RESUMEN
Devil facial tumor disease (DFTD) is an emergent transmissible cancer exclusive to Tasmanian devils (Sarcophilus harrisii) and threatening the species with extinction in the wild. Research on DFTD began 10 years ago, when nothing was known about the tumor and little about the devils. The depth of knowledge gained since then is impressive, with research having addressed significant aspects of the disease and the devils' responses to it. These include the cause and pathogenesis of DFTD, the immune response of the devils and the immune evasion mechanisms of the tumor, the transmission patterns of DFTD, and the impacts of DFTD on the ecosystem. This review aims to collate this information and put it into the context of conservation strategies designed to mitigate the impacts of DFTD on the devil and the Tasmanian ecosystem.
Asunto(s)
Neoplasias Faciales/veterinaria , Marsupiales/inmunología , Animales , Evolución Biológica , Conservación de los Recursos Naturales , Neoplasias Faciales/epidemiología , Neoplasias Faciales/patología , Variación Genética , Geografía , Inmunidad Celular , Inmunidad Humoral , Marsupiales/genéticaRESUMEN
Tasmanian devils (Sarcophilus harrisii) risk extinction from a contagious cancer, devil facial tumour disease (DFTD) in which the infectious agent is the tumor cell itself. Because devils are unable to produce an immune response against the tumor cells no devil has survived 'infection'. To promote an immune response we immunized healthy devils with killed DFTD tumor cells in the presence of adjuvants. Immune responses, including cytotoxicity and antibody production, were detected in five of the six devils. The incorporation of adjuvants that act via toll like receptors may provide additional signals to break 'immunological ignorance'. One of these devils was protected against a challenge with viable DFTD cells. This was a short-term protection as re-challenge one year later resulted in tumor growth. These results suggest that Tasmanian devils can generate immune responses against DFTD cells. With further optimization of immune stimulation it should be possible to protect Tasmanian devils against DFTD with an injectable vaccine.
Asunto(s)
Anticuerpos Antineoplásicos/sangre , Vacunas contra el Cáncer/inmunología , Citotoxicidad Inmunológica , Neoplasias Faciales/veterinaria , Inmunidad Humoral , Manitol/análogos & derivados , Marsupiales/inmunología , Ácidos Oléicos/inmunología , Adyuvantes Inmunológicos , Animales , Australia , Vacunas contra el Cáncer/administración & dosificación , Línea Celular , Ensayo de Inmunoadsorción Enzimática , Neoplasias Faciales/inmunología , Neoplasias Faciales/prevención & control , Humanos , Manitol/administración & dosificación , Manitol/inmunología , Ácidos Oléicos/administración & dosificación , Vacunación/veterinariaRESUMEN
Ultraviolet B (UVB) irradiation of the skin has the benefit of causing the local production of previtamin D3 but also results in cutaneous DNA damage and suppression of the skin immune system (SIS). Strains of mice differ in their ability to be suppressed by UVB irradiation: BALB/c mice are considered "resistant" and C57BL/6 "sensitive". This study evaluated whether vitamin D-replete (D+) and deficient (D-) BALB/c and C57BL/6 mice differed in their cutaneous response to UVB irradiation. Immunosuppression was assessed by measuring the contact hypersensitivity (CHS) response, DNA damage and repair determined by counting thymine dimer positive keratinocyte nuclei, and cutaneous inflammation and epidermal hyperplasia evaluated by light microscopy. The suppression in the CHS response induced by the UVB irradiation was reduced in the D+ C57BL/6 mice compared with the D- C57BL/6 mice. Similarly there was a reduction in DNA damage and promotion of its repair in the D+ C57BL/6 mice compared with the D- C57BL/6 mice. A reduction in inflammation in female D+ C57BL/6 mice compared with D- C57BL/6 females also occurred. In contrast, the suppression in the CHS response, DNA damage and its repair, and inflammation induced by UVB irradiation were similar in the D+ and D- BALB/c mice. These results indicate that dietary vitamin D3 can reduce UVB-induced suppression of the CHS response depending on the genetic background of the mice, an effect that may relate to the reduction in DNA damage and an increase in its rate of repair.
Asunto(s)
Colecalciferol/farmacología , Dieta , Piel/efectos de los fármacos , Piel/efectos de la radiación , Rayos Ultravioleta/efectos adversos , Animales , Daño del ADN , Dermatitis por Contacto/inmunología , Femenino , Tolerancia Inmunológica/efectos de los fármacos , Tolerancia Inmunológica/efectos de la radiación , Masculino , Ratones , Dímeros de Pirimidina/metabolismo , Piel/inmunología , Piel/metabolismo , Especificidad de la EspecieRESUMEN
Devil facial tumor disease (DFTD) is a transmissible neoplasm that is threatening the survival of the Tasmanian devil. Genetic analyses have indicated that the disease is a peripheral nerve sheath neoplasm of Schwann cell origin. DFTD cells express genes characteristic of myelinating Schwann cells, and periaxin, a Schwann cell protein, has been proposed as a marker for the disease. Diagnosis of DFTD is currently based on histopathology, cytogenetics, and clinical appearance of the disease in affected animals. As devils are susceptible to a variety of neoplastic processes, a specific diagnostic test is required to differentiate DFTD from cancers of similar morphological appearance. This study presents a thorough examination of the expression of a set of Schwann cell and other neural crest markers in DFTD tumors and normal devil tissues. Samples from 20 primary DFTD tumors and 10 DFTD metastases were evaluated by immunohistochemistry for the expression of periaxin, S100 protein, peripheral myelin protein 22, nerve growth factor receptor, nestin, neuron specific enolase, chromogranin A, and myelin basic protein. Of these, periaxin was confirmed as the most sensitive and specific marker, labeling the majority of DFTD cells in 100% of primary DFTD tumors and DFTD metastases. In normal tissues, periaxin showed specificity for Schwann cells in peripheral nerve bundles. This marker was then evaluated in cultured devil Schwann cells, DFTD cell lines, and xenografted DFTD tumors. Periaxin expression was maintained in all these models, validating its utility as a diagnostic marker for the disease.
Asunto(s)
Biomarcadores de Tumor/análisis , Neoplasias Faciales/veterinaria , Marsupiales , Proteínas de la Membrana/análisis , Neoplasias de la Vaina del Nervio/veterinaria , Animales , Biomarcadores de Tumor/metabolismo , Células Cultivadas , Neoplasias Faciales/patología , Técnica del Anticuerpo Fluorescente/veterinaria , Xenoinjertos , Inmunohistoquímica/veterinaria , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Ratones SCID , Neoplasias de la Vaina del Nervio/patología , Células de Schwann/metabolismo , Sensibilidad y Especificidad , Células Tumorales CultivadasRESUMEN
The number of Tasmanian devils in the wild is rapidly declining owing to a transmissible cancer, devil facial tumor disease (DFTD). Although progress has been made to understand the spread of this disease, crucial research on the pathogenesis of DFTD has been limited because of the threatened status of the host species. Here, the authors describe the development of a NOD/SCID (nonobese diabetic / severe combined immunodeficiency) mouse model that reproduces DFTD and provides a much-needed model to undertake studies into this intriguing transmissible cancer. Histologically, the DFTD produced in NOD/SCID mice (xenografted DFTD) was indistinguishable from the DFTD identified in Tasmanian devils. At the protein level, all xenografted DFTD tumors expressed periaxin, a marker that confirmed the diagnosis of DFTD. The karyotype of DFTD in NOD/SCID mice reproduced similar chromosomal alterations as seen in diseased devils. Furthermore, each NOD/SCID mouse inoculated with cultured DFTD tumor cells developed tumors, whereas DFTD did not develop in any of the inoculated immune-competent BALB/c mice.
Asunto(s)
Modelos Animales de Enfermedad , Transmisión de Enfermedad Infecciosa/veterinaria , Especies en Peligro de Extinción , Neoplasias Faciales/patología , Neoplasias Faciales/veterinaria , Marsupiales , Animales , Biomarcadores de Tumor/metabolismo , Neoplasias Faciales/genética , Inmunohistoquímica/veterinaria , Cariotipificación , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Ratones SCID , Trasplante de Neoplasias/veterinariaRESUMEN
To ascertain the influence of vitamin D3 and its metabolites on the function of the skin immune system and the induction of the contact hypersensitivity (CHS) response, a population of vitamin D3-deficient BALB/c mice was established, through dietary vitamin D3 restriction and limitation of exposure to UVB irradiation. Vitamin D3 normal female mice had higher CHS responses than their male counterparts, and dietary vitamin D3 deficiency significantly increased the CHS responses in male, but not in female, mice. This change in the vitamin D3-deficient male mice was not due to an alteration in skin dendritic cell function including antigen carriage, migration or costimulatory molecule expression. In addition, 18 h after sensitisation, the lymph node populations in the vitamin D3-deficient and normal male mice showed similar proliferation and IFN-gamma production. However, during the sensitisation phase of CHS, there was lower lymphocyte recruitment to the skin draining lymph nodes of the vitamin D3-deficient and normal male mice compared with their female counterparts which could account for the difference between the sexes in the extent of the CHS response. These results indicate the vitamin D system can influence cutaneous immune responses in male mice, but this did not occur through the modulation of the dendritic cell functions analysed.
Asunto(s)
Colecalciferol/inmunología , Dermatitis por Contacto/inmunología , Piel/inmunología , Deficiencia de Vitamina D/inmunología , Adyuvantes Inmunológicos , Animales , Antígenos/inmunología , Proliferación Celular , Células Cultivadas , Colecalciferol/administración & dosificación , Citocinas/inmunología , Dieta , Femenino , Humanos , Interferón gamma/inmunología , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Linfocitos/citología , Linfocitos/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Oxazolona/inmunología , Piel/efectos de la radiación , Rayos UltravioletaRESUMEN
OBJECTIVE: As the platypus (Ornithorhynchus anatinus), the Tasmanian devil (Sarcophilus harrisi) and the eastern barred bandicoot (Perameles gunni) are currently at risk of serious population decline or extinction from fatal diseases in Tasmania, the goal of the present study was to describe the normal immune response of these species to challenge using the lymphocyte proliferation assay, to give a solid basis for further studies. METHODS: For this preliminary study, we performed lymphocyte proliferation assays on peripheral blood mononuclear cells (PBMC) from the three species. We used the common mitogens phytohaemagglutinin (PHA), concanavalin A (ConA), lipopolysaccharide (LPS) and pokeweed mitogen (PWM). RESULTS: All three species recorded the highest stimulation index (SI) with the T-cell mitogens PHA and ConA. Tasmanian devils and bandicoots had greater responses than platypuses, although variability between individual animals was high. CONCLUSION: For the first time, we report the normal cellular response of the platypus, the Tasmanian devil and the eastern barred bandicoot to a range of commonly used mitogens.
Asunto(s)
Leucocitos Mononucleares/inmunología , Activación de Linfocitos , Marsupiales/inmunología , Murinae/inmunología , Ornitorrinco/inmunología , Animales , Animales Salvajes/inmunología , Linfocitos B/inmunología , Concanavalina A/inmunología , Concanavalina A/farmacología , Conservación de los Recursos Naturales , Recuento de Leucocitos , Mitógenos/inmunología , Mitógenos/farmacología , Fitohemaglutininas/inmunología , Fitohemaglutininas/farmacología , Mitógenos de Phytolacca americana/inmunología , Mitógenos de Phytolacca americana/farmacología , Valores de Referencia , Especificidad de la Especie , Linfocitos T/inmunologíaRESUMEN
BACKGROUND: Skin develops through a process of epidermal proliferation, maturation, and remodelling of the epidermis and dermis. This period also involves the maturation of the skin immune system, such that antigen applied though the skin of a neonatal mouse always results in immunosuppression, whereas in adults, immunity will occur. OBJECTIVES: Using proteomics, to identify proteins uniquely involved in the development of the skin and skin immune system. METHODS: Proteins were extracted from whole skin of mice aged 4 and 21 days, and separated using two-dimensional electrophoresis. RESULTS: Of the 25 proteins that were sequenced by peptide mass fingerprinting with matrix-assisted laser desorption/ionization-time of flight-mass spectrometry, three were known markers of keratinocyte differentiation and proliferation. These were cyclophilin A, epidermal fatty acid binding protein 5 and stefin A. Of interest were the two isoforms of stefin A, an intracellular protease inhibitor, found in neonatal skin. The strong expression of stefin A in neonates was confirmed by immunohistochemical analysis, suggesting an important role in the development of the epidermis. Additionally, Western blotting identified two larger isoforms in adult skin, revealing a change in the stefin A during development. CONCLUSIONS: We propose that stefin A is involved in development of the skin, that development of the skin and of immune function is linked, and that stefin A has an important function in neonatal skin and potentially the neonatal immune response.
Asunto(s)
Western Blotting/métodos , Cistatinas/biosíntesis , Proteómica/métodos , Piel/metabolismo , Animales , Western Blotting/normas , Cistatina A , Cistatinas/análisis , Electroforesis en Gel Bidimensional , Femenino , Humanos , Inmunohistoquímica , Masculino , Ratones , Mapeo Peptídico , Piel/citologíaRESUMEN
Infection with a retrovirus, Jaagsiekte sheep retrovirus (JSRV), causes ovine pulmonary adenocarcinoma (OPA). The excess production of surfactant proteins by alveolar tumour cells results in increased production of pulmonary fluid, which is characteristically expelled through the nostrils of affected sheep. The immune response to JSRV and the tumour is poorly understood: no JSRV-specific circulating antibodies or T cells have been detected to date. The aim of the present study was to obtain phenotypic evidence for a local immune response in OPA lungs. Specific-pathogen free lambs were infected intratracheally with JSRV. When clinical signs of OPA were apparent, the lungs were removed at necropsy and immunohistochemistry (IHC) was performed on lung sections using a panel of mouse anti-sheep mAbs. No influx of dendritic cells, B cells, CD4, CD8 or gammadelta T cells was seen in the neoplastic nodules or in their periphery. MHC Class II-positive cells were found intratumourally, peritumourally and in the surrounding alveolar lumina. In the tumours, many of these cells were shown to be fibroblasts and the remainder were likely to be mature macrophages. In the alveolar lumen, the MHC Class II-positive cells were CD14-positive and expressed high levels of IFN-gamma. They appeared to be immature monocytes or macrophages which then differentiated to become CD14-negative as they reached the periphery of the tumours. A high level of MHC Class I expression was detected on a range of cells in the OPA lungs but the tumour nodules themselves contained no MHC Class I-positive cells. On the basis of these findings, it is proposed that the lack of an effective immune response in OPA could result from a mechanism of peripheral tolerance in which the activity of the invading macrophages is suppressed by the local environment, possibly as a consequence of the inhibitory properties of the surfactant proteins.
Asunto(s)
Macrófagos/inmunología , Adenomatosis Pulmonar Ovina/inmunología , Animales , Antígenos de Histocompatibilidad Clase II/metabolismo , Inmunohistoquímica , Interferón gamma/biosíntesis , Retrovirus Ovino Jaagsiekte/patogenicidad , Receptores de Lipopolisacáridos/metabolismo , Pulmón/inmunología , Pulmón/patología , Macrófagos/patología , Adenomatosis Pulmonar Ovina/etiología , Adenomatosis Pulmonar Ovina/patología , OvinosRESUMEN
BACKGROUND: In people with a history of sting allergy, only prior reaction severity and older age are known to predict subsequent reaction risk. Furthermore, no diagnostic test other than a deliberate sting challenge has been found to identify people in whom venom immunotherapy (VIT) has been unsuccessful. OBJECTIVE: We aimed to assess the utility of a number of in vitro tests to diagnose venom allergy and to monitor immunotherapy. METHODS: During a double-blind randomized placebo-controlled crossover trial of Myrmecia pilosula ant VIT the following venom-specific tests were performed at enrolment, and at completion of treatment prior to a diagnostic sting challenge; leucocyte stimulation index (SI), IL-4 production, IgE RAST, histamine release test (HRT), leukotriene release test (LRT) and basophil activation test (BAT). Intradermal venom skin testing (VST) was also performed at trial entry. RESULTS: Only VST and HRT identified those at risk of sting anaphylaxis in the placebo group. Although IgE RAST, leucocyte SI and IL-4 production, LRT and BAT all correlated well with intradermal VSTs, they did not predict sting challenge outcome. After successful VIT, venom-induced leucocyte IL-4 production tended to fall, whereas IgE RAST increased and a natural decline in HRT reactivity was reversed. A confounding seasonal affect on laboratory results was suspected. CONCLUSION: The HRT warrants further assessment for diagnosis of venom allergy. Uninformative performance of the commercially available LRT and BAT tests may be due to pre-incubation with IL-3. None of the tests evaluated appear to be reliable markers of successful VIT.
Asunto(s)
Venenos de Hormiga/inmunología , Mordeduras y Picaduras , Desensibilización Inmunológica/métodos , Hipersensibilidad/tratamiento farmacológico , Monitorización Inmunológica/métodos , Animales , Prueba de Desgranulación de los Basófilos , Estudios Cruzados , Citocinas/inmunología , Liberación de Histamina , Humanos , Hipersensibilidad/diagnóstico , Hipersensibilidad/inmunología , Inmunoglobulina E/sangre , Leucotrienos/inmunología , Activación de Linfocitos , Pruebas Cutáneas , Resultado del TratamientoRESUMEN
Cutaneous tolerance to antigens may be induced in mice through application of antigen during the first few days following birth. The mechanism governing this neonatally induced tolerance remains uncertain. We employed a contact hypersensitivity model to analyse dendritic cell (DC) function and the expression of classical and non-classical lymphocyte populations within the neonate. Examination of draining lymph node DC after antigenic challenge of the skin revealed these DC to be significantly deficient in their ability to stimulate antigen-specific T cell proliferation. Co-stimulatory molecule (CD40, CD80 and CD86) expression of these cells was deficient in comparison to adult DC, and functional tests revealed these cells to possess a critical absence of CD40 signalling. A numerical analysis of classical and non-classical lymphocyte expression demonstrated that while the neonatal spleen is devoid of T cells, the lymph nodes have a normal repertoire of T, B, gammadelta and CD4+CD25+ lymphocytes but an increased expression of natural killer (NK) cells. This study indicates that functionally deficient DC are likely contributors to neonatally induced cutaneous tolerance.
Asunto(s)
Antígenos CD40/análisis , Dermatitis por Contacto/inmunología , Células de Langerhans/inmunología , Ganglios Linfáticos/inmunología , Transducción de Señal/fisiología , Animales , Animales Recién Nacidos , Antígenos CD/inmunología , Antígeno B7-1/inmunología , Antígeno B7-2 , Células Asesinas Naturales/inmunología , Activación de Linfocitos , Glicoproteínas de Membrana/inmunología , Ratones , Ratones Endogámicos BALB C , Modelos Animales , Linfocitos T/inmunologíaRESUMEN
Whilst the role of ceramide, a second messenger of the sphingolipid family, in the initiation of receptor-mediated apoptosis is controversial, a growing body of evidence is emerging for a role of ceramide in the amplification of apoptosis via mitochondrial perturbations that culminate in the activation of execution caspases. Treatment of Jurkat T cells with the cell-permeable analog, C(2)-ceramide, resulted in the rapid onset of apoptosis as evidenced by Annexin V-FITC staining of externalised phosphatidylserine residues. Cells bearing this early apoptotic marker had a reduced mitochondrial transmembrane potential (Delta(Psi)m) that was preceded by the release of cytochrome c from mitochondria. Subsequent activation of caspase-3 provides the link between these ceramide-induced mitochondrial changes and execution caspases that ultimately result in the physical destruction of the cell. Collectively these results demonstrate that ceramide signalling results in caspase-mediated apoptosis via mitochondrial cytochrome c release and are further supportive of the role of ceramide in the amplification of apoptosis.
Asunto(s)
Apoptosis/fisiología , Caspasas/metabolismo , Ceramidas/metabolismo , Grupo Citocromo c/metabolismo , Células Eucariotas/metabolismo , Membranas Intracelulares/metabolismo , Mitocondrias/metabolismo , Esfingosina/análogos & derivados , Anexina A5/metabolismo , Apoptosis/efectos de los fármacos , Caspasa 3 , Células Eucariotas/citología , Células Eucariotas/efectos de los fármacos , Fluoresceína-5-Isotiocianato , Humanos , Membranas Intracelulares/efectos de los fármacos , Membranas Intracelulares/ultraestructura , Células Jurkat , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Mitocondrias/efectos de los fármacos , Mitocondrias/ultraestructura , Fosfatidilserinas/metabolismo , Esfingosina/farmacologíaRESUMEN
The immunological function of the Langerhans cell (LC) network in neonatal skin was examined by defining the development of cutaneous immunity relative to the structure, phenotype and function of the epidermal LC network in neonatal, juvenile and adult mice. Analysis of epidermal sheets showed the presence of major histocompatibility complex (MHC) II+, multilectin receptor DEC-205- cells within the epidermis of 3-day-old mice; both cell density and DEC-205 expression increased until day 14. When visualized with antibodies directed at MHC II, the network was poorly formed in 3- and 7-day-old mice, as there was a lower cell density and poor MHC II expression on dendritic processes, compared to mice at day14. Application of a fluorescent antigen to 3-day-old mice revealed that the LC were inefficient in transporting antigen to the draining lymph node. There was an improvement at day 7 and by day 14 comparable numbers of antigen carrying cells were detected in the lymph nodes of 6-week-old mice. The reduced antigen carriage in 3- and 7-day-old mice correlated with a poor contact sensitivity response. This was not simply due to failure to present antigen, but development of immunosuppression, as transfer of T cells from adult mice that were previously treated with antigen when they were 3 days old, to adult recipients resulted in antigen specific immunosuppression. Analysis of CD80 and CD86 expression showed that LC from day 3 skin expressed CD80, but not CD86 and application of antigen through this skin was inefficient in upregulating CD86. These findings indicate that when the neonatal LC network is poorly developed it is functionally immature and antigen applied through this 'functionally immature network' results in antigen specific immunosuppression.
Asunto(s)
Envejecimiento/inmunología , Epidermis/inmunología , Células de Langerhans/inmunología , Animales , Animales Recién Nacidos , Antígenos CD/metabolismo , Antígeno B7-1/metabolismo , Antígeno B7-2 , Técnicas de Cultivo de Célula , Dermatitis por Contacto/inmunología , Epidermis/crecimiento & desarrollo , Antígenos de Histocompatibilidad Clase II/metabolismo , Tolerancia Inmunológica , Ganglios Linfáticos/inmunología , Masculino , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos BALB C , Cloruro de Picrilo/inmunologíaRESUMEN
Autoimmune gastritis develops in 20-60% of BALB/c mice following thymectomy at 3 days after birth (3dnTx). Previously we identified the gastric H+/K+ ATPase as the causative autoantigen and mapped the immunoreactive T cell epitope to a carboxyl-terminal peptide on the gastric H+/K+ ATPase beta subunit. Here we show that autoimmune gastritis can be suppressed by immunizing 3dnTx mice through neonatal skin with the beta subunit peptide, in combination with the contact sensitizer TNCB. When spleen cells were transferred from suppressed mice to nude mice a proportion of recipient mice developed gastritis. These results indicate that pathogenic T cells were still present in the 3dnTx mice but the absence of gastritis indicates that their activity can be regulated following induction of cutaneous tolerance by immunizing through neonatal skin. We propose that cutaneous tolerance is induced through mediation of immature Langerhans cells in neonatal skin and that this tolerance prevented the autoreactivity of pathogenic T cells. This procedure will have implications for strategies to suppress autoimmunity.
Asunto(s)
Enfermedades Autoinmunes/prevención & control , Autoinmunidad/inmunología , Tolerancia Inmunológica/inmunología , Células de Langerhans/inmunología , Piel/inmunología , Secuencia de Aminoácidos , Animales , Autoanticuerpos/análisis , Autoantígenos/inmunología , Enfermedades Autoinmunes/inmunología , Recuento de Células , Dermatitis Alérgica por Contacto/inmunología , Dermatitis Alérgica por Contacto/prevención & control , Gastritis/inmunología , Gastritis/prevención & control , ATPasa Intercambiadora de Hidrógeno-Potásio/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Datos de Secuencia Molecular , Cloruro de Picrilo/efectos adversos , Cloruro de Picrilo/inmunología , Linfocitos T/inmunología , TimectomíaRESUMEN
PURPOSE: To improve the control of hyperuricemia in patients with leukemia or lymphoma, we tested a newly developed uricolytic agent, recombinant urate oxidase (SR29142; Rasburicase; Sanofi-Synthelabo, Inc, Paris, France), which catalyzes the oxidation of uric acid to allantoin, a highly water-soluble metabolite readily excreted by the kidneys. PATIENTS AND METHODS: We administered Rasburicase intravenously, at 0.15 or 0.20 mg/kg, for 5 to 7 consecutive days to 131 children, adolescents, and young adults with newly diagnosed leukemia or lymphoma, who either presented with abnormally high plasma uric acid concentrations or had large tumor cell burdens. Blood levels of uric acid, creatinine, phosphorus, and potassium were measured daily. The pharmacokinetics of Rasburicase, the urinary excretion rate of allantoin, and antibodies to Rasburicase were also studied. RESULTS: At either dosage, the recombinant enzyme produced a rapid and sharp decrease in plasma uric acid concentrations in all patients. The median level decreased by 4 hours after treatment, from 9.7 to 1 mg/dL (P =.0001), in the 65 patients who presented with hyperuricemia, and from 4.3 to 0.5 mg/dL (P =.0001) in the remaining 66 patients. Despite cytoreductive chemotherapy, plasma uric acid concentrations remained low throughout the treatment (daily median level, 0.5 mg/dL). The urinary excretion rate of allantoin increased during Rasburicase treatment, peaking on day 3. Serum phosphorus concentrations did not change significantly during the first 3 days of treatment, decreased significantly by day 4 in patients presenting with hyperuricemia (P =.0003), and fell within the normal range in all patients by 48 hours after treatment. Serum creatinine levels decreased significantly after 1 day of treatment in patients with or without hyperuricemia at diagnosis (P =.0003 and P =.02, respectively) and returned to normal range in all patients by day 6 of treatment. Toxicity was negligible, and none of the patients required dialysis. The mean plasma half-lives of the agent were 16.0 +/- 6.3 (SD) hours and 21.1 +/- 12.0 hours, respectively, in patients treated at dosages of 0.15 or 0.20 mg/kg. Seventeen of the 121 assessable patients developed antibodies to the enzyme. CONCLUSION: Rasburicase is safe and highly effective for the prophylaxis or treatment of hyperuricemia in patients with leukemia or lymphoma.
Asunto(s)
Linfoma de Burkitt/complicaciones , Linfoma de Células B/complicaciones , Linfoma no Hodgkin/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Urato Oxidasa/uso terapéutico , Ácido Úrico/sangre , Adolescente , Linfoma de Burkitt/sangre , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Lactante , Linfoma de Células B/sangre , Linfoma no Hodgkin/sangre , Masculino , Fósforo/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Proteínas Recombinantes/sangre , Proteínas Recombinantes/uso terapéutico , Urato Oxidasa/sangreRESUMEN
BACKGROUND: Leukaemia cells differ from their normal counterparts in that their ability to properly regulate survival, proliferation, differentiation, and apoptosis is aberrant. Understanding the molecular mechanisms controlling cell proliferation and developing therapeutic strategies to correct nonfunctional regulatory mechanisms are emerging areas of medical research. Ceramide, a metabolite of membrane sphingomyelin hydrolysis, has recently emerged as a key regulator of cellular proliferation, differentiation, and apoptosis in leukaemia cells. METHODS: Leukaemia cell lines were treated with a biologically active analogue of ceramide, C(2)-ceramide. Cell cycle status was assessed flow cytometrically using propidium iodide. Induction of apoptosis was confirmed by annexin V staining of externalised phosphatidylserine and retinoblastoma activation was determined by Western blotting. RESULTS: C(2)-ceramide induced activation of retinoblastoma tumour suppressor protein, G(0)/G(1) cell cycle arrest, or apoptosis in leukaemia cell lines. In addition, these effects differed depending upon cell type, thus confirming the pleiotropic nature of the ceramide signalling pathway. Most cells studied responded to exogenous C(2)-ceramide by entering growth arrest, evidently resulting from activation of retinoblastoma protein, and by displaying some degree of apoptosis. CONCLUSIONS: Taken together, these findings suggest that signalling via ceramide has novel therapeutic applications for treatment of leukaemia.
Asunto(s)
Ciclo Celular/fisiología , Células Madre Hematopoyéticas/citología , Proteína de Retinoblastoma/metabolismo , Esfingosina/análogos & derivados , Esfingosina/farmacología , Ciclo Celular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Citometría de Flujo/métodos , Fase G1 , Células HL-60 , Humanos , Células Jurkat , Leucemia , Fosforilación , Fase de Descanso del Ciclo Celular , Proteína de Retinoblastoma/efectos de los fármacos , Células Tumorales Cultivadas , Células U937RESUMEN
Exposure of the skin to environmental stimuli, such as chemical or physical carcinogens, modifies the local skin environment, including depletion of epidermal Langerhans' cells (LC). Any subsequent exposure of the LC-depleted skin to antigen results in the generation of antigen-specific tolerance. In this study we evaluated the antigen-bearing cells in the draining lymph nodes by capitalizing on the fluorescent nature of the contact sensitizer, fluorescein isothiocyanate (FITC). When FITC was applied to the skin of normal mice, two distinct populations of antigen-bearing cells were identified in the draining lymph nodes. They were classified as either FITChi or FITClo on the basis of their fluorescence intensity and thus the amount of antigen they internalized. Only FITClo cells were detected in the lymph nodes draining FITC-treated murine skin that had been depleted of epidermal LC by prior treatment with the complete carcinogen 9,10-dimethyl 1,2-benzanthracene (DMBA). Functional analysis of these cells revealed that the FITChi cells, but not the FITClo cells, induced antigen-specific T-cell proliferation. Further analysis of the FITClo cells from the DMBA-treated mice demonstrated that these cells had reduced levels of CD80 expression, had substantially reduced levels of CD86 expression and performed poorly as co-stimulator cells in an anti-CD3-mediated proliferative assay. Nonetheless these cells still induced early signs of T-cell activation and interleukin-12 production. Consequently the FITClo cells migrating from the LC-depleted skin, through a combination of reduced antigen presentation and reduced co-stimulatory activity, induced a state of unresponsiveness or anergy in the responder T cells in a similar manner to that observed when antigen presentation occurs in the absence of co-stimulation. We propose that these unresponsive, or anergic cells, account for the antigen-specific tolerance observed in these experiments.
Asunto(s)
9,10-Dimetil-1,2-benzantraceno/farmacología , Carcinógenos/farmacología , Células Dendríticas/inmunología , Tolerancia Inmunológica , Inmunoconjugados , Activación de Linfocitos , Linfocitos T/inmunología , Abatacept , Animales , Antígenos CD/inmunología , Antígenos de Diferenciación , Antígeno B7-1/inmunología , Antígeno B7-2 , Complejo CD3/inmunología , Antígeno CTLA-4 , Células Dendríticas/efectos de los fármacos , Citometría de Flujo , Fluoresceína-5-Isotiocianato/farmacología , Colorantes Fluorescentes/farmacología , Interleucina-12/análisis , Interleucina-12/inmunología , Glicoproteínas de Membrana/inmunología , Ratones , Ratones Endogámicos BALB CRESUMEN
OBJECTIVE: To examine the patterns of children's and caregivers' descriptions of pain and the comfort measures used to relieve the pain of sickle cell disease (SCD) at home and in the hospital. DESIGN: Qualitative and quantitative techniques were used to obtain data. Participants were seen twice, first with and then without a vaso-occlusive episode. Multiple simultaneous methodological triangulation was used to integrate the findings from ethnographic interviews and observations as well as limited quantitative findings about pain and comfort measures used. SETTING: A Midwestern children's hospital with a regional SCD service. PARTICIPANTS: Twenty-one African American children and adolescents with SCD, aged 6 to 15 years, and 21 family caregivers. RESULTS: An 8-phase chronology of pain and comfort was revealed from the data about pain and comfort in children with SCD. Although this chronology was an unexpected finding, it was consistent with the original aim of the investigation. Phase 1 (baseline) represented the usual state of the child's condition, which for most was free of pain. Phase 2 or the "pre-pain" state involved no vasoocclusive pain but the child began to show prodromal signs and symptoms of painful episodes, such as yellowing of the eyes or fatigue. Phases 2 through 7 involved increasing then decreasing levels of pain, including the pain start point (phase 3), pain acceleration (phase 4), peak pain experience (phase 5), pain decrease start point (phase 6), and steady pain decline (phase 7). A trip to the emergency department usually occurred during phase 5. In phase 8 (pain resolution), the pain had decreased to a manageable level so that the child could be discharged from the hospital. As pain increased and decreased, so did the number and variety of comfort measures. CONCLUSIONS: A chronology of the pain and comfort experiences for children and adolescents during a vasoocclusive event of SCD emerged from the descriptive data of this study. Findings need to be examined further in larger, quantitative, longitudinal studies that examine more closely the duration, intensity, and character of pain at different times during vaso-occlusive episodes as well as the comfort measures used during specific phases of the pain event.
Asunto(s)
Anemia de Células Falciformes/fisiopatología , Dolor/fisiopatología , Adolescente , Adulto , Cuidadores , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Periodicidad , Factores de RiesgoRESUMEN
Myofibromatosis is a rare congenital disorder consisting of one or more fibrous nodules in the skin, soft tissues, bones, and internal organs. The authors report the unique case of a newborn who presented with obstructive jaundice caused by a single myofibroma in the head of the pancreas that was treated successfully by pancreatoduodenectomy on the eighth day of life.
Asunto(s)
Miofibromatosis , Neoplasias Pancreáticas , Pancreaticoduodenectomía , Humanos , Recién Nacido , Masculino , Miofibromatosis/epidemiología , Miofibromatosis/cirugía , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/cirugíaRESUMEN
Nonsteroidal anti-inflammatory drugs are often used in the management of those with acute pain secondary to sickle cell disease due to potent analgesic effects along with a lack of addictive potential, respiratory depression, and central nervous system effects, as may occur with narcotics. Caution should be observed in the use of nonsteroidal anti-inflammatory drugs in patients with compromised renal function. We present a case of a 17-year-old sickle cell disease patient with an acute painful episode and normal renal function indices who subsequently developed irreversible renal failure and a perirenal hematoma following the administration of ketorolac, despite adequate hydration. Due to its inhibitory effect on prostaglandin-mediated vasodilation, we advise caution in the use of ketorolac for the pain management of sickle cell painful episodes. We recommend following the administration guidelines for ketorolac for renal-compromised patients in those with painful episodes of sickle cell disease, and if used in this patient population, renal function must be very closely monitored.