RESUMEN
Induction of trained immunity by Bacille-Calmette-Guérin (BCG) vaccination mediates beneficial heterologous effects, but the mechanisms underlying its persistence and magnitude remain elusive. In this study, we show that BCG vaccination in healthy human volunteers induces a persistent transcriptional program connected to myeloid cell development and function within the hematopoietic stem and progenitor cell (HSPC) compartment in the bone marrow. We identify hepatic nuclear factor (HNF) family members 1a and b as crucial regulators of this transcriptional shift. These findings are corroborated by higher granulocyte numbers in BCG-vaccinated infants, HNF1 SNP variants that correlate with trained immunity, and elevated serum concentrations of the HNF1 target alpha-1 antitrypsin. Additionally, transcriptomic HSPC remodeling was epigenetically conveyed to peripheral CD14+ monocytes, displaying an activated transcriptional signature three months after BCG vaccination. Taken together, transcriptomic, epigenomic, and functional reprogramming of HSPCs and peripheral monocytes is a hallmark of BCG-induced trained immunity in humans.
Asunto(s)
Vacuna BCG/inmunología , Granulocitos/citología , Hematopoyesis/inmunología , Células Madre Hematopoyéticas/citología , Monocitos/citología , Médula Ósea/inmunología , Células de la Médula Ósea/citología , Células de la Médula Ósea/inmunología , Citocinas/metabolismo , Femenino , Voluntarios Sanos , Factor Nuclear 1-alfa del Hepatocito/genética , Factor Nuclear 1-beta del Hepatocito/genética , Humanos , Receptores de Lipopolisacáridos/metabolismo , Masculino , Monocitos/inmunología , Mycobacterium bovis/inmunología , Transcripción Genética/genética , Transcriptoma/genética , Vacunación , Adulto Joven , alfa 1-Antitripsina/sangreRESUMEN
The literature suggests that cancer survivors with more aggressive treatments are more at risk for postcancer fatigue. In this study, we investigated the prevalence of fatigue after completion of stem cell transplantation (SCT). Furthermore, we studied if medical variables are associated with fatigue and if the model of perpetuating factors of postcancer fatigue derived from previous studies in cancer survivors, without SCT, is applicable in SCT survivors. Ninety-eight patients treated with autologous or allogeneic SCT filled out several questionnaires. Medical characteristics were obtained from the medical charts. All patients had to be in persistent complete remission for at least 1 year. Thirty-five per cent of the patients experienced severe fatigue. The percentage of patients with severe fatigue remained stable during the years after transplantation. Several psychosocial factors, but no medical factors, were associated with fatigue. The model of perpetuating factors appeared to be applicable. Contrary to cancer survivors without SCT, we found no decrease in fatigue complaints during the first years after SCT. Cognitive behaviour therapy (CBT) is a general form of psychotherapy directed at changing condition-related cognitions and behaviours. CBT especially designed for postcancer fatigue, aimed at perpetuating factors, can also be used to manage fatigue in cancer survivors treated with SCT.
