RESUMEN
OBJECTIVE: IL-4 plus IL-10 prevents blood-induced cartilage damage. The aim of the present study was to evaluate whether cartilage damage can still be averted by addition of IL-4 plus IL-10 when added after the onset of a bleed and whether aspiration of blood prior to addition of IL-4 plus IL-10 is of additive protective value. METHODS: Healthy canine hip and human shoulder cartilage was exposed to whole blood for 4 days. IL-4 plus IL-10 was administered directly or after a delay of several hours up to 2 days. Furthermore, blood was aspirated after 1 or 2 days and subsequently IL-4 plus IL-10 was added. IL-1ß concentration and cartilage matrix proteoglycan turnover were determined. RESULTS: Exposure of canine and human cartilage to blood decreased the proteoglycan synthesis rate and content and increased proteoglycan release. IL-4 plus IL-10 only prevented blood-induced damage of canine cartilage when added directly, not after 4 h or later. For human cartilage, IL-4 plus IL-10 limited blood-induced damage as well as IL-1ß production when administered within 4-8 h after the onset of a bleed, but not thereafter. Aspiration of blood within 24 h fully prevented cartilage damage. Subsequent addition of IL-4 plus IL-10 was not of additive value. CONCLUSION: For humans, there is a short time window after onset of a joint bleed in which IL-4 plus IL-10 can limit blood-induced cartilage damage. Furthermore, aspiration of a joint to shorten blood exposure fully prevents cartilage damage. Both options can be considered in the treatment of a joint haemorrhage.
Asunto(s)
Cartílago Articular/efectos de los fármacos , Hemartrosis/tratamiento farmacológico , Interleucina-10/uso terapéutico , Interleucina-4/uso terapéutico , Animales , Cartílago Articular/metabolismo , Cartílago Articular/patología , Perros , Hemartrosis/metabolismo , Hemartrosis/patología , Humanos , Interleucina-1beta/metabolismoRESUMEN
Omidubicel (nicotinamide-expanded cord blood) is a potential alternative source for allogeneic hematopoietic cell transplantation (HCT) when an HLA-identical donor is lacking. A phase I/II trial with standalone omidubicel HCT showed rapid and robust neutrophil and platelet engraftment. In this study, we evaluated the immune reconstitution (IR) of patients receiving omidubicel grafts during the first 6 months post-transplant, as IR is critical for favorable outcomes of the procedure. Data was collected from the omidubicel phase I-II international, multicenter trial. The primary endpoint was the probability of achieving adequate CD4+ T-cell IR (CD4IR: > 50 × 106/L within 100 days). Secondary endpoints were the recovery of T-cells, natural killer (NK)-cells, B-cells, dendritic cells (DC), and monocytes as determined with multicolor flow cytometry. LOESS-regression curves and cumulative incidence plots were used for data description. Thirty-six omidubicel recipients (median 44; 13-63 years) were included, and IR data was available from 28 recipients. Of these patients, 90% achieved adequate CD4IR. Overall, IR was complete and consisted of T-cell, monocyte, DC, and notably fast NK- and B-cell reconstitution, compared to conventional grafts. Our data show that transplantation of adolescent and adult patients with omidubicel results in full and broad IR, which is comparable with IR after HCT with conventional graft sources.
Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Reconstitución Inmune , Adolescente , Adulto , Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , NiacinamidaRESUMEN
BACKGROUND: The CLN3 disease spectrum ranges from a childhood-onset neurodegenerative disorder to a retina-only disease. Given the lack of metabolic disease severity markers, it may be difficult to provide adequate counseling, particularly when novel genetic variants are identified. In this study, we assessed whether lymphocyte vacuolization, a well-known yet poorly explored characteristic of CLN3 disease, could serve as a measure of disease severity. METHODS: Peripheral blood obtained from healthy controls and CLN3 disease patients was used to assess lymphocyte vacuolization by (a) calculating the degree of vacuolization using light microscopy and (b) quantifying expression of lysosomal-associated membrane protein 1 (LAMP-1), using flow cytometry in lymphocyte subsets as well as a qualitative analysis using electron microscopy and ImageStream analysis. RESULTS: Quantifying lymphocyte vacuolization allowed to differentiate between CLN3 disease phenotypes (P = .0001). On immunofluorescence, classical CLN3 disease lymphocytes exhibited abundant vacuole-shaped LAMP-1 expression, suggesting the use of LAMP-1 as a proxy for lymphocyte vacuolization. Using flow cytometry in lymphocyte subsets, quantifying intracellular LAMP-1 expression additionally allowed to differentiate between infection and storage and to differentiate between CLN3 phenotypes even more in-depth revealing that intracellular LAMP-1 expression was most pronounced in T-cells of classical-protracted CLN3 disease while it was most pronounced in B-cells of "retina-only" CLN3 disease. CONCLUSION: Lymphocyte vacuolization serves as a proxy for CLN3 disease severity. Quantifying vacuolization may help interpretation of novel genetic variants and provide an individualized readout for upcoming therapies.