No description available.

Les granulocytes, neutrophiles et éosinophiles, sont des cellules effectrices de l'immunité innée. La régulation de la vie des granulocytes par le mécanisme de mort programmée cellulaire quest lapoptose procure un équilibre judicieux entre leur fonction de cellules effectrices dans la défense de lorganisme et le renouvellement sécurisé de ces cellules potentiellement dangereuses. Lapoptose spontanée constitue un processus nécessaire pour le maintien de lhoméostasie des cellules immunes, telles que les granulocytes. Mon travail de doctorat a permis didentifier de nouveaux mécanismes régulateurs de l'apoptose des granulocytes. La première étude démontre le rôle important des céramides de type C16 et C24 en tant que messagers secondaires dans la transmission du signal de mort dans les neutrophiles vieillissants. En effet, nous montrons que ces céramides, générées par la voie de synthèse de novo, s'accumulent spontanément dans les neutrophiles et précèdent l'apparition des signes de l'apoptose précoce ainsi que l'activation des caspases-8, -9 et -3. L'inhibition ou l'accélération pharmacologiques de cette accumulation ralenti ou accélère l'apoptose des neutrophiles, respectivement. Laccumulation des céramides C16 et C24 est également inhibée par le traitement des neutrophiles avec du GM-CSF, une cytokine proinflammatoire et anti-apoptotique. Par contre, nos résultats montrent que la mort induite par l'activation du récepteur Fas ne dépend pas de la synthèse de céramides par la voie de novo. Au cours de la seconde étude, nous avons identifié un mécanisme spécifique dans la régulation de l'apoptose des éosinophiles. Nous montrons que les éosinophiles expriment spontanément CD40 à leur surface et que lengagement de CD40 s'oppose à la mort des éosinophiles via l'induction de la protéine inhibitrice de l'apoptose cytoplasmique-2 (c-IAP2). En outre, nous apportons les évidences de l'existence d'un mécanisme similaire in vivo, en particulier dans l'inflammation allergique des voies respiratoires.

Includes copies of articles co-authored by the author during the preparation of this thesis, in back pocket. / Errata attached to back flyleaf. / Includes bibliographical references (leaves 127-139). / 139 leaves : ill. (some col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / The results presented lend further evidence to previous work suggesting that cold shock domain factors function to repress granulocyte macrophage-colony stimulating factor transcription via DNA binding to single stranded regions across the proximal promoter. / Thesis (Ph.D.)--Adelaide University, Dept. of Medicine, 2001

Normal tissue homeostasis and appropriate responses to injury and infection are dependent on cellular communication mediated by cell surface receptors that respond to extrinsic stimuli. The GM-CSF receptor was the major focus of this project. This receptor shares a common signalling subunit, β [subscript c], with the IL-3 and IL-5 receptors. The unique GM-CSF receptor α-subunit ( GMRα ) confers ligand binding specificity to the complex and is essential for GM-CSF receptor signalling, although the full complement of signalling events mediated by GMRα remains elusive. Through cloning of candidate interacting proteins, expression and co-immunoprecipitation studies, we have confirmed interactions for two proteins previously reported to interact with the GMRα, p85 and IKKβ. Additionally, we identified the Src family kinase, Lyn, as a novel direct interacting partner of GMRα and provide insights into possible roles of this kinase in initiating signalling from the GM-CSF receptor. In addition to GMRα associated events we aimed to further characterise the role of the common β [subscript c] subunit in GM-CSF mediated signalling. We utilised two classes of consitutively active β [subscript c] mutants ( extracellular or transmembrane ) which transform the bi-potential myeloid FDB1 cell line to either factor-independent growth and survival, or granulocyte-macrophage differentiation, respectively. Here we report a comprehensive biochemical analysis of signalling by these two classes of mutants in this cell line. The two activated GMR mutants displayed distinct and non-overlapping signalling capacity. In particular, expression of a mutant with a substitution in the transmembrane domain ( V449E ) selectively activated JAK / STAT5 and MAPK pathways resulting in a high level of sensitivity to JAK and MEK inhibitors. In contrast, expression of a mutant with a 37 amino acid duplication in its extracellular domain ( FI Δ ) selectively activates the PI3K / AKT and IKKβ / NFkB pathways. Cells responding to this mutant display a relative high level of sensitivity to two independent PI3K inhibitors and relative resistance to inhibition of MEK and JAK2. The non-overlapping nature of signalling by these two activated mutants suggests that there are alternative modes of receptor activation that differentially dependent on JAK2 and that act synergistically in the mature liganded cytokine receptor complex. Further detailed analysis of these mutants will facilitate the dissection of the signalling pathways involved in the GM-CSF response that mediate proliferation, survival and differentiation. / Thesis (Ph.D.)--School of Medicine, 2007.

No description available.

Thesis (Ph.D.) -- University of Adelaide, Dept. of Obstetrics and Gynaecology, 1999. / Errata posted inside back end-paper (leaf 250). Bibliography: leaves 204-249.

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfillment of the requirements for the degree of Master of Medicine in the branch of Obstetrics and Gynaecology. Johannesburg, 2017 / Background Recurrent IVF failures may result from implantation defects of which a thin endometrium is often implicated. Studies show that improved endometrial thickness increases the probability of successful IVF. Objectives To evaluate the effects of transcervical instillation of G-CSF as an adjunct to IVF. The study looked at the influence of G-CSF on the endometrium and on the achievement of pregnancy. Methods A retrospective cross-sectional study of women attending Bio ART Fertility Centre, who had two or more failed IVFs previously. Results There were a total of 49 women studied with a mean age of 38.9. Mean number of previous IVFs were 3.1. Comparison between those that achieved pregnancy and those that did not showed that age was a statistically significant factor (p-value 0.0005). Mean endometrial thickness pre and post-GCSF between the groups was not statistically significant (p-values >0.05). Conclusion With the use of G-CSF we achieved a clinical pregnancy rate of 34.69% and a statistically significant overall expansion of endometrial thickness (p-value 0.0029). However we failed to show any association between endometrial expansion and pregnancy outcome. / MT 2018

Thesis (Ph. D.)--University of Maryland, 1996. / eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (Ph. D.)--University of Maryland, 1996. / Includes bibliographical references.

Pneumocystis carinii is an opportunistic fungal pathogen that causes lifethreatening pneumonia in immunocompromised individuals. Infants appear to be particularly susceptible to Pneumocystis (PC) pulmonary infections. The higher incidence of PC as well as other pulmonary infections among infants is likely due to an immature immune system. The neonatal lung environment is deficient immunologically in preterm as well as term infants (1, 2). Decreased phagocytic capacity of macrophages in newborns may increase the risk of infection from inhaled pathogens (1, 2). We have previously demonstrated that there is approximately a 3-week delay in the clearance of PC organisms from pup mouse lungs compared to adults. Herein, we demonstrate that there is also a 1-week delay in the infiltration of AMs in pup compared to adult PC-infected mice. We go on to show that there is a delay in pup versus adult lung macrophage phenotypic expression and cytokine production in response to PC organisms. We demonstrated that pup AMs are competent to produce cytokine in response to LPS and that stimulation with zymosan generates cytokine production in pup AMs that is comparable to adult cytokine production. These data indicate that pup lung macrophages are specifically poorly responsive to PC organisms and likely require exogenous stimulation to mount a significant immune response and expedite clearance of the organism. We go on to show that heat-killed Escheriae coli improves cytokine response, cellular infiltration and reduces organism burden in PC-infected pup mice. The clinically relevant cytokine, GM-CSF, has been used to improve the clearance of several pulmonary infections, including PC in adult animal models. We show that monotherapy with GM-CSF is insufficient to improve PC clearance in pup mice; however, when combined with TMP/SMX it improves PC clearance and maintains a reduced PC burden following discontinuation of therapy. Furthermore, we have shown that GM-CSF improves the ability of human infant lung macrophages to phagocytose PC organsms without generating an increased inflammatory response. These data suggest that combination therapy with TMP/SMX and GM-CSF may be a viable treatment option for infants failing or intolerant to standard therapy.