Assuntos
Antígenos CD55/genética , Rejeição de Enxerto/fisiopatologia , Transplante de Fígado/fisiologia , Transplante Heterólogo/métodos , Doença Aguda , Animais , Animais Geneticamente Modificados , Anticorpos Heterófilos/sangue , Eritrócitos/imunologia , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/metabolismo , Testes de Hemaglutinação , Transplante de Fígado/imunologia , Transplante de Fígado/patologia , Linfócitos/imunologia , Modelos Animais , Papio , Suínos , Fatores de Tempo , Transplante Heterólogo/imunologia , Transplante Heterólogo/fisiologiaAssuntos
Desequilíbrio Ácido-Base/fisiopatologia , Antígenos CD55/genética , Eletrólitos/sangue , Transplante de Fígado/imunologia , Fígado/imunologia , Animais , Animais Geneticamente Modificados , Antígenos CD55/fisiologia , Humanos , Transplante de Fígado/fisiologia , Modelos Animais , Papio , SuínosRESUMO
BACKGROUND: It is not known whether the pig liver is capable of functioning efficiently when transplanted into a primate, neither is there experience in transplanting a liver from a transgenic pigs expressing the human complement regulator human complement regulator decay accelerating factor (h-DAF) into a baboon. The objective of this study was to determine whether the porcine liver would support the metabolic functions of non-human primates and to establish the effect of hDAF expression in the prevention of hyperacute rejection of porcine livers transplanted into primates. METHODS: Five orthotopic liver xenotransplants from pig to baboon were carried out: three from unmodified pigs and two using livers from h-DAF transgenic pigs. FINDINGS: The three control animals transplanted with livers from unmodified pigs survived for less than 12 hr. Baboons transplanted with livers from h-DAF transgenic pigs survived for 4 and 8 days. Hyperacute rejection was not detected in the baboons transplanted with hDAF transgenic pig livers; however, it was demonstrated in the three transplants from unmodified pigs. Baboons transplanted with livers from h-DAF transgenic pigs were extubated at postoperative day 1 and were awake and able to eat and drink. In the recipients of hDAF transgenic pig livers the clotting parameters reached nearly normal levels at day 2 after transplantation and remained normal up to the end of the experiments. In these hDAF liver recipients, porcine fibrinogen was first detected in the baboon plasma 2 hr postreperfusion, and was present up to the end of the experiments. One animal was euthanized at day 8 after development of sepsis and coagulopathy, the other animal arrested at day 4, after an episode of vomiting and aspiration. The postmortem examination of the hDAF transgenic liver xenografts did not demonstrate rejection. INTERPRETATION: The livers from h-DAF transgenic pigs did not undergo hyperacute rejection after orthotopic xenotransplantation in baboons. When HAR is abrogated, the porcine liver maintains sufficient coagulation and protein levels in the baboon up to 8 days after OLT.
Assuntos
Antígenos CD55/farmacologia , Transplante de Fígado/imunologia , Transplante Heterólogo/imunologia , Transplante Heterólogo/fisiologia , Doença Aguda , Animais , Animais Geneticamente Modificados , Fatores de Coagulação Sanguínea/análise , Complemento C3/metabolismo , Complemento C4/metabolismo , Ensaio de Atividade Hemolítica de Complemento , Rejeição de Enxerto/prevenção & controle , Humanos , Fígado/patologia , Transplante de Fígado/mortalidade , Transplante de Fígado/patologia , Papio , Taxa de Sobrevida , Suínos , Fatores de TempoAssuntos
Antígenos CD55/fisiologia , Transplante de Fígado/fisiologia , Transplante Heterólogo/fisiologia , Animais , Animais Geneticamente Modificados , Antígenos CD55/genética , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/fisiologia , Homeostase , Humanos , Transplante de Fígado/imunologia , Papio , Suínos , Transplante Heterólogo/imunologiaAssuntos
Coagulação Sanguínea , Rejeição de Enxerto/imunologia , Transplante de Fígado/imunologia , Transplante Heterólogo/imunologia , Animais , Formação de Anticorpos , Ciclofosfamida/uso terapêutico , Ciclosporina/uso terapêutico , Endotélio Vascular/patologia , Hepatectomia/métodos , Imunidade Celular , Imunossupressores/uso terapêutico , Transplante de Fígado/métodos , Transplante de Fígado/patologia , Metilprednisolona/uso terapêutico , Papio , Suínos , Transplante Heterólogo/métodos , Transplante Heterólogo/patologiaAssuntos
Fatores de Coagulação Sanguínea/metabolismo , Transplante de Fígado/fisiologia , Transplante Heterólogo/fisiologia , Animais , Fatores de Coagulação Sanguínea/análise , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Hepatectomia , Papio , Tempo de Tromboplastina Parcial , Tempo de Protrombina , SuínosRESUMO
In the late 1980s, a functional and anatomical model of basal ganglia organization was proposed in order to explain the clinical syndrome of Parkinson's disease. According to this model, the pathological overactivity observed in the subthalamic nucleus and the output station of the basal ganglia plays a crucial role in the pathophysiology of the motor signs of Parkinson's disease. The hyperactivity of subthalamic neurons in Parkinsonism is viewed as a direct consequence of a pathological hypoactivity of the external segment of the pallidum. This article reviews recent data from different experimental approaches that challenge the established model of basal ganglia organization by reinterpreting the functional interaction between the external segment of the pallidum and the subthalamic nucleus in both the normal and pathological state. Indeed, recent neurobiochemical studies have rather unexpectedly shown that the GABAergic and metabolic activities of the external pallidum are not decreased in human and non-human primates with Parkinsonism. This absence of any decrease in activity might be explained by the functionally antagonistic influences of the striatal and subthalamic afferences within the external pallidum, as suggested by several anatomical studies. In addition, there are clues from electrophysiological studies to suggest that the hyperactivity found in the subthalamic neurons in Parkinsonism may not depend solely on the level of activity in the external pallidum. In such a framework, the hyperactivity of the subthalamic neurons would have to be explained, at least in part, by other sources of excitation or disinhibition. However, any explanation for the origin of the subthalamic overactivity in Parkinsonism remains speculative.
Assuntos
Gânglios da Base/anatomia & histologia , Gânglios da Base/patologia , Doença de Parkinson/patologia , Animais , Gânglios da Base/citologia , Gânglios da Base/fisiopatologia , Globo Pálido/citologia , Globo Pálido/patologia , Globo Pálido/fisiopatologia , Humanos , Doença de Parkinson/fisiopatologiaRESUMO
The cellular expression of dopamine D2 receptor mRNA was examined in striatal (caudate nucleus and putamen) neurones of 9 Macaca fascicularis monkeys rendered parkinsonian by systemic injection of MPTP. Messenger RNA abundance was determined by quantitative in situ hybridization using human-specific 35S-labelled oligonucleotides. Control monkeys were untreated and received neither MPTP nor L-DOPA while the rest were rendered parkinsonian and received chronic levodopa therapy to induce dyskinesia. In the control brains a strong dopamine D2 receptor hybridization signal was detected overlying medium-sized and some large neurons in both the caudate nucleus and putamen. Neurons from the lateral and medial regions of the caudate nucleus, and from the dorsal and ventral regions of the putamen were analysed separately. A significant increase in the cellular abundance of dopamine D2 receptor mRNA was seen in the striatum of MPTP-treated monkeys; this increase being restricted to the population of medium-sized striatal cells. No such increase in dopamine D2 receptor mRNA was observed in (dyskinetic) L-DOPA-treated monkeys suggesting that levodopa-therapy normalises D2 receptor expression in post-synaptic striatal cells. The cellular abundance of dopamine D2 receptor mRNA expressed by large striatal neurons (putative cholinergic cells) was unaffected by either MPTP treatment or levodopa therapy. The implications of these findings for the development of levodopa-induced dyskinesias is discussed.