RESUMEN
BACKGROUND AIMS: Regulatory T cells (Tregs) are the main mediators of peripheral tolerance. Treg-directed therapy has shown promising results in preclinical studies of diverse immunopathologies. At present, the clinical applicability of adoptive Treg transfer is limited by difficulties in generating Tregs at sufficient cell dose and purity. METHODS: We developed a Good Manufacturing Practice (GMP) compliant method based on closed-system multiparametric Fluorescence-Activated Cell Sorting (FACS) to purify Tregs, which are then expanded in vitro and gene-marked with a clinical grade retroviral vector to enable in vivo fate tracking. Following small-scale optimization, we conducted four clinical-scale processing runs. RESULTS: We showed that Tregs could be enriched to 87- 92% purity following FACS-sorting, and expanded and transduced to yield clinically relevant cell dose of 136-732×106 gene-marked cells, sufficient for a cell dose of at least 2 × 106 cells/kg. The expanded Tregs were highly demethylated in the FOXP3 Treg-specific demethylated region (TSDR), consistent with bona fide natural Tregs. They were suppressive in vitro, but a small percentage could secrete proinflammatory cytokines, including interferon-γ and interleukin-17A. CONCLUSIONS: This study demonstrated the feasibility of isolating, expanding and gene-marking Tregs in clinical scale, thus paving the way for future phase I trials that will advance knowledge about the in vivo fate of transferred Tregs and its relationship with concomitant Treg-directed pharmacotherapy and clinical response.
Asunto(s)
Citometría de Flujo , Factores de Transcripción Forkhead , Linfocitos T Reguladores , Linfocitos T Reguladores/inmunología , Humanos , Citometría de Flujo/métodos , Factores de Transcripción Forkhead/metabolismo , Factores de Transcripción Forkhead/genética , Separación Celular/métodos , Vectores Genéticos/genéticaRESUMEN
BACKGROUND: Interleukin 6 mediates graft-versus-host disease (GVHD) in experimental allogeneic stem-cell transplantation (allogeneic SCT) and represents an attractive therapeutic target. We aimed to assess whether the humanised anti-interleukin-6 receptor monoclonal antibody, tocilizumab, could attenuate the incidence of acute GVHD. METHODS: We undertook a single-group, single-institution phase 1/2 study at the Royal Brisbane and Women's Hospital Bone Marrow Transplantation unit, QLD, Australia. Eligible patients were 18-65 years old and underwent T-replete HLA-matched allogeneic SCT with either total body irradiation-based myeloablative or reduced-intensity conditioning from unrelated or sibling donors. One intravenous dose of tocilizumab (8 mg/kg, capped at 800 mg, over 60 mins' infusion) was given the day before allogeneic SCT along with standard GVHD prophylaxis (cyclosporin [5 mg/kg per day on days -1 to +1, then 3 mg/kg per day to maintain therapeutic levels (trough levels of 140-300 ng/mL) for 100 days plus methotrexate [15 mg/m(2) on day 1, then 10 mg/m(2) on days 3, 6, and 11]). The primary endpoint was incidence of grade 2-4 acute GVHD at day 100, assessed and graded as per the Seattle criteria. Immunological profiles were compared with a non-randomised group of patients receiving allogeneic SCT, but not treated with tocilizumab. This trial is registered with the Australian and New Zealand Clinical Trials Registry, number ACTRN12612000726853. FINDINGS: Between Jan 19, 2012, and Aug 27, 2013, 48 eligible patients receiving cyclosporin and methotrexate as GVHD prophylaxis were enrolled into the study. The incidence of grade 2-4 acute GVHD in patients treated with tocilizumab at day 100 was 12% (95% CI 5-24), and the incidence of grade 3-4 acute GVHD was 4% (1-13). Grade 2-4 acute GVHD involving the skin developed in five (10%) patients of 48 treated with tocilizumab, involving the gastrointestinal tract in four (8%) patients; there were no reported cases involving the liver. Low incidences of grade 2-4 acute GVHD were noted in patients receiving both myeloablative total body irradiation-based conditioning (12% [95% CI 2-34) and fludarabine and melphalan reduced-intensity conditioning (12% [4-27]). Immune reconstitution was preserved in recipients of interleukin-6 receptor inhibition, but qualitatively modified with suppression of known pathogenic STAT3-dependent pathways. INTERPRETATION: Interleukin 6 is the main detectable and dysregulated cytokine secreted after allogeneic SCT and its inhibition is a potential new and simple strategy to protect from acute GVHD despite robust immune reconstitution; a randomised, controlled trial assessing tocilizumab in addition to standard GVHD prophylaxis in these patients is warranted. FUNDING: National Health and Medical Research Council and Queensland Health.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Neoplasias Hematológicas/complicaciones , Interleucina-6/antagonistas & inhibidores , Trasplante de Células Madre/efectos adversos , Adolescente , Adulto , Anciano , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/terapia , Humanos , Interleucina-6/inmunología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Prospectivos , Tasa de Supervivencia , Trasplante Homólogo , Adulto JovenRESUMEN
BACKGROUND: Major ABO mismatch in hematopoietic progenitor cell transplantation (HPCT) is associated with a range of immunohematologic consequences including progenitor cell infusion (PCI)-related hemolysis, delayed red blood cell engraftment, and pure red cell aplasia (PRCA). Although pretransplant (recipient) isoagglutinin reduction may be associated with decreased immunohematologic complications in this setting, there is no consensus with respect to strategies for isoagglutinin reduction. STUDY DESIGN AND METHODS: This observational study assessed the efficacy of a standardized pretransplant isoagglutinin reduction strategy incorporating donor-type secretor plasma infusions with or without plasma exchange to prevent PCI-associated hemolysis and PRCA in major or bidirectional ABO-mismatched peripheral blood HPCT. All major or bidirectional ABO-mismatched HPCTs performed between 1999 and 2010 were identified from an institutional database. Immunohematologic outcomes were determined retrospectively by review of individual medical records. RESULTS: In total 110 major or bidirectional ABO-mismatched HPCTs had been performed. No patient developed hemolysis after PCI. With respect to PRCA incidence, 16 patients (15%) were excluded due to early mortality and three (3%) due to incomplete data; of the remaining 91 patients, five (5%) developed PRCA. Patients with PRCA had significantly higher pretransplant isoagglutinin titers (p = 0.0001) compared to those who did not develop PRCA. CONCLUSIONS: Use of a standardized pretransplant isoagglutinin reduction strategy including donor-type secretor plasma infusions is both safe and efficient in preventing PCI-associated hemolysis and is associated with low rates of posttransplant PRCA.
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Sistema del Grupo Sanguíneo ABO/inmunología , Donantes de Sangre , Incompatibilidad de Grupos Sanguíneos , Fucosiltransferasas/metabolismo , Trasplante de Células Madre Hematopoyéticas , Intercambio Plasmático/métodos , Acondicionamiento Pretrasplante/métodos , Adolescente , Adulto , Anciano , Aglutininas/sangre , Aglutininas/metabolismo , Incompatibilidad de Grupos Sanguíneos/sangre , Incompatibilidad de Grupos Sanguíneos/inmunología , Tipificación y Pruebas Cruzadas Sanguíneas , Femenino , Enfermedades Hematológicas/sangre , Enfermedades Hematológicas/diagnóstico , Enfermedades Hematológicas/inmunología , Enfermedades Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Procedimientos de Reducción del Leucocitos/métodos , Masculino , Persona de Mediana Edad , Intercambio Plasmático/efectos adversos , Estudios Retrospectivos , Trasplante Homólogo , Resultado del Tratamiento , Adulto Joven , Galactósido 2-alfa-L-FucosiltransferasaRESUMEN
Changes to donor availability, collection center capacity, and travel restrictions during the early phase of the COVID-19 pandemic led to routine cryopreservation of most unrelated donor products for hematopoietic transplantation prior to the recipient commencing the conditioning regimen. We investigated the effect of this change on unrelated donor product quality and clinical outcomes. Product information was requested from transplantation centers in Australia and New Zealand and clinical outcome data from the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR). In total, 191 products were collected between April 1, 2021, and September 30, 2021, and most (74%) were from international collection centers. Median post-thaw CD34 recovery was 78% (range 25% to 176%) and median post-thaw CD34 viability was 87% (range 34% to 112%). Median time to neutrophil recovery was 17 days (interquartile range 10 to 24 days), and graft failure occurred in 6 patients (4%). These clinical outcomes were similar to those of "fresh" unrelated donor transplants reported to the ABMTRR in 2019. However, recipient transplantation centers reported problems with 29% of products in the form of damage during transit, low cell dose, inadequate labeling, missing representative samples, or missing documentation. These problems were critical in 7 cases (4%). At last follow-up, 22 products (12%) had not been infused. Routine cryopreservation of unrelated donor hemopoietic progenitor cell products has enabled safe continuation of allogeneic transplant services during the COVID-19 pandemic. However, practices for product tracing, documentation, and transportation can be optimized, and measures to reduce the incidence of unused unrelated donor product are required.
Asunto(s)
COVID-19 , Criopreservación , Células Madre Hematopoyéticas , Humanos , Pandemias , SARS-CoV-2RESUMEN
Donor registries and transplantation societies recommend cryopreservation of unrelated donor hemopoietic progenitor cell (HPC) products before the recipient commences conditioning therapy to mitigate the donor and travel risks associated with the COVID-19 pandemic. However, little is known regarding the postthaw quality of such allogeneic products or the effect of precryopreservation storage and processing on these characteristics. We investigated the postthaw CD34+ cell recovery and viability of 305 allogeneic HPC products cryopreserved at 9 laboratories across Australia. Median postthaw CD34+ cell recovery was 76% and ranged from 6% to 122%. Longer transit time before cryopreservation, white cell count (WCC) during storage, and complex product manipulation before cryopreservation were independently associated with inferior postthaw CD34+ cell recovery. Longer precryopreservation transit time and WCC were also associated with inferior postthaw CD34+ cell viability. We conclude that although postthaw CD34+ cell recovery and viability of cryopreserved allogeneic HPC is generally acceptable, there is a significant risk of poor postthaw product quality, associated with prolonged storage time, higher WCC, and complex product manipulation precryopreservation. Awareness of expected postthaw recovery and practices that influence it will assist collection, processing, and transplant centers in optimizing outcomes for transplant recipients.
Asunto(s)
Antígenos CD34/análisis , Criopreservación , Células Madre Hematopoyéticas/citología , COVID-19 , Supervivencia Celular , Infecciones por Coronavirus/epidemiología , Trasplante de Células Madre Hematopoyéticas , Humanos , Pandemias , Neumonía Viral/epidemiología , Trasplante HomólogoRESUMEN
PURPOSE: Inducible caspase 9 (iCasp9) is a cellular safety switch that can make T-cell therapy safer. The purpose of this phase I trial was to investigate the use of iCasp9-transduced T-cell addback in adult patients undergoing haploidentical stem cell transplantation for high-risk hematologic malignancies. PATIENTS AND METHODS: Patients undergoing myeloablative, CD34-selected haploidentical stem cell transplantation were treated with 0.5-1.0 × 106/kg donor-derived iCasp9-transduced T cells on day +25 or 26 post-transplant, with additional doses allowed for disease relapse, infection, or mixed chimerism. RESULTS: Three patients were enrolled. iCasp9-transduced T cells were readily detectable by 4 weeks post-infusion in all patients and remained at high level (114 cells/µL, 11% of T cells) in 1 patient alive at 3.6 years. One patient developed donor-derived Epstein-Barr virus-associated post-transplant lymphoproliferative disease (EBV-PTLD), which was followed by a marked expansion of iCasp9 T cells and cytokine release syndrome (CRS). These iCasp9-transduced T cells infiltrated the affected lymph nodes and secreted IFNγ and IL-10. They peaked at 1,848 cells/µL and were found to be monoclonal by T-cell receptor (TCR) clonotype and oligoclonal by viral integrant analysis, representing a 6-log in vivo expansion of the dominant T-cell clone. These T cells were not autonomous and contracted with the resolution of EBV-PTLD, which did not recur. CONCLUSIONS: iCasp9-transduced T cells could persist long-term. They retained very high in vivo clonotypic proliferative capacity and function, and could cause CRS in response to de novo lymphoma development.
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Caspasa 9/metabolismo , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Agonistas Mieloablativos/administración & dosificación , Linfocitos T/trasplante , Adolescente , Adulto , Caspasa 9/genética , Caspasa 9/inmunología , Femenino , Neoplasias Hematológicas/inmunología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Depleción Linfocítica/efectos adversos , Depleción Linfocítica/métodos , Masculino , Persona de Mediana Edad , Agonistas Mieloablativos/efectos adversos , Recurrencia Local de Neoplasia , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Factores de Tiempo , Acondicionamiento Pretrasplante/métodos , Trasplante Haploidéntico/efectos adversos , Trasplante Haploidéntico/métodos , Resultado del Tratamiento , Adulto JovenRESUMEN
Projects in Australia and internationally over the past two decades have sought to define and clarify competencies required to work in health promotion. It is now apparent that such competencies are very useful to health promotion practice. However, to date little attempt has been made to describe those uses. More than 200 health promotion practitioners throughout Australia were engaged in workshops to explore and define potential uses of health promotion competencies. The suggestions from these 10 workshops are summarised in eight categories of uses. Agreed health promotion competencies have potential to impact on recruitment, training, employment policy and health promotion practice.
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Educación Basada en Competencias/normas , Educadores en Salud/educación , Promoción de la Salud/normas , Evaluación de Necesidades , Competencia Profesional , Personal Administrativo/educación , Personal Administrativo/normas , Actitud del Personal de Salud , Australia , Habilitación Profesional , Curriculum , Educadores en Salud/normas , Promoción de la Salud/organización & administración , Humanos , Solicitud de Empleo , Rol Profesional , Especialización , Recursos HumanosRESUMEN
This important research builds on past projects in Australia and internationally that have sought to define and clarify competencies required to work in health promotion. The paper briefly explains the process undertaken in 2005 to update the Australian health promotion competencies as a collaboration of several leading health promotion agencies. The article reports findings from research undertaken in 2001 and 2005 and compares trends in perceptions of health promotion competencies across time. This dialogue among researchers, health promotion academics and practitioners can help to further the impact of competencies research on professional practice in health promotion globally. This project placed a priority on methodology that engaged the health promotion workforce in Australia. A two-stage process was employed including expert consultation with 39 senior health promotion professionals, followed by a modified Delphi process to engage 400 practitioners. Space was allowed for comment on the competencies including suggested word changes, and respondents were also invited to add additional competencies. The research involved a modified Delphi study where participants were invited to rate each competency as "essential", "desirable" or "not relevant", and to suggest changes to wording, as well as additions to the list. Responses were received from 400 practitioners and the results were presented and compared with the 2001 survey results. Results indicate a substantial shift in perceptions about health promotion practice in Australia during the initial years of the 21(st) century.The overall significant changes in perceptions indicate that by 2005 the Australian health promotion workforce had substantially moved away from an individual behaviour-dominated perception of health promotion practice. Increasing recognition was given to competencies that reflect environmental, economic and policy influences on health, and increased recognition that these processes are legitimate and essential components of the health promotion process.
Asunto(s)
Promoción de la Salud/organización & administración , Competencia Profesional/normas , Australia , Técnica Delphi , Conocimientos, Actitudes y Práctica en Salud , Promoción de la Salud/normas , HumanosRESUMEN
Contemporary health promotion is now a well-defined discipline with a strong (albeit diverse) theoretical base, proven technologies (based on program planning) for addressing complex social problems, processes to guide practice and a body of evidence of efficacy and increasingly, effectiveness. Health promotion has evolved principally within the health sector where it is frequently considered optional rather than core business. To maximize effectiveness, quality health promotion technologies and practices need to be adopted as core business by the health sector and by organizations in other sectors. It has proven difficult to develop the infrastructure, workforce and resource base needed to ensure the routine introduction of high-quality health promotion into organizations. Recognizing these problems, this paper explores the use of organizational theory and practice in building the capacity of organizations to design, deliver and evaluate health promotion effectively and efficiently. The paper argues that organizational change is an essential but under-recognized function for the sustainability of health promotion practice and a necessary component of capacity-building frameworks. The interdependence of quality health promotion with organizational change is discussed in this paper through three case studies. While each focused on different aspects of health promotion development, the centrality of organizational change in each of them was striking. This paper draws out elements of organizational change to demonstrate that health promotion specialists and practitioners, wherever they are located, should be building organizational change into both their practice and capacity-building frameworks because without it, effectiveness and sustainability are at risk.
Asunto(s)
Promoción de la Salud/organización & administración , Evaluación de Programas y Proyectos de Salud , Australia , Innovación OrganizacionalRESUMEN
Mobilization of stem cells with pegylated granulocyte colony-stimulating factor (peg-G-CSF) modulates donor T- and natural killer T-cell (NKT-cell) functions, thus separating graft-versus-host from graft-versus-leukemia disease in animal models. We report a phase I/II study that analyzed the feasibility of mobilizing stem cells from normal donors with peg-G-CSF and the ability of these cells to restore hematopoiesis in allogeneic transplant recipients after myeloablative conditioning. Administration of 6 mg of peg-G-CSF resulted in suboptimal stem cell mobilization, with a peak peripheral blood CD34+ count of 29+/-5/microL. Apheresis 4 days after peg-G-CSF yielded 2.7+/-.4x10(6) CD34+ cells/kg recipient weight, and all donors required a second collection on day 5 to yield a total of 4.2+/-.5x10(6) CD34+ cells/kg recipient weight. After escalation of the dose to 12 mg, the peak CD34+ count was 99+/-11/microL and 12 of 13 donors collected sufficient stem cells for transplantation in a single apheresis (8.9+/-1.4x10(6) CD34+ cells/kg recipient weight). Late transient increases in serum hepatic transaminases were noted, but other side effects (predominantly bone pain) were otherwise similar to those seen in donors mobilized with standard G-CSF. Median neutrophil and platelet engraftments occurred on days 18 and 14, respectively, after transplantation and were identical to those seen with in recipients of grafts mobilized with standard G-CSF. With a median follow-up of 357 days, the incidence of grade II-IV acute graft-versus-host disease was 50% and there have been no relapses to date. Mobilization of stem cells with peg-G-CSF in normal donors is feasible and 12 mg results in mobilization characteristics similar to those of standard G-CSF.
Asunto(s)
Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Movilización de Célula Madre Hematopoyética/métodos , Leucemia/terapia , Polietilenglicoles/uso terapéutico , Trasplante de Células Madre/métodos , Adulto , Ciclofosfamida/uso terapéutico , Quimioterapia Combinada , Femenino , Enfermedad Injerto contra Huésped/prevención & control , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Humanos , Inmunosupresores/uso terapéutico , Leucemia/clasificación , Masculino , Persona de Mediana Edad , Polietilenglicoles/efectos adversos , Estudios Retrospectivos , Donantes de Tejidos , Acondicionamiento Pretrasplante/métodos , Irradiación Corporal TotalRESUMEN
This important research builds on past projects in Australia and internationally that have sought to define and clarify competencies required to work in health promotion. The paper briefly explains the process undertaken in 2005 to update the Australian health promotion competencies as a collaboration of several leading health promotion agencies. The article reports findings from research undertaken in 2001 and 2005 and compares trends in perceptions of health promotion competencies across time. This dialogue among researchers, health promotion academics and practitioners can help to further the impact of competencies research on professional practice in health promotion globally. This project placed a priority on methodology that engaged the health promotion workforce in Australia. A two-stage process was employed including expert consultation with 39 senior health promotion professionals, followed by a modified Delphi process to engage 400 practitioners. Space was allowed for comment on the competencies including suggested word changes, and respondents were also invited to add additional competencies. The research involved a modified Delphi study where participants were invited to rate each competency as essential, desirable or not relevant, and to suggest changes to wording, as well as additions to the list. Responses were received from 400 practitioners and the results were presented and compared with the 2001 survey results. Results indicate a substantial shift in perceptions about health promotion practice in Australia during the initial years of the 21(st) century. The overall significant changes in perceptions indicate that by 2005 the Australian health promotion workforce had substantially moved away from an individual behaviour dominated perception of health promotion practice. Increasing recognition was given to competencies that reflect environmental, economic and policy influences on health, and increased recognition that these processes are legitimate and essential components of the health promotion process. (AU)
Asunto(s)
Promoción de la Salud/organización & administración , Promoción de la Salud/normas , Competencia Profesional/normas , Técnica Delphi , Conocimientos, Actitudes y Práctica en Salud , AustraliaRESUMEN
Contemporary health promotion is now a well-defined discipline with a strong (albeit diverse) theoretical base, proven technologies (based on program planning) for addressing complex social problems, processes to guide practice and a body of evidence of efficacy and increasingly, effectiveness. Health promotion has evolved principally within the health sector where it is frequently considered optional rather than core business. To maximize effectiveness, quality health promotion technologies and practices need to be adopted as core business by the health sector and by organizations in other sectors. It has proven difficult to develop the infrastructure, workforce and resource base needed to ensure the routine introduction of high-quality health promotion into organizations. Recognizing these problems, this paper explores the use of organizational theory and practice in building the capacity of organizations to design, deliver and evaluate health promotion effectively and efficiently. The paper argues that organizational change is an essential but under-recognized function for the sustainability of health promotion practice and a necessary component of capacity-building frameworks. The interdependence of quality health promotion with organizational change is discussed in this paper through three case studies. While each focused on different aspects of health promotion development, the centrality of organizational change in each of them was striking. This paper draws out elements of organizational change to demonstrate that health promotion specialists and practitioners, wherever they are located, should be building organizational change into both their practice and capacity-building frameworks because without it, effectiveness and sustainability are at risk. (AU)