Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Linköping : Univ., 2002. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 4 uppsatser.

Lic.-avh. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 3 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 5 uppsatser.

Thesis (Ph.D.) - University of Queensland, 2006. / Includes bibliography.

Οι λοιμώξεις από διάφορους παθογόνους μικροοργανισμούς αποτελούν σημαντική αιτία νοσηρότητας και θνησιμότητας κατά τη διάρκεια της περιγεννητικής περιόδου. Η αυξημένη ευαισθησία των νεογνών σε βακτηριακές λοιμώξεις έχει αποδοθεί σε ανωριμότητα της έμφυτης ανοσίας. Θεωρείται ότι ένας από τους μηχανισμούς που ευθύνεται είναι η μειωμένη φαγοκυτταρική λειτουργία των ουδετερόφιλων και μονοκυττάρων. Ο σκοπός της παρούσας μελέτης ήταν να διερευνήσουμε την φαγοκυτταρική ικανότητα των νεογνικών ουδετερόφιλων και μονοκυττάρων στο αίμα του ομφάλιου λώρου και στο περιφερικό αίμα 3 ημέρες μετά τη γέννηση. Μέθοδος: Διερευνήσαμε την φαγοκυτταρική ικανότητα των ουδετερόφιλων και μονοκυττάρων σε μια ομάδα 42 νεογνών. Η in vitro φαγοκυτταρική δραστηριότητα υπολογίστηκε με βάση το Phagotest kit (Opregen Pharma, Heidelberg, Γερμανία) χρησιμοποιώντας κυτταρομετρία ροής, η οποία εκτιμά την πρόσληψη E. Coli από τα φαγοκύτταρα, στον ομφάλιο λώρο και στο περιφερικό αίμα την τρίτη μέρα ζωής. Τυχαία επιλεγμένοι 15 ξένοι υγιείς ενήλικες συμπεριελήφθησαν στη μελέτη και αποτέλεσαν την ομάδα ελέγχου-controls. Αποτελέσματα: Η φαγοκυτταρική ικανότητα των ουδετερόφιλων στο αίμα του ομφάλιου λώρου ήταν σημαντικά μειωμένη σε σύγκριση με εκείνη των ενηλίκων. Την 3η μεταγεννητική ημέρα η φαγοκυτταρική ικανότητα των ουδετερόφιλων είχε αυξηθεί σε σύγκριση με εκείνη στο αίμα του ομφάλιου λώρου και δεν διαφέρει σημαντικά από εκείνη των ενηλίκων. Η φαγοκυτταρική ικανότητα των μονοκυττάρων δεν διέφερε από αυτή των ενηλίκων, τόσο κατά τη γέννηση όσο και την τρίτη μεταγεννητική μέρα. Συμπέρασμα: Η μελέτη μας έδειξε ότι η πρόσληψη του E. Coli από τα φαγοκύτταρα είναι μειωμένη στα νεογνά (πρόωρα και τελειόμηνα) στη γέννηση, σε σύγκριση με τους ενήλικες. Αυτή η ατέλεια είναι παροδική, καθώς την 3η ημέρα μετά τη γέννησή η φαγοκυτταρική ικανότητα των νεογνών φτάνει στα επίπεδα των ενηλίκων. / Infections by a variety of pathogens are a significant cause of morbidity and mortality during perinatal period. The susceptibility of neonates to bacterial infections has been attributed to immaturity of innate immunity. It is considered that one of the impaired mechanisms is the phagocytic function of neutrophils and monocytes. The purpose of the present study was to investigate the phagocytic ability of neonates at birth and the third postnatal day. Methods: The phagocytic ability of neutrophils and monocytes of 42 neonates was determined using the Phagotest flow cytometry method, that assesses the intake of E. Coli by phagocytes, in cord blood and in peripheral blood 3 days after birth. Fifteen healthy adults were included in the study as controls. Results: The phagocytic ability of neutrophils in the cord blood of neonates was significantly reduced compared to adults. The 3rd postnatal day the reduction of phagocytic ability of neutrophils was no longer significant compared to adults. The phagocytic ability of monocytes did not show any difference from that of adults either at birth or the 3rd postnatal day. Conclusions: Our findings indicate that the intake of E. Coli by phagocytes is impaired at birth in both preterm and full term neonates compared to adults. This defect is transient, with the phagocytic ability in neonates reaching that of the adults 3 days after birth.

O vírus da imunodeficiência humana (HIV) é o responsável pela pandemia mundial da síndrome da imunodeficiência adquirida (AIDS). Uma vez infectado pelo HIV, o hospedeiro apresenta a forma aguda da doença, caracterizada por aumento da carga viral circulante, rápido declínio das células TCD4+ e ativação da resposta imune inata. Quando o HIV se estabelece no organismo, induz latência em algumas células e leva à cronicidade da infecção e nessa fase o principal alvo do HIV são as células T CD4+, observa-se então constante diminuição desta população, que tem como consequência a imunodeficiência, com desativação de outras células imunes, como os monócitos, macrófagos, células Natural Killer e neutrófilos. Portanto, há o favorecimento das infecções oportunistas por fungos, bactérias, parasitas e outros vírus, além do surgimento de neoplasias principais responsáveis pela morbidade e mortalidade relacionadas à AIDS. Para conter a destruição do sistema imune pelo vírus, inicia-se a terapia antirretroviral (TARV), sendo que o parâmetro disponível na clínica para início da terapia é a carga viral e contagem de células TCD4+. Neste sentido, investigamos se fatores relacionados à função e fenótipo de monócitos de pacientes HIV+ poderiam servir como biomarcadores da progressão da infecção. Para tanto, monócitos provenientes do sangue periférico de indivíduos HIV+, virgens ou não de tratamento e de indivíduos controle foram ou não infectadas in vitro com Salmonella Enteritidis. A capacidade fagocítica, a atividade microbicida, a produção de óxido nítrico (NO) e de citocinas foi avaliada e para avaliar a produção de espécies reativas do oxigênio (EROs), os monócitos foram ainda estimulados ou não com PMA. Concluímos que a infecção pelo HIV leva ao aumento da capacidade fagocítica de monócitos de homens quando comparados à mulheres nas mesmas condições, entretanto a infecção não altera funções como a atividade microbicida, produção de EROs ou NO, entretanto, o perfil de citocinas entre os grupos foi muito diferente, entretanto o uso de TARV é capaz de recuperar parcialmente as correlações formadas entre citocinas comparadas ao grupo controle. Desta forma uma bioassinatura funcional poderia ser descrita, tendo como base a produção diferencial de citocinas e quimiocinas, como IL-1?, IL-6 e IL-12p70. / The human immunodeficiency virus (HIV) is the responsible for the acquired immunodeficiency syndrome (AIDS) global pandemic. Once infected with HIV, the host has an acute form of the disease, characterized by a very high circulating level of virus and a rapid decline in CD4+ T cells, and then, the activation of innate immune response. The HIV is established in the body, inducing latency in some cells and leads to chronic infection, phase which the main target of HIV are the CD4+ T cells, and then what we observe is the constant decline of this population, which brings the immunodeficiency as a consequence, characterized by the deactivation of other immune cells, such as monocytes, macrophages, natural killer and neutrophils. In this way, opportunistic infections by fungal, bacteria, parasites and others viuses in adition to the neoplasm are established, being the main responsible for the morbidity and mortality related to AIDS. To contain the immune system destruction by the virus, the antiretroviral therapy (HAART) can be initiated, and the clinical parameter available considered to the onset of therapy to is the viral load and CD4+ T cell counts. In this sense, we have investigated if the factors related to the function and phenotype of monocytes from HIV+ patients could serve as biomarkers of the progression of infection. To this end, monocytes from the peripheral blood of HIV+ patients treated or not with HAART and control subjects were infected or not in vitro with Salmonella Enteritidis. The phagocytic capacity, microbicidal activity, the production of nitric oxide (NO) or cytokines were evaluated and when monocytes were stimulated or not with PMA, the production of reactive oxygen species (ROS) was evaluated. We conclude that HIV infection leads to increased phagocytic ability of monocytes of men compared to women in the same conditions, however, the infection does not alter functions such as microbicidal activity and ROS and NO production, however, the cytokine profile between groups was very different, however the use of HAART is able to partially recover the correlations formed between cytokines compared to the control group. Thus a functional biosignature could be described based on the differential production of cytokines and chemokines such as IL-1?, IL-6 and IL-12p70.

Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro / Lipoxinas (LXs) são metabólitos do ácido araquidônico com reconhecidas atividades antiinflamatórias e pró-resolução. Apesar do grande número de trabalhos publicados descrevendo o papel das LXs e seus análogos em leucócitos e outros tipos celulares envolvidos em doenças inflamatórias, pouco é sabido a respeito dos mecanismos de ação que desencadeiam estas respostas. Neste trabalho investigamos o papel do 15-epi-16-(para-flúor)-fenoxi-lipoxina A4 (ATL-1), um análogo sintético da 15-epi-lipoxina A4, sobre diversos processos de ativação de monócitos. Caracterizamos, pela primeira vez, o receptor da lipoxina A4 (ALX) na linhagem monocítica U937, através da avaliação de sua expressão gênica e protéica e de sua funcionalidade analisando a ativação de ERK-2, o que torna esta célula uma ferramenta apta para estudo dos mecanismos de ação das LXs e seus análogos sobre os monócitos. Além disso, demonstramos que o ATL-1 aumenta a expressão da enzima heme oxigenase (HO) -1 em células U937 via ativação da p38 MAP quinase (MAPK) e diminui a secreção da Monocyte chemoattractant protein-1 (MCP-1), uma quimiocina envolvida com o recrutamento de monócitos para o foco inflamatório, em células U937 estimuladas com LPS. A inibição da secreção de MCP-1 foi revertida pela utilização do SB203580, sugerindo que este efeito é dependente da ativação da via p38 MAPK. O presente estudo elucida alguns dos mecanismos envolvidos na ativação de monócitos pelas lipoxinas que podem levar a novas abordagens para o controle de diversas doenças nas quais o componente inflamatório é importante / Lipoxins (LXs) are arachidonic acid metabolites with well recognized anti-inflammatory and pro-resolution activities. Despite the large number of studies describing the role of LXs and their analogs in leukocytes and other cell types involved in inflammatory diseases, little is known about the mechanisms of action that trigger these responses. This work investigated the role of 15-epi-16-(para-fluoro)-phenoxy-lipoxin A4 (ATL-1), a synthetic analog of 15-epi-lipoxin A4 on various processes of monocyte activation. We characterized, for the first time, the lipoxin A4 receptor (ALX) in the monocytic lineage U937, through the assessment of its gene expression and protein and its functionality through the activation of ERK-2, which makes this cell line a suitable tool to study the mechanisms of action of LXs and their analogs on the monocytes. Furthermore, we demonstrated that ATL-1 increases the expression of the enzyme heme oxygenase (HO)-1 in the U937 cells via activation of p38 MAP kinase (MAPK) and decreases the secretion of Monocyte chemoattractant protein-1 (MCP-1), a chemokine involved in the recruitment of monocytes to the inflammatory focus in LPS-stimulated U937 cells. MCP-1 secretion inhibition by ATL-1 was reverted by SB203580 indicating that this effect is dependent on the activation of p38 MAPK pathway. This study clarifies some of the mechanisms involved in the activation of monocytes by lipoxins which may lead to new approaches for the control of different pathologies where the inflammatory component is relevant

End-stage renal disease patients have a greatly increased risk of cardiovascular disease partly attributed to the elevated levels of systemic inflammation observed in uraemia. One of the key mechanisms underlying inflammation appears to be the immune dysfunction that afflicts almost every aspect of the uraemic immune system. As a consequence patients experience immunosuppression and reduced responsiveness to antigen as well as a simultaneous over-activation leading to a pro-inflammatory environment. In addition, the haemodialysis (HD) treatment itself induces a proinflammatory response but may provide an otherwise opportune time to complete supervised exercise.