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|Title: ||Role of the protective gene Heme Oxygenase-1 in the control of T cell mediated responses|
|Authors: ||Chora, Ângelo António Ferreira Chaves do Rosário, 1974-|
|Advisor: ||Soares, Miguel, 1968-|
Parreira, Leonor, 1952-
|Keywords: ||Heme oxigenase (desciclizante)|
Teses de doutoramento
|Issue Date: ||2008|
|Abstract: ||As reacções inflamatórias, geralmente desencadeadas por infeccões e/ou lesões a nível dos tecidos, desempenham um papel fundamental na iniciação de respostas imunes adaptativas e conduzem, em última análise, à eliminação do evento instigador. São vários os mecanismos intrínsecos a esta resposta complexa que asseguram, após a remoção do estímulo nocivo, a correcta reparação quer a nível estrutural quer funcional do tecido afectado, ou seja, o regresso à homeostase. A importância destes mecanismos pode ser comprovada pelo facto de a não resolução das reacções inflamatórias ser uma etapa crítica para o estabelecimento e/ou progressão de um número crescente de patologias. Um dos mecanismos envolvidos na resolução da inflamação consiste na expressão do enzima Heme Oxygenase-1 (HO-1). Em condições inflamatórias, a HO-1 torna-se o enzima limitante no catabolismo dos grupos hémicos livres dando origem a quantidades equimolares de monoxido de carbono (CO), ferro (Fe) e biliverdina (BV). Estes produtos reduzem a reacção inflamatória e evitam o desenvolvimento de doenças inflamatórias. Esta Tese teve como objectivo examinar o papel da HO-1 na regulação do estabelecimento e progressão de condições neuroinflamatórias mediadas por linfócitos T. O trabalho agora apresentado sugere que a HO-1 dita o resultado patológico associado com processos neuroinflamatórios em ratinho, tais como a encefalomielite autoimune experimental (EAE), um modelo de esclerose múltipla (EM), ou a malária cerebral experimental (MCE) resultante da infecção com Plasmodium spp.|
Inflammatory reactions, elicited in most cases upon infection and/or injury, are critical for the initiation of adaptive immunity and ultimately lead to the removal of the inciting stimuli. Intrinsic to this complex response, there are several mechanisms that operate to ensure that, once the inciting stimulus is dealt with, structural and functional repair of the injured site is attained, i.e. return to homeostasis. However, failure to resolve inflammatory reactions is thought to contribute in a critical manner to the establishment and/or progression of a growing list of pathologic conditions. One of the mechanisms involved in the resolution of inflammation relies in the expression of Heme Oxygenase (HO)-1. Under inflammatory conditions, HO-1 becomes the rate-limiting enzyme in the catabolism of heme, yielding equimolar amounts of carbon monoxide (CO), free iron (Fe) and biliverdin (BV). These heme degradation products dampen inflammation and prevent the development of inflammatory diseases. The focus of this Thesis was to address whether HO-1 regulates the establishment and progression of T cell-mediated neuroinflammatory conditions. The body of work presented herewith suggests that HO-1 can dictate the pathologic outcome of neuroinflammation in mice, as it occurs either during autoimmunity-driven experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), or during experimental cerebral malaria (ECM) triggered upon infection with Plasmodium spp. Induction of EAE in HO-1-deficient (Hmox-1-/-) mice led to enhanced central nervous system (CNS) demyelination, paralysis and mortality, as compared to wild-type (Hmox-1+/+) mice. Pharmacological induction of HO-1 expression after EAE onset improved the clinical course of the disease, an effect associated with inhibition of T helper (TH) and CD8+ T cell accumulation, proliferation and effector function within the CNS. HO-1 did not act via modulation of the suppressor activity of naturally occurring regulatory T cells (Treg), known to ensure peripheral tolerance to self-antigens and immune homeostasis. Furthermore, under homeostatic conditions Treg development, maintenance and function were found to be independent of HO-1, as assessed in Hmox-1-/- mice. Instead, the mechanism underlying the protective effect of HO-1 is shown to rely on its ability to inhibit major histocompatibility complex (MHC) class II expression by antigen presenting cells, including dendritic cells, microglia and macrophages. Likewise, Hmox-1 deletion or pharmacological inhibition of its activity resulted in increased ECM incidence in otherwise resistant mouse strains whereas pharmacological induction of HO-1 greatly reduced ECM incidence in susceptible mouse strains. The protection afforded by pharmacological induction of HO-1 expression was associated with decreased CD8+ T cell sequestration in the CNS, a critical event in the development of neurological damage associated with ECM. In both pathologies, i.e. EAE and ECM, exogenous CO mimicked these protective effects, suggesting that CO is the main contributor to the protective action of HO-1. Finally, we present evidence of a novel mechanism by which CO counters the development of one of these pathologies, ECM, based on its ability to bind hemoglobin, prevent its oxidation and subsequently the generation of free heme, a central effector molecule in the pathogenesis of ECM. Overall, the findings presented in this Thesis suggest that, during the establishment and/or progression of neuroinflammation, HO-1 and/or CO limit the deleterious effects associated with neuroinflammatory responses, possibly by modulating antigen presenting cells activity, in a manner that prevents the pathologic outcome of these conditions. Further, these results support the notion that pharmacological modulation of HO-1 or CO administration might be potential therapeutic strategies to counter neuroinflammatory diseases.
|Description: ||Tese de doutoramento em Ciências Biomédicas, (Ciências Biopatológicas), apresentada à Universidade de Lisboa através da Faculdade de Medicina, 2008|
|Appears in Collections:||FM - Teses de Doutoramento|
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