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BACKGROUND: It has been suggested that bone marrow cell injection may have beneficial effects in patients with chronic ischaemic heart disease. However, previous trials have led to discrepant results of cell-based therapy in patients with chronic heart failure. The aim of this study was to evaluate the efficacy of intramyocardial injection of mononuclear bone marrow cells in patients with chronic ischaemic heart failure with limited stress-inducible myocardial ischaemia. METHODS AND RESULTS: This multicentre, randomised, placebo-controlled trial included 39 patients with no-option chronic ischaemic heart failure with a follow-up of 12 months. A total of 19 patients were randomised to autologous intramyocardial bone marrow cell injection (cell group) and 20 patients received a placebo injection (placebo group). The primary endpoint was the group difference in change of left ventricular ejection fraction, as determined by single-photon emission tomography. On follow-up at 3 and 12 months, change of left ventricular ejection fraction in the cell group was comparable with change in the placebo group (Pâ¯= 0.47 and Pâ¯= 0.08, respectively). Also secondary endpoints, including left ventricle volumes, myocardial perfusion, functional and clinical parameters did not significantly change in the cell group as compared to placebo. Neither improvement was demonstrated in a subgroup of patients with stress-inducible ischaemia (Pâ¯= 0.54 at 3month and Pâ¯= 0.15 at 12-month follow-up). CONCLUSION: Intramyocardial bone marrow cell injection does not improve cardiac function, nor functional and clinical parameters in patients with severe chronic ischaemic heart failure with limited stress-inducible ischaemia. CLINICAL TRIAL REGISTRATION: NTR2516.
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BACKGROUND: Mesenchymal stromal cells (MSCs) may reduce inflammation and promote tissue repair in pulmonary emphysema. AIM: To study the safety and feasibility of bone marrow-derived autologous (BM-) MSC intravenous administration to patients with severe emphysema. DESIGN: A phase I, prospective open-label study registered at ClinicalTrials.gov as NCT01306513 Eligible patients had lung volume reduction surgery (LVRS) on two separate occasions. During the first LVRS bone marrow was collected, from which MSCs were isolated and expanded ex vivo After 8 weeks, patients received two autologous MSC infusions 1 week apart, followed by the second LVRS procedure at 3 weeks after the second BM-MSC infusion. METHODS: Up to 3 weeks after the last MSC infusion adverse events were recorded. Using immunohistochemistry and qPCR for analysis of cell and proliferation markers, emphysematous lung tissue obtained during the first surgery was compared with lung tissue obtained after the second surgical session to assess BM-MSC effects. RESULTS: From 10 included patients three were excluded: two did not receive MSCs due to insufficient MSC culture expansion, and one had no second surgery. No adverse events related to MSC infusions occurred and lung tissue showed no fibrotic responses. After LVRS and MSC infusions alveolar septa showed a 3-fold increased expression of the endothelial marker CD31 (P = 0.016). CONCLUSIONS: Autologous MSC treatment in severe emphysema is feasible and safe. The increase in CD31 expression after LVRS and MSC treatment suggests responsiveness of microvascular endothelial cells in the most severely affected parts of the lung.
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Trasplante de Células Madre Mesenquimatosas/métodos , Enfisema Pulmonar/terapia , Células del Estroma/trasplante , Adulto , Anciano , Células de la Médula Ósea/citología , Proliferación Celular , Células Endoteliales/citología , Células Endoteliales/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Pulmón/irrigación sanguínea , Pulmón/cirugía , Masculino , Persona de Mediana Edad , Neovascularización Fisiológica , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Neumonectomía , Estudios Prospectivos , Enfisema Pulmonar/patología , Enfisema Pulmonar/fisiopatología , Índice de Severidad de la Enfermedad , Trasplante Autólogo , Resultado del TratamientoRESUMEN
Over the past 15 years, SCT has emerged as a promising treatment option for patients with severe autoimmune diseases (ADs). Mechanistic studies recently provided the proof-of-concept that restoration of immunological tolerance can be achieved by haematopoietic SCT in chronic autoimmunity through eradication of the pathologic, immunologic memory and profound reconfiguration of the immune system, that is, immune 'resetting'. Nevertheless, a number of areas remain unresolved and warrant further investigation to refine our understanding of the underlying mechanisms of action and to optimize clinical SCT protocols. Due to the low number of patients transplanted in each centre, it is essential to adequately collect and analyse biological samples in a larger cohort of patients under standardized conditions. The European society for blood and marrow transplantation Autoimmune Diseases and Immunobiology Working Parties have, therefore, undertaken a joint initiative to develop and implement guidelines for 'good laboratory practice' in relation to procurement, processing, storage and analysis of biological specimens for immune reconstitution studies in AD patients before, during and after SCT. The aim of this document is to provide practical recommendations for biobanking of samples and laboratory immune monitoring in patients with ADs undergoing SCT, both for routine supportive care purposes and investigational studies.
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Enfermedades Autoinmunes/terapia , Bancos de Muestras Biológicas/normas , Trasplante de Células Madre Hematopoyéticas , Preservación Biológica/normas , Congresos como Asunto , Trasplante de Células Madre Hematopoyéticas/métodos , Trasplante de Células Madre Hematopoyéticas/normas , Humanos , Guías de Práctica Clínica como Asunto , Índice de Severidad de la Enfermedad , Sociedades MédicasRESUMEN
OBJECTIVES: Traumatic brachial plexus injury causes severe functional impairment of the arm. Elbow flexion is often affected. Nerve surgery or tendon transfers provide the only means to obtain improved elbow flexion. Unfortunately, the functionality of the arm often remains insufficient. Stem cell therapy could potentially improve muscle strength and avoid muscle-tendon transfer. This pilot study assesses the safety and regenerative potential of autologous bone marrow-derived mononuclear cell injection in partially denervated biceps. METHODS: Nine brachial plexus patients with insufficient elbow flexion (i.e., partial denervation) received intramuscular escalating doses of autologous bone marrow-derived mononuclear cells, combined with tendon transfers. Effect parameters included biceps biopsies, motor unit analysis on needle electromyography and computerised muscle tomography, before and after cell therapy. RESULTS: No adverse effects in vital signs, bone marrow aspiration sites, injection sites, or surgical wound were seen. After cell therapy there was a 52% decrease in muscle fibrosis (p = 0.01), an 80% increase in myofibre diameter (p = 0.007), a 50% increase in satellite cells (p = 0.045) and an 83% increase in capillary-to-myofibre ratio (p < 0.001) was shown. CT analysis demonstrated a 48% decrease in mean muscle density (p = 0.009). Motor unit analysis showed a mean increase of 36% in motor unit amplitude (p = 0.045), 22% increase in duration (p = 0.005) and 29% increase in number of phases (p = 0.002). CONCLUSIONS: Mononuclear cell injection in partly denervated muscle of brachial plexus patients is safe. The results suggest enhanced muscle reinnervation and regeneration. Cite this article: Bone Joint Res 2014;3:38-47.
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The hematopoietic stem cell (HSC) is the prototype organ-regenerating stem cell (SC), and by far the most studied type of SC in the body. Currently, HSC-based therapy is the only routinely used SC therapy; however, advances in the field of embryonic SCs and induced pluripotent SCs may change this situation. Interest into in vitro generation of HSCs, including signals for HSC expansion and differentiation from these more primitive SCs, as well as advances in other organ-specific SCs, in particular the intestine, provide promising new applications for SC therapies. Here, we review the basic principles of different SC systems, and on the basis of the experience with HSC-based SC therapy, provide recommendations for clinical application of emerging SC technologies.
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Trasplante de Células Madre , Células Madre/citología , Adulto , Animales , Células de la Médula Ósea/citología , Ensayos Clínicos como Asunto/métodos , Modelos Animales de Enfermedad , Células Madre Embrionarias/citología , Terapia Genética/métodos , Vectores Genéticos/administración & dosificación , Vectores Genéticos/uso terapéutico , Células Madre Hematopoyéticas/citología , Humanos , Células Madre Pluripotentes Inducidas/citología , Intestinos/citología , Ratones , Células Madre Neoplásicas/citología , Especificidad de Órganos , Selección de Paciente , Medicina Regenerativa/métodos , Trasplante de Células Madre/efectos adversos , Trasplante de Células Madre/métodos , Células Madre/clasificaciónRESUMEN
AIM: Monocytes play a significant role in neovascularisation. The stimuli that differentiate monocytes along a pro-angio-/arteriogenic-supporting pathway are currently unclear. We investigated whether pre-stimulation of human monocytes with soluble T-cell-derived factors improves revascularisation in murine hind limb ischaemia as a new option for therapeutic angio- and arteriogenesis. DESIGN: Human monocytes were cultured with or without soluble T-cell-derived factors. Unstimulated and pre-stimulated monocytes were transfused after induction of hind limb ischaemia in nude mice. METHODS: Blood flow was measured with laser Doppler perfusion imaging. Collaterals were visualised by immunohistochemistry and angiography. Monocytes were characterised by flowcytometry and Bio-Plex assays. RESULTS: Transfusion of T-cell-pre-stimulated monocytes significantly improved blood flow recovery after hind limb ischaemia and increased collateral size and collateral and capillary number in the post-ischaemic paw. Pre-stimulated monocytes produced a wide variety of factors that support neovascularisation such as platelet-derived growth factor-BB, vascular-endothelial growth factor, interleukin-4 and tumour necrosis factor-α. Few transfused human cells were detected in the muscle tissue, suggesting that paracrine rather than direct effects appear responsible for the enhanced recovery of blood flow observed. CONCLUSION: These results show a beneficial role for T-cell-pre-stimulated monocytes in neovascularisation, rendering the monocyte a potential candidate for regenerative cell therapy that promotes revascularisation in peripheral arterial disease patients.
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Linfocitos T CD4-Positivos/inmunología , Isquemia/cirugía , Monocitos/trasplante , Músculo Esquelético/irrigación sanguínea , Neovascularización Fisiológica , Proteínas Angiogénicas/metabolismo , Animales , Velocidad del Flujo Sanguíneo , Capilares/inmunología , Capilares/fisiopatología , Células Cultivadas , Circulación Colateral , Modelos Animales de Enfermedad , Citometría de Flujo , Miembro Posterior , Humanos , Inmunohistoquímica , Isquemia/diagnóstico por imagen , Isquemia/inmunología , Isquemia/fisiopatología , Flujometría por Láser-Doppler , Receptores de Lipopolisacáridos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Monocitos/inmunología , Comunicación Paracrina , Radiografía , Flujo Sanguíneo Regional , Factores de TiempoRESUMEN
When compared with BMT, umbilical cord blood transplantation (UCBT) is associated with a lower rate of engraftment and delayed hematological/immunological recovery. This leads to increased risk of TRM in the early post transplantation period due to infection. Acute GVHD, although occurring less frequently in UCBT compared with BMT, is also significantly associated with increased rate of early TRM. BM MSCs are known to support normal in vivo hematopoiesis, and co-transplantation of MSCs has been shown to enhance engraftment of human cord blood hematopoietic cells in nonobese diabetic/SCID mice. In 13 children with hematological disorders (median age 2 years) undergoing UCBT, we co-transplanted paternal, HLA-disparate MSCs with the aim of improving hematological recovery and reducing rejection. We observed no differences in hematological recovery or rejection rates compared with 39 matched historical controls, most of whom received G-CSF after UCBT. However, the rate of grade III and IV acute GVHD was significantly decreased in the study cohort when compared with controls (P=0.05), thus resulting in reduced early TRM. Although these data do not support the use of MSCs in UCBT to support hematopoietic engraftment, they suggest that MSCs, possibly because of their immunosuppressive effect, may abrogate life-threatening acute GVHD and reduce early TRM.
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Trasplante de Células Madre de Sangre del Cordón Umbilical/efectos adversos , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Mesenquimatosas , Enfermedad Aguda , Adolescente , Antígenos CD34/sangre , Niño , Preescolar , Trasplante de Células Madre de Sangre del Cordón Umbilical/mortalidad , Femenino , Rechazo de Injerto , Prueba de Histocompatibilidad , Humanos , Lactante , Masculino , Riesgo , Trasplante HomólogoRESUMEN
BACKGROUND: Immunomagnetic selection of CD34(+) hematopoietic progenitor cells (HPC) using CliniMACS CD34 selection technology is widely used to provide high-purity HPC grafts. However, the number of nucleated cells and CD34+ cells recommended by the manufacturer for processing in a single procedure or with 1 vial of CD34 reagent is limited. METHODS: In this retrospective evaluation of 643 CliniMACS CD34-selection procedures, we validated the capacity of CliniMACS tubing sets and CD34 reagent. Endpoints of this study were the recovery and purity of CD34+ cells, T-cell depletion efficiency and recovery of colony-forming units-granulocyte-macrophage (CFU-GM). RESULTS: Overloading normal or large-scale tubing sets with excess numbers of total nucleated cells, without exceeding the maximum number of CD34+ cells, had no significant effect on the recovery and purity of CD34+ cells. In contrast, overloading normal or large-scale tubing sets with excess numbers of CD34+ cells resulted in a significantly lower recovery of CD34+ cells. Furthermore, the separation capacity of 1 vial of CD34 reagent could be increased safely from 600 x 10(6) CD34+ cells to 1000 x 10(6) CD34+ cells with similar recovery of CD34(+) cells. Finally, T-cell depletion efficiency and the fraction of CD34+ cells that formed CFU-GM colonies were not affected by out-of-specification procedures. DISCUSSION: Our validated increase of the capacity of CliniMACS tubing sets and CD34 reagent will reduce the number of selection procedures and thereby processing time for large HPC products. In addition, it results in a significant cost reduction for these procedures.
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Antígenos CD34/inmunología , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/inmunología , Leucaféresis/métodos , Citometría de Flujo , Humanos , Leucaféresis/economía , Leucaféresis/instrumentación , Depleción Linfocítica , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
AIM: Recent evidence indicates that bone marrow mononuclear cells (BMC) promote collateral vessel formation in patients with severe peripheral arterial disease (PAD). However, aspects concerning optimal administration mode, durability and long-term safety require consideration. Combined intra-arterial (IA) plus intramuscular (IM) BMC delivery may be more effective than exclusive intramuscular injections. The aim of this study was to evaluate feasibility, safety and effect of exclusive IM versus combined IM+IA delivery of autologous BMC in patients who were not candidates for surgical or endovascular treatment. METHODS: Twenty-seven patients were treated with either combined IA+IM (N=12) or sole IM (N=15) administration of autologous BMC. Efficacy was assessed after 1, 6 and 12 months. Limb salvage, pain-free walking distance, ankle-brachial pressure index (ABI) and pain scores were evaluated. RESULTS: There were no adverse reactions related to injection of the cells. Three patients died within the first year of follow-up due to non-procedure related causes. Two patients in the IA+IM group required limb amputation because of ongoing critical ischemia versus 7 patients in the IM group (P=0.17). BMC treatment in the remaining patients resulted in a significant and sustained (>12 months) improvement. Pain-free walking distance improved from 81+/-56 meters at baseline to 257+/-126 meters at t=6 months (P=0.0002). Mean ABI increased 23% after 6 months (P=0.01) and pain score reduced for up to 50% as shown by Brief Pain Inventory (P=0.001). CONCLUSION: Both IM and combined IM/IA delivery of autologous BMC are safe, and result in relevant and sustained improvement in a considerable proportion of patients with severe PAD who are not amenable for conventional treatment.
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Trasplante de Médula Ósea/métodos , Isquemia/cirugía , Leucocitos Mononucleares/trasplante , Extremidad Inferior/irrigación sanguínea , Adulto , Anciano , Amputación Quirúrgica , Tobillo/irrigación sanguínea , Presión Sanguínea , Trasplante de Médula Ósea/efectos adversos , Arteria Braquial/fisiopatología , Estudios de Factibilidad , Femenino , Humanos , Inyecciones Intraarteriales , Inyecciones Intramusculares , Claudicación Intermitente/etiología , Claudicación Intermitente/fisiopatología , Isquemia/complicaciones , Isquemia/mortalidad , Isquemia/fisiopatología , Recuperación del Miembro , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Recuperación de la Función , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del Tratamiento , CaminataRESUMEN
OBJECTIVE: Systemic sclerosis (SSc) is a generalised autoimmune disease, causing morbidity and a reduced life expectancy, especially in patients with rapidly progressive diffuse cutaneous SSc. As no proven treatment exists, autologous haematopoietic stem cell transplantation (HSCT) is employed as a new therapeutic strategy in patients with a poor prognosis. This study reports the effects on survival, skin and major organ function of HSCT in patients with severe diffuse cutaneous SSc. PATIENTS AND METHODS: A total of 26 patients were evaluated. Peripheral blood stem cells were collected using cyclophosphamide (4 g/m2) and rHu G-CSF (5 to 10 microg/kg/day) and were reinfused after positive CD34+ selection. For conditioning, cyclophosphamide 200 mg/kg was used. RESULTS: After a median follow-up of 5.3 (1-7.5) years, 81% (n = 21/26) of the patients demonstrated a clinically beneficial response. The Kaplan-Meier estimated survival at 5 years was 96.2% (95% CI 89-100%) and at 7 years 84.8% (95% CI 70.2-100%) and event-free survival, defined as survival without mortality, relapse or progression of SSc, resulting in major organ dysfunction was 64.3% (95% CI 47.9-86%) at 5 years and 57.1% (95% CI 39.3-83%) at 7 years. CONCLUSION: This study confirms that autologous HSCT in selected patients with severe diffuse cutaneous SSc results in sustained improvement of skin thickening and stabilisation of organ function up to 7 years after transplantation.
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Trasplante de Células Madre Hematopoyéticas/métodos , Esclerodermia Sistémica/terapia , Adolescente , Adulto , Anciano , Ciclofosfamida/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Movilización de Célula Madre Hematopoyética/métodos , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Morbilidad , Agonistas Mieloablativos/uso terapéutico , Proteínas Recombinantes , Esclerodermia Sistémica/mortalidad , Tasa de Supervivencia , Acondicionamiento Pretrasplante/métodos , Trasplante AutólogoRESUMEN
The aim of the present study was to identify trends in numbers of European patients treated with autologous and allogeneic haematopoietic stem cell transplantation (HSCT) as well as to provide anticipated transplant rates for the upcoming years. The following indications were considered: haematological malignancies (acute leukaemias, myeloproliferative disorders, lymphoproliferative disorders and multiple myeloma), solid tumours and non-malignant diseases. Numbers of patients treated from 1990 to 2004 were extracted from the European Group for Blood and Marrow Transplantation database, extrapolated to 2012 using mathematic models and adjusted to the literature study and expert opinion. In Europe, a 13% raise in HSCT utilisation is to be expected from 2005 to 2010, mostly due to the growing application of reduced-intensity conditioning regimens followed by allogeneic HSCT. Growing transplant rates are likely to exert health expenditure budgets and put pressure on health care providers and health insurers in Europe. Therefore, the rapid expansion would ideally imply a simultaneous increase in HSCT budgets.
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Enfermedades Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/tendencias , Europa (Continente)/epidemiología , Femenino , Enfermedades Hematológicas/epidemiología , Trasplante de Células Madre Hematopoyéticas/estadística & datos numéricos , Humanos , MasculinoRESUMEN
Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiation into several mesodermal lineages. These cells have been isolated from various tissues, such as adult bone marrow, placenta, and fetal tissues. The comparative potential of these cells originating from different tissues to differentiate into the chondrogenic lineage is still not fully defined. The aim of our study was to investigate the chondrogenic potential of MSCs isolated from different sources. MSCs from fetal and adult tissues were phenotypically characterized and examined for their differentiation capacity, based on morphological criteria and expression of extracellular matrix components. Our results show that both fetal and adult MSCs have chondrogenic potential under appropriate conditions. The capacity of bone marrow-derived MSCs to differentiate into chondrocytes was reduced on passaging of cells. MSCs of bone marrow origin, either fetal or adult, exhibit a better chondrogenesis than fetal lung- and placenta-derived MSCs, as demonstrated by the appearance of typical morphological features of cartilage, the intensity of toluidine blue staining, and the expression of collagen type II, IX, and X after culture under chondrogenic conditions. As MSCs represent an attractive tool for cartilage tissue repair strategies, our data suggest that bone marrow should be considered the preferred MSC source for these therapeutic approaches.
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Células de la Médula Ósea/citología , Diferenciación Celular , Condrogénesis , Células Madre Mesenquimatosas/citología , Adipogénesis , Proliferación Celular , Forma de la Célula , Células Cultivadas , Femenino , Humanos , Inmunofenotipificación , OsteogénesisAsunto(s)
Trasplante de Médula Ósea/métodos , Isquemia Miocárdica/terapia , Anciano , Enfermedad Crónica , Contraindicaciones , Prueba de Esfuerzo , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Isquemia Miocárdica/fisiopatología , Revascularización Miocárdica , Volumen Sistólico , Resultado del TratamientoRESUMEN
For a 74-year-old man with angina pectoris and demonstrated myocardial ischaemia, optimal medical treatment was insufficient. He was ineligible for coronary revascularization. To improve myocardial perfusion, autologous bone-marrow stem cells were injected into the ischaemic myocardium. During the months following the injection, the frequency of angina attacks decreased and myocardial perfusion and cardiac function improved.
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Angina de Pecho/terapia , Trasplante de Médula Ósea , Isquemia Miocárdica/terapia , Anciano , Circulación Coronaria/fisiología , Humanos , Masculino , Trasplante Autólogo , Resultado del TratamientoRESUMEN
Graft-versus-host disease (GVHD) is a major cause of mortality and morbidity after allogeneic stem cell transplantation (alloSCT) but can be prevented by removing T-lymphocytes from the graft. Campath (anti-CD52) antibodies have been widely used in vivo for T-cell depletion following conventional and reduced intensity conditioning regimens. The use of Campath in vivo was associated with a significant reduction in GVHD but at the cost of impaired immune reconstitution. We evaluated the long-term outcome of 73 myeloablative allogeneic stem cell transplants with HLA-identical sibling donors using Campath "in the bag" as method of in vitro T-cell depletion. All patients engrafted and hematopoietic recovery was uneventful, resulting in a median of 99% donor chimerism at 3 months after alloSCT. Cytomegalovirus (CMV) reactivation occurred in 53% of the patients. No CMV disease was observed probably as a result of pre-emptive (val)ganciclovir treatment. The incidence of aGVHD was low (22% grade II). No grades III-IV aGVHD was observed and extensive chronic GVHD (cGVHD) occurred in 19% of the patients. The low incidence of GVHD and successful pre-emptive antiviral therapy resulted in low TRM of 8%. Sixteen patients died due to disease relapse after alloSCT, resulting in an overall survival of 48% at 5-years after alloSCT.
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Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Antineoplásicos/administración & dosificación , Antineoplásicos/administración & dosificación , Enfermedad Injerto contra Huésped/prevención & control , Depleción Linfocítica , Trastornos Linfoproliferativos/terapia , Trasplante de Células Madre , Acondicionamiento Pretrasplante , Adulto , Alemtuzumab , Anticuerpos Monoclonales Humanizados , Antivirales/administración & dosificación , Infecciones por Citomegalovirus/etiología , Infecciones por Citomegalovirus/mortalidad , Infecciones por Citomegalovirus/prevención & control , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Ganciclovir/administración & dosificación , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Humanos , Depleción Linfocítica/métodos , Trastornos Linfoproliferativos/complicaciones , Trastornos Linfoproliferativos/mortalidad , Masculino , Persona de Mediana Edad , Países Bajos , Estudios Retrospectivos , Trasplante de Células Madre/efectos adversos , Trasplante de Células Madre/mortalidad , Acondicionamiento Pretrasplante/mortalidad , Trasplante HomólogoRESUMEN
BACKGROUND: Immunoablative therapy combined with haematopoietic stem cell transplantation (SCT) is a possible treatment for patients with severe rheumatoid arthritis (RA). CASE REPORT: A patient with rheumatoid factor positive, progressively erosive RA, refractive to treatment, was treated with high dose cyclophosphamide, followed by reinfusion of an unmanipulated peripheral blood graft derived from her identical twin sister. The clinical response was unsatisfactory, necessitating reinstitution of treatment with disease modifying antirheumatic drugs, which was associated with persistence of host serum autoantibodies and a cellular infiltrate in synovium, notably of plasma cells. DISCUSSION: The effectiveness of syngeneic SCT may be critically dependent on the degree of immunoablation achieved or on the composition of the graft.
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Antirreumáticos/uso terapéutico , Artritis Reumatoide/terapia , Autoanticuerpos/sangre , Trasplante de Células Madre Hematopoyéticas , Membrana Sinovial/patología , Adulto , Artritis Reumatoide/inmunología , Artritis Reumatoide/patología , Ciclofosfamida/uso terapéutico , Femenino , Humanos , Inmunosupresores/uso terapéutico , Insuficiencia del TratamientoRESUMEN
For many children with life-threatening hematological diseases, hematopoietic stem cell transplantation (HSCT) is the only curative option. In children lacking a matched related or unrelated donor and with the certainty that, left untreated, death will ensue alternative donors must be sought. Haplo-identical peripheral blood stem cell transplantation (PBSCT) from a healthy parent is a feasible alternative. To reduce the risk of fatal graft-versus-host disease (GvHD) as a complication of transplant across major histocompatibility antigens, intense T-cell depletion is required. Large numbers of purified, cytokine mobilized peripheral stem cells (the so-called mega-dose concept) are required to compensate for the significantly increased risk of either graft failure or early rejection. In our unit, despite this approach, graft dysfunction has, in a significant group of children, proved problematic and, despite salvage attempts at re-transplantation, usually fatal. In children with hematological malignant disease, our overall relapse-free survival is 41%. However, successful transplant outcome has been associated with considerable delays in immune reconstitution that can be implicated in subsequent viral reactivation. We are investigating new strategies to improve the outcome of haplo-identical PBSCT, which may allow us to offer this form of treatment to more children requiring urgent HSCT.
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Rechazo de Injerto , Enfermedades Hematológicas/terapia , Sistema Inmunológico , Trasplante de Células Madre de Sangre Periférica , Recuperación de la Función , Adolescente , Antígenos CD34 , Niño , Preescolar , Femenino , Rechazo de Injerto/inmunología , Supervivencia de Injerto , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/prevención & control , Enfermedades Hematológicas/mortalidad , Humanos , Lactante , Depleción Linfocítica/métodos , Masculino , Trasplante de Células Madre de Sangre Periférica/mortalidad , Terapia Recuperativa/métodos , Terapia Recuperativa/mortalidad , Linfocitos T/inmunologíaRESUMEN
BACKGROUND: The effect of interferon-alpha 2b (IFN-alpha-2b) on progression-free and overall survival as well as quality of life (QoL) was studied in mainly elderly patients with multiple myeloma (MM), who reached a plateau phase after melphalan/prednisone induction. PATIENTS AND METHODS: In an open phase III trial, 262 patients, median age 69 years (range 34-91), received at least 10 monthly courses of melphalan/prednisone followed by response evaluation. Plateau phase was reached by 128 patients. Next, 90 patients were randomized between IFN-alpha-2b and no maintenance therapy. Reasons for non-randomization were: refusal (18), concomitant disease (nine), protocol violation (six), WHO performance status >2 (four) and allogeneic transplantation (one) RESULTS: At a median follow-up from diagnosis of 97 months (0-140) for those patients alive, IFN-alpha-2b therapy was associated with improved progression-free survival (median 13.5 versus 8.4 months from randomization), although this did not translate in a better overall survival (41 versus 38.4 months). One-third of patients discontinued IFN-alpha due to toxicity. No differences were observed between patient groups in QoL. CONCLUSIONS: IFN maintenance therapy in MM prolongs progression-free survival and, provided that the burden of toxicity is not too high, does not adversely affect QoL.
Asunto(s)
Interferón-alfa/administración & dosificación , Mieloma Múltiple/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Interferón alfa-2 , Interferón-alfa/efectos adversos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/fisiopatología , Mieloma Múltiple/psicología , Calidad de Vida/psicología , Proteínas Recombinantes , Análisis de SupervivenciaRESUMEN
BACKGROUND: Consistent average length differences between species and chromosome arm differences within species indicate that telomere length is genetically determined. This seems to contradict an observed large variation in lengths of the same human telomere between metaphases of the same individual. We examined the extent to which the variation in the telomeres of the human X and Y chromosomes is heritable, induced, or technical in origin. METHODS: Metaphase chromosomes were stained by fluorescence in situ hybridization with a telomere repeat-specific probe, and fluorescence intensities of the X and Y chromosomes were measured. If telomere length variation is predominantly genetically determined and a 50% probability of meiotic recombination between the pseudo-autosomal regions of Yp and Xp in the father is taken into account, one expects an equal chance that the Yp telomere of a son is derived from his father's Xp or Yp telomere. This implies that the Yp/Yq telomere ratios in fathers and sons will be identical in the absence of paternal meiotic recombination and different when recombination occurs. RESULTS: Among five father-son pairs, four showed similar Yp/Yq ratios (P > 0.05), whereas one pair exhibited a large difference in the Yp/Yq ratio that was attributable to a significantly longer Xp than Yp telomere in the father and a presumptive meiotic exchange between X and Y during paternal meiosis. Further, the Xq telomere exhibited a generally shorter telomere length than the others. CONCLUSIONS: The high variation in telomere length appeared to be intracellular (between sister chromatids) and, hence, technical in nature. We found no measurable induced variation in the cells studied, implying that, if induced variation exists, it is small compared with the technical variation.