto-HSCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Infecções/tratamento farmacológico , Infecções/microbiologia , Complicações Pós-Operatórias/microbiologia , Complicações Pós-Operatórias/prevenção & controle , Padrões de Prática Médica/estatística & dados numéricos , Criança , Resistência a Medicamentos , Humanos , Inquéritos e Questionários
9.
Biol Blood Marrow Transplant ; 25(7): 1374-1381, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30878608

RESUMO

Family psychosocial risk screening is an important initial step in delivering evidence-based care in hematopoietic stem cell transplantation (HCT). Establishing an evidence-based screening approach that is acceptable, reliable, and valid is an essential step in psychosocial care delivery. This is a 3-institution multimethod study. In part 1, caregivers of children about to undergo HCT (n = 140) completed the Psychosocial Assessment Tool-Hematopoietic Cell Transplantation (PAT-HCT), a brief parent report screener adapted for HCT, and validating questionnaires. Families received feedback on their risks identified on the PAT-HCT. In part 2, 12 caregivers completed a semistructured interview about their perceptions of the PAT and the feedback process. The reliability and validity of the PAT-HCT total and subscale scores were tested using Kuder-Richardson-20 (KR-20) and Pearson correlations. Thematic content analysis was used to analyze the qualitative interview data. Internal consistency for the total score (KR-20 = .88) and the Child Problems, Sibling Problems, Family Problems, and Stress Reactions subscales were strong (KR-20 >.70). Family Structure, Social Support, and Family Beliefs subscales were adequate (KR-20 = .55 to .63). Moderate to strong correlations with the criteria measures provided validation for the total and subscale scores. Feedback was provided to 97.14% of the families who completed the PAT-HCT, and the mean rating of acceptability was >4.00 (on a 5-point scale). The qualitative data indicate that families appreciate the effort to provide screening and feedback. The PAT-HCT is a psychometrically sound screener for use in HCT. Feedback can be given to families. Both the screener and the feedback process are acceptable to caregivers.


Assuntos
Cuidadores/psicologia , Família/psicologia , Transplante de Células-Tronco Hematopoéticas/psicologia , Neoplasias/psicologia , Estresse Psicológico/psicologia , Inquéritos e Questionários , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Neoplasias/terapia , Psicometria
10.
Pediatr Blood Cancer ; 66(10): e27889, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31276304

RESUMO

OBJECTIVE: Currently, no evidence-based psychosocial clinical care pathways (PCCP) exist to triage psychosocial risk levels and guide delivery of psychosocial care to youth receiving a hematopoietic stem cell transplantation (HCT) and their families. The purpose of this paper is to describe the use of qualitative research methodologies to develop PCCP in pediatric HCT consistent with the Standards for Psychosocial Care developed for children with cancer. METHODS: We previously used qualitative methodologies to interview parents to identify four principles to inform the development of PCCPs. Then in this study a focus group with parents and multidisciplinary clinicians was conducted to assess the acceptability of the PCCP, suggest modifications, and provide input on its use. RESULTS: The PCCP is six-step pathway, starting with a standardized screening assessment with the Psychosocial Assessment Tool (PAT-HCT) that identifies the family's specific care needs. The focus group data support overall assessment with the PAT-HCT and the care principles underlying this approach. CONCLUSIONS: This PCCP is a systemic multidisciplinary model for providing psychosocial care that is ready for the next stage of development and evaluation in clinical care.


Assuntos
Procedimentos Clínicos , Transplante de Células-Tronco Hematopoéticas/psicologia , Neoplasias/terapia , Psico-Oncologia/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Grupos Focais , Humanos , Lactente , Masculino , Neoplasias/psicologia , Psicometria/métodos , Adulto Jovem
11.
Biol Blood Marrow Transplant ; 24(8): 1651-1656, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29753157

RESUMO

This multicenter study evaluated a treosulfan-based regimen in children and young adults with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplant (HCT). Forty patients with median age 11 years (range, 1 to 19) underwent allogeneic HCT for AML in first (n = 18), second (n = 11), and third or greater remission (n = 3) or MDS (n = 8) using bone marrow (n = 25), peripheral blood stem cells (n = 5), or cord blood (n = 9). The regimen consisted of body surface area (BSA)-based treosulfan 10 g/m2/day (BSA ≤ .5 m2), 12 g/m2/day (BSA > .5 to 1.0 m2), or 14 g/m2/day (BSA > 1.0 m2) on days -6 to -4; fludarabine 30 mg/m2/day on days -6 to -2; and a single fraction of 200 cGy total body irradiation on day -1. Graft-versus-host disease (GVHD) prophylaxis included tacrolimus and methotrexate for marrow and peripheral blood stem cell and cyclosporine/mycophenolate mofetil for cord blood. One-year overall survival, disease-free survival, and nonrelapse mortality were 80%, 73%, and 3%, respectively. One-year relapse was 38% for AML and 13% for MDS. No serious organ toxicities were observed. All 37 assessable patients engrafted. Cumulative incidences of grades II to IV acute GVHD and chronic GVHD were 22% and 40%, respectively. BSA-based treosulfan dosing resulted in predictable area under the curve and maximum concentration, which is required for dosing without measuring individual pharmacokinetic parameters. Observed differences in pharmacokinetics did not impact disease control or regimen toxicity. This BSA-based treosulfan regimen resulted in excellent engraftment and disease-free survival and minimal toxicity and transplant-related mortality (3%) in children and young adults with AML and MDS.


Assuntos
Bussulfano/análogos & derivados , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Irradiação Corporal Total , Adolescente , Bussulfano/administração & dosagem , Bussulfano/uso terapêutico , Criança , Pré-Escolar , Feminino , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Lactente , Leucemia Mieloide Aguda/mortalidade , Masculino , Síndromes Mielodisplásicas/mortalidade , Análise de Sobrevida , Transplante Homólogo , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico , Adulto Jovem
12.
Pediatr Blood Cancer ; 64(2): 267-274, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27650428

RESUMO

BACKGROUND: While significant improvements have been made for children with acute lymphoblastic leukemia (ALL) in the United States over the past 20 years, black patients continue to have inferior outcomes. The full impact of socioeconomic variables on outcomes in this minority population is not entirely understood. PROCEDURE: Disease characteristics, demographic, and socioeconomic status (SES) variables were collected on black (n = 44) and white (n = 178) patients diagnosed at the University of Alabama at Birmingham. Cox proportional hazard regression was used to evaluate the influence of SES and insurance status on survival. RESULTS: As a cohort, 5-year overall survival (OS) was 87% (82-91%), with a median follow-up of 99 months. In univariable analysis, black race was not significantly associated with a higher risk of death or relapse and death. White and black patients with standard-risk leukemia had excellent outcomes, with 97% (91-99%) and 96% (75-99%) 5-year OS, respectively. In contrast, for high-risk disease, white patients had a statistically significant improved 5-year OS rates compared with black patients (79% [68-87%] vs. 52% [28-72%]). Black children were more likely to have public insurance, and, in multivariable analysis, this was associated with a trend toward an improved outcome. Black patients also had poorer census tract-level SES parameters, but these variables were not associated with survival. CONCLUSION: Our study demonstrates significantly inferior outcomes for black children with high-risk leukemia. These outcome disparities were not related to SES variables, including poverty or private insurance coverage, suggesting the involvement of other factors and highlighting the need for a prospective investigative analysis.


Assuntos
Negro ou Afro-Americano/estatística & dados numéricos , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , População Branca/estatística & dados numéricos , Adolescente , Criança , Pré-Escolar , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Estadiamento de Neoplasias , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prognóstico , Fatores de Risco , Fatores Socioeconômicos , Taxa de Sobrevida
13.
J Immunol ; 193(10): 4769-77, 2014 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25381358

RESUMO

Th17 cells have emerged as important mediators of host defense and homeostasis at barrier sites, particularly the intestines, where the greatest number and diversity of the microbiota reside. A critical balance exists between protection of the host from its own microbiota and pathogens and the development of immune-mediated disease. Breaches of local innate immune defenses provide critical stimuli for the induction of Th17 cell development, and additional cues within these tissues promote Th17 cell survival and/or plasticity. Normally, this results in eradication of the microbial threat and restitution of homeostasis. When dysregulated, however, Th17 cells can cause a range of immune-mediated diseases, whether directed against Ags derived from the microbiota, such as in inflammatory bowel disease, or against self-Ags in a range of autoimmune diseases. This review highlights recent discoveries that provide new insights into ways in which environmental signals impact Th17 cell development and function in the intestines.


Assuntos
Doenças Inflamatórias Intestinais/imunologia , Intestinos/imunologia , Microbiota/imunologia , Transdução de Sinais/imunologia , Células Th17/imunologia , Autoantígenos/genética , Autoantígenos/imunologia , Sobrevivência Celular , Citocinas/genética , Citocinas/imunologia , Células Dendríticas/imunologia , Células Dendríticas/microbiologia , Células Dendríticas/patologia , Dieta , Regulação da Expressão Gênica , Homeostase/imunologia , Humanos , Imunidade Inata , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/patologia , Intestinos/microbiologia , Intestinos/patologia , Células Th17/microbiologia , Células Th17/patologia
14.
N Engl J Med ; 367(9): 805-16, 2012 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-22931314

RESUMO

BACKGROUND: Of the cancers treated with allogeneic hematopoietic stem-cell transplantation (HSCT), acute myeloid leukemia (AML) is most sensitive to natural killer (NK)-cell reactivity. The activating killer-cell immunoglobulin-like receptor (KIR) 2DS1 has ligand specificity for HLA-C2 antigens and activates NK cells in an HLA-dependent manner. Donor-derived NK reactivity controlled by KIR2DS1 and HLA could have beneficial effects in patients with AML who undergo allogeneic HSCT. METHODS: We assessed clinical data, HLA genotyping results, and donor cell lines or genomic DNA for 1277 patients with AML who had received hematopoietic stem-cell transplants from unrelated donors matched for HLA-A, B, C, DR, and DQ or with a single mismatch. We performed donor KIR genotyping and evaluated the clinical effect of donor KIR genotype and donor and recipient HLA genotypes. RESULTS: Patients with AML who received allografts from donors who were positive for KIR2DS1 had a lower rate of relapse than those with allografts from donors who were negative for KIR2DS1 (26.5% vs. 32.5%; hazard ratio, 0.76; 95% confidence interval [CI], 0.61 to 0.96; P=0.02). Of allografts from donors with KIR2DS1, those from donors who were homozygous or heterozygous for HLA-C1 antigens could mediate this antileukemic effect, whereas those from donors who were homozygous for HLA-C2 did not provide any advantage (24.9% with homozygosity or heterozygosity for HLA-C1 vs. 37.3% with homozygosity for HLA-C2; hazard ratio, 0.46; 95% CI, 0.28 to 0.75; P=0.002). Recipients of KIR2DS1-positive allografts mismatched for a single HLA-C locus had a lower relapse rate than recipients of KIR2DS1-negative allografts with a mismatch at the same locus (17.1% vs. 35.6%; hazard ratio, 0.40; 95% CI, 0.20 to 0.78; P=0.007). KIR3DS1, in positive genetic linkage disequilibrium with KIR2DS1, had no effect on leukemia relapse but was associated with decreased mortality (60.1%, vs. 66.9% without KIR3DS1; hazard ratio, 0.83; 95% CI, 0.71 to 0.96; P=0.01). CONCLUSIONS: Activating KIR genes from donors were associated with distinct outcomes of allogeneic HSCT for AML. Donor KIR2DS1 appeared to provide protection against relapse in an HLA-C-dependent manner, and donor KIR3DS1 was associated with reduced mortality. (Funded by the National Institutes of Health and others.).


Assuntos
Antígenos HLA-C/genética , Leucemia Mieloide Aguda/prevenção & controle , Receptores KIR/genética , Idoso , Genótipo , Antígenos HLA-C/metabolismo , Transplante de Células-Tronco Hematopoéticas , Humanos , Estimativa de Kaplan-Meier , Células Matadoras Naturais/imunologia , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Modelos de Riscos Proporcionais , Receptores KIR/fisiologia , Estudos Retrospectivos , Prevenção Secundária , Transplante Homólogo , Doadores não Relacionados
15.
J Immunol ; 190(9): 4650-60, 2013 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-23554313

RESUMO

NK cells are regulated by inhibiting and activating cell surface receptors. Most inhibitory receptors recognize MHC class I Ags and protect healthy cells from NK cell-mediated autoaggression. However, certain activating receptors, including the human activating killer cell Ig-like receptor (KIR) 2DS1, also recognize MHC class I. This fact raises the question of how NK cells expressing such activating receptors are tolerized to host tissues. We investigated whether the presence of HLA-C2, the cognate ligand for 2DS1, induces tolerance in 2DS1-expressing NK cells. Anti-HLA-C2 activity could be detected in vitro in some 2DS1 positive NK clones irrespective of the presence or absence of HLA-C2 ligand in the donor. The frequency of anti-HLA-C2 reactivity was high in donors homozygous for HLA-C1. Surprisingly, no significant difference was seen in the frequency of anti-HLA-C2 cytotoxicity in donors heterozygous for HLA-C2 and donors without HLA-C2 ligand. However, donors homozygous for HLA-C2, compared with all other donors, had significantly reduced frequency of anti-HLA-C2 reactive clones. The 2DS1 positive clones that express inhibitory KIR for self-HLA class I were commonly noncytotoxic, and anti-HLA-C2 cytotoxicity was nearly exclusively restricted to 2DS1 single positive clones lacking inhibitory KIR. 2DS1 single positive NK clones with anti-HLA-C2 reactivity were also present posttransplantation in HLA-C2 positive recipients of hematopoietic stem cell transplants from 2DS1 positive donors. These results demonstrate that many NK cells with anti-HLA-C2 reactivity are present in HLA-C1 homozygous and heterozygous donors with 2DS1. In contrast, 2DS1 positive clones from HLA-C2 homozygous donors are frequently tolerant to HLA-C2.


Assuntos
Antígenos HLA-C/imunologia , Tolerância Imunológica/imunologia , Células Matadoras Naturais/imunologia , Receptores KIR/imunologia , Receptores KIR/metabolismo , Antígenos CD/imunologia , Antígenos CD/metabolismo , Regulação para Baixo/imunologia , Antígenos HLA-C/metabolismo , Transplante de Células-Tronco Hematopoéticas , Humanos , Interleucina-15/imunologia , Interleucina-15/metabolismo , Células Matadoras Naturais/metabolismo , Receptor B1 de Leucócitos Semelhante a Imunoglobulina , Ligantes , Receptores Imunológicos/imunologia , Receptores Imunológicos/metabolismo , Doadores de Tecidos
16.
Biol Blood Marrow Transplant ; 19(6): 876-87, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23523972

RESUMO

Bone marrow graft failure and poor graft function are frequent complications after hematopoietic stem cell transplantation and result in significant morbidity and mortality. Both conditions are associated with graft-versus-host disease (GVHD), although the mechanism remains undefined. Here we show, in 2 distinct murine models of GVHD (complete MHC- and class II-disparate) that mimic human peripheral blood stem cell transplantation, that Th1 CD4(+) cells induce bone marrow failure in allogeneic recipients. Bone marrow failure after transplantation of allogeneic naïve CD4(+) T cells was associated with increased CD4(+) Th1 cell development within bone marrow and lymphoid tissues. Using IFNγ-reporter mice, we found that Th1 cells generated during GVHD induced bone marrow failure after transfers into secondary recipients. Homing studies demonstrated that transferred Th1 cells express CXCR4, which was associated with accumulation within bone marrow and spleen. Allogeneic Th1 cells were activated by radiation-resistant host bone marrow cells and induced bone marrow failure through an IFNγ-dependent mechanism. Thus, allogeneic Th1 CD4(+) cells generated during GVHD traffic to hematopoietic sites and induce bone marrow failure via IFNγ-mediated toxicity. These results have important implications for prevention and treatment of bone marrow graft failure after hematopoietic stem cell transplantation.


Assuntos
Células da Medula Óssea/imunologia , Medula Óssea/imunologia , Doença Enxerto-Hospedeiro/imunologia , Interferon gama/imunologia , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Aplasia Pura de Série Vermelha/imunologia , Baço/imunologia , Células Th1/imunologia , Animais , Medula Óssea/metabolismo , Medula Óssea/patologia , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Comunicação Celular , Feminino , Expressão Gênica , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/patologia , Teste de Histocompatibilidade , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Complexo Principal de Histocompatibilidade/genética , Complexo Principal de Histocompatibilidade/imunologia , Camundongos , Modelos Animais , Receptores CXCR4/genética , Receptores CXCR4/imunologia , Aplasia Pura de Série Vermelha/etiologia , Aplasia Pura de Série Vermelha/metabolismo , Aplasia Pura de Série Vermelha/patologia , Baço/metabolismo , Baço/patologia , Células Th1/metabolismo , Células Th1/patologia , Transplante Homólogo
17.
Bioorg Med Chem Lett ; 23(5): 1450-5, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23352509

RESUMO

We have carried out a pharmacological evaluation of arylmethylene quinuclidine derivatives interactions with human α3ß4 nAChRs subtype, using cell-based receptor binding, calcium-influx, electrophysiological patch-clamp assays and molecular modeling techniques. We have found that the compounds bind competitively to the α3ß4 receptor with micromolar affinities and some of the compounds behave as non-competitive antagonists (compounds 1, 2 and 3), displaying submicromolar IC(50) values. These evidences suggest a mixed mode of action for these compounds, having interactions at the orthosteric site and more pronounced interactions at an allosteric site to block agonist effects. One of the compounds, 1-benzyl-3-(diphenylmethylene)-1-azoniabicyclo[2.2.2]octane chloride (compound 3), exhibited poorly reversible use-dependent block of α3ß4 channels. We also found that removal of a phenyl group from compound 1 confers a partial agonism to the derived analog (compound 6). Introducing a hydrogen-bond acceptor into the 3-benzylidene quinuclidine derivative (compound 7) increases agonism potency at the α3ß4 receptor subtype. Docking into the orthosteric binding site of a α3ß4 protein structure derived by comparative modeling accurately predicted the experimentally-observed trend in binding affinity. Results supported the notion that binding requires a hydrogen bond formation between the ligand basic nitrogen and the backbone carbonyl oxygen atom of the conserved Trp-149.


Assuntos
Quinuclidinas/química , Quinuclidinas/farmacologia , Receptores Nicotínicos/química , Receptores Nicotínicos/metabolismo , Animais , Sítios de Ligação , Células CHO , Cricetulus , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Relação Estrutura-Atividade
18.
J Chem Inf Model ; 53(2): 327-42, 2013 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-23244494

RESUMO

The pharmacokinetic and safety profiles of clinical drug candidates are greatly influenced by their requisite physicochemical properties. In particular, it has been shown that 2D molecular descriptors such as fraction of Sp3 carbon atoms (Fsp3) and number of stereo centers correlate with clinical success. Using the proteomic off-target hit rate of nicotinic ligands, we found that shape-based 3D descriptors such as the radius of gyration and shadow indices discriminate off-target promiscuity better than do Fsp3 and the number of stereo centers. We have deduced the relevant descriptor values required for a ligand to be nonpromiscuous. Investigating the MDL Drug Data Report (MDDR) database as compounds move from the preclinical stage toward the market, we have found that these shape-based 3D descriptors predict clinical success of compounds at preclinical and phase1 stages vs compounds withdrawn from the market better than do Fsp3 and LogD. Further, these computed 3D molecular descriptors correlate well with experimentally observed solubility, which is among well-known physicochemical properties that drive clinical success. We also found that about 84% of launched drugs satisfy either Shadow index or Fsp3 criteria, whereas withdrawn and discontinued compounds fail to meet the same criteria. Our studies suggest that spherical compounds (rather than their elongated counterparts) with a minimal number of aromatic rings may exhibit a high propensity to advance from clinical trials to market.


Assuntos
Descoberta de Drogas , Preparações Farmacêuticas/química , Animais , Ensaios Clínicos como Assunto , Bases de Dados de Produtos Farmacêuticos , Descoberta de Drogas/métodos , Humanos , Ligantes , Preparações Farmacêuticas/metabolismo , Farmacologia , Proteínas/metabolismo , Solubilidade , Relação Estrutura-Atividade
19.
Blood Adv ; 7(14): 3612-3623, 2023 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-36219586

RESUMO

The National Institutes of Health Consensus criteria for chronic graft-versus-host disease (cGVHD) diagnosis can be challenging to apply in children, making pediatric cGVHD diagnosis difficult. We aimed to identify diagnostic pediatric cGVHD biomarkers that would complement the current clinical criteria and help differentiate cGVHD from non-cGVHD. The Applied Biomarkers of Late Effects of Childhood Cancer (ABLE) study, open at 27 transplant centers, prospectively evaluated 302 pediatric patients after hematopoietic cell transplant (234 evaluable). Forty-four patients developed cGVHD. Mixed and fixed effect regression analyses were performed on diagnostic cGVHD onset blood samples for cellular and plasma biomarkers, with individual markers declared relevant if they met 3 criteria: an effect ratio ≥1.3 or ≤0.75; an area under the curve (AUC) of ≥0.60; and a P value <5.814 × 10-4 (Bonferroni correction) (mixed effect) or <.05 (fixed effect). To address the complexity of cGVHD diagnosis in children, we built a machine learning-based classifier that combined multiple cellular and plasma biomarkers with clinical factors. Decreases in regulatory natural killer cells, naïve CD4 T helper cells, and naïve regulatory T cells, and elevated levels of CXCL9, CXCL10, CXCL11, ST2, ICAM-1, and soluble CD13 (sCD13) characterize the onset of cGVHD. Evaluation of the time dependence revealed that sCD13, ST2, and ICAM-1 levels varied with the timing of cGVHD onset. The cGVHD diagnostic classifier achieved an AUC of 0.89, with a positive predictive value of 82% and a negative predictive value of 80% for diagnosing cGVHD. Our polyomic approach to building a diagnostic classifier could help improve the diagnosis of cGVHD in children but requires validation in future prospective studies. This trial was registered at www.clinicaltrials.gov as #NCT02067832.


Assuntos
Síndrome de Bronquiolite Obliterante , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Criança , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Molécula 1 de Adesão Intercelular , Proteína 1 Semelhante a Receptor de Interleucina-1 , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Biomarcadores
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