Cellular activation pathways and interaction networks in vascularized composite allotransplantation

Vascularized composite allotransplantation (VCA) is an evolving field of reconstructive surgery that has revolutionized the treatment of patients with devastating injuries, including those with limb losses or facial disfigurement. The transplanted units are typically comprised of different tissue types, including skin, mucosa, blood and lymphatic vasculature, muscle, and bone. It is widely accepted that the antigenicity of some VCA components, such as skin, is particularly potent in eliciting a strong recipient rejection response following transplantation. The fine line between tolerance and rejection of the graft is orchestrated by different cell types, including both donor and recipient-derived lymphocytes, macrophages, and other immune and donor-derived tissue cells (e.g., endothelium). Here, we delineate the role of different cell and tissue types during VCA rejection. Rejection of VCA grafts and the necessity of life-long multidrug immunosuppression remains one of the major challenges in this field. This review sheds light on recent developments in decoding the cellular signature of graft rejection in VCA and how these may, ultimately, influence the clinical management of VCA patients by way of novel therapies that target specific cellular processes

IBC's 21st Annual Antibody Engineering and 8th Annual Antibody Therapeutics International Conferences and 2010 Annual Meeting of The Antibody Society: December 5–9, 2010, San Diego, CA USA

The 21st Annual Antibody Engineering and 8th Annual Antibody Therapeutics international conferences, and the 2010 Annual Meeting of The Antibody Society, organized by IBC Life Sciences with contributions from The Antibody Society and two Scientific Advisory Boards, was held December 5–9, 2010 in San Diego, CA. The conferences featured over 100 presentations and 100 posters, and included a pre-conference workshop on deep-sequencing of antibody genes. The total number of delegates exceeded 800, which set a new attendance record for the conference

Les protéines de stress HSP90 et Gp96 dans la maladie du greffon contre l'hôte : implication physiopathologique, diagnostique et thérapeutique

Allogeneic hematopoietic cell transplantation is a treatment for certain disorders including hematologic malignancies. Graft-versus-host-disease (GvHD) is a major, life-threatening complication. It is due to the recognition of recipient antigens by donor T cells, which activate and damage tissues. Intestinal barrier alteration plays a critical role in GvHD. Heat shock proteins (HSP)90 include five members, three cytosolic members named HSP90, and one member localized in endoplasmic reticulum (ER) called Gp96 and able to gain extracellular level in case of stress. We show in our thesis that 17AAG, a HSP90 inhibitor, reduces GvHD mortality in a mouse model. This effect is associated with an increase in ER stress pathway in intestinal epithelial cells as figured by transcription factor XBP-1 splicing, correlated to a decrease in intestinal tissue damage. These results suggest that 17AAG could be considered in GvHD prevention in human. Moreover, we show that Gp96 is secreted in serum of patients developing an acute GvHD with intestinal involvement. We propose to validate the relevance of Gp96 as an intestinal GvHD biomarker is a larger study. Finally, we find that Gp96 associate with complement component 3, a protein involved in innate and adaptive immunity, and inhibit some of its functions. Functional consequences of this association are discussed.L’allogreffe de cellules hématopoïétiques est une stratégie thérapeutique importante dans les hémopathies malignes. La maladie du greffon contre l’hôte (GvH) en est une complication majeure menaçant le pronostic vital. Elle est due à la reconnaissance des antigènes du receveur par les lymphocytes T du donneur et à l’activation de ceux-ci, à l’origine de dommages tissulaires. L’altération de la barrière intestinale joue un rôle critique dans la GvH. La famille des protéines de choc thermique (HSP)90 comporte cinq membres dont trois cytosoliques dénommés HSP90, et un localisé dans le réticulum endoplasmique (RE), Gp96, qui peut être sécrété en cas de stress. Nous montrons dans nos travaux de thèse que la 17AAG, un inhibiteur des HSP90, réduit la mortalité liée à la GvH dans un modèle murin. Cet effet est associé à une augmentation de la réponse au stress du RE dans les cellules épithéliales intestinales comme en atteste l’augmentation de l’épissage du facteur de transcription XBP-1, corrélée à une diminution du dommage tissulaire intestinal. Ces résultats permettent d’envisager une place pour la 17AAG ou d’autres inhibiteurs de HSP90 dans la prévention de la GvH chez l’homme. D’autre part, nous montrons que Gp96 est sécrétée dans le sérum de patients développant une GvH aiguë sévère avec atteinte intestinale. Nous suggérons de valider la pertinence de Gp96 comme biomarqueur de GvH intestinale dans une étude de plus grande ampleur. Enfin, nous trouvons que Gp96 s’associe avec le composant 3 du complément, une protéine impliquée dans l’immunité innée et adaptative, et inhibe certaines de ses fonctions. Les conséquences fonctionnelles de cette association sont discutées

MicroRNAs in haematopoietic stem cell transplantation outcome

PhD ThesisAllogeneic haematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for numerous haematological malignancies. Graft-versus-host disease (GVHD) is the major complication causing mortality and is classified into acute (aGVHD) and chronic. MicroRNAs play a significant role in inflammation and have reported potential as biomarkers of different diseases. This study has investigated the role of microRNAs in allo-HSCT outcomes and had two main aims; (1) identification of microRNAs specific to the aGVHD target organ, skin and (2) an investigation into the role of immune specific miRNAs (miR-146a and miR-155) in peripheral blood. Initially, pathway mining was performed on a list of 18 genes that were shown previously, to have deregulated expression levels with regards to GVHD. The pathway mining identified specific immunological pathways in relation to the genes and potential microRNA targets. Global microRNA profiling was performed on a discovery cohort that identified a signature microRNA list in skin biopsies obtained from patients at the time of cutaneous histopathological aGVHD onset (grades I-III) and healthy volunteers. Twelve microRNAs were selected for further validation and it was shown that miR-34a-5p, miR-34a-3p, miR-503-5p and let-7c-5p were elevated and significantly involved in allo-HSCT outcomes. There was an interaction between miR-34a-3p and miR-503-5p which was significantly diagnostic of aGVHD and let-7c-5p was significantly predictive of disease relapse. MiR-34a-5p protein targets; p53 and c-Myc were then evaluated in the same cohort. MiR-34a-5p expression levels and cells stained positively for p53 were significantly correlated in the epidermis. Preliminary optimization of miR-34a-5p knockdown study was successfully conducted which showed promising results in the reduction of T cell proliferation. The whole blood study showed that miR-146a-5p and its interaction with miR-155-5p was predictive of aGVHD incidence in pre-disease onset (Day+28) samples. Interestingly, the expression levels of miR-146a-5p and miR-155-5p negatively correlated with SPI1 (PU.1). In conclusion, these investigations showed that (1) the microRNAs studied in this investigation may regulate the expression levels of the selected 18 genes, (2) microRNA expression levels in clinical skin biopsies obtained at the time of aGVHD onset could potentially be used as diagnostic biomarkers for aGVHD and as predictive biomarkers for overall survival as well as relapse and (3) miR-146a-5p and miR-155-5p expression levels in whole blood could be used as predictive biomarkers for aGVHD incidence

The Retina in Health and Disease

Vision is the most important sense in higher mammals. The retina is the first step in visual processing and the window to the brain. It is not surprising that problems arising in the retina lead to moderate to severe visual impairments. We offer here a collection of reviews as well as original papers dealing with various aspects of retinal function as well as dysfunction. New approaches in retinal research are described, such as the expression and localization of the endocannabinoid system in the normal retina and the role of cannabinoid receptors that could offer new avenues of research in the development of potential treatments for retinal diseases. Moreover, new insights are offered in advancing knowledge towards the prevention and cure of visual pathologies, mainly AMD, RP, and diabetic retinopathy

Embryonic Stem Cells

Embryonic stem cells are one of the key building blocks of the emerging multidisciplinary field of regenerative medicine, and discoveries and new technology related to embryonic stem cells are being made at an ever increasing rate. This book provides a snapshot of some of the research occurring across a wide range of areas related to embryonic stem cells, including new methods, tools and technologies; new understandings about the molecular biology and pluripotency of these cells; as well as new uses for and sources of embryonic stem cells. The book will serve as a valuable resource for engineers, scientists, and clinicians as well as students in a wide range of disciplines