Cell therapy for autoimmune diseases

Cell therapy, pioneered for the treatment of malignancies in the form of bone marrow transplantation, has subsequently been tested and successfully employed in autoimmune diseases. Autologous haemopoietic stem cell transplantation (HSCT) has become a curative option for conditions with very poor prognosis such as severe forms of scleroderma, multiple sclerosis, and lupus, in which targeted therapies have little or no effect. The refinement of the conditioning regimens has virtually eliminated transplant-related mortality, thus making HSCT a relatively safe choice. Although HSCT remains a nonspecific approach, the knowledge gained in this field has led to the identification of new avenues. In fact, it has become evident that the therapeutic efficacy of HSCT cannot merely be the consequence of a high-dose immuno-suppression, but rather the result of a resetting of the abnormal immune regulation underlying autoimmune conditions. The identification of professional and nonprofessional immunosuppressive cells and their biological properties is generating a huge interest for their clinical exploitation. Regulatory T cells, found abnormal in several autoimmune diseases, have been proposed as central to achieve long-term remissions. Mesenchymal stem cells of bone marrow origin have more recently been shown not only to be able to differentiate into multiple tissues, but also to exert a potent antiproliferative effect that results in the inhibition of immune responses and prolonged survival of haemopoietic stem cells. All of these potential resources clearly need to be investigated at the preclinical level but support a great deal of enthusiasm for cell therapy of autoimmune diseases

Heparin Induces Apoptosis in Lymphocytes from B-cell Chronic Lymphocytic Leukemia.

It has been shown that glycosaminoglycans play a role in the regulation of immune response. In particular, heparin exerts an antiproliferative and apoptotic action in different cellular systems. In this study we evaluate whether heparin can also induce a naturally occurring programmed cell death in lymphocytes from B-chronic lymphocytic leukemia (B-CLL), a neoplastic lineage where apoptosis is blocked by the expression of the proto-oncogene bc1-2. Peripheral blood lymphocytes (PBL) from 7 cases of B-CLL patients in different stages were cultured with three different heparin sodium concentrations for 4 days. Apoptosis was evaluated by agarose gel electrophoresis and by cytofluorimetric analysis. Bcl-2 expression was tested by flow cytometric analysis and immunohistochemistry on cytospin preparations. Agarose gel electrophoresis showed the characteristic DNA fragmentation pattern of apoptosis in all the cases of B-CLL stage III and IV after heparin incubation. DNA from normal and neoplastic lymphocytes cultured without heparin did not undergo spontaneous apoptosis. Cytofluorimetric analysis confirmed the agarose gel pattern and found a level of apoptosis over 50% after culture of neoplastic PBL with heparin. In these cases bcl-2 expression was found to be significantly reduced after heparin incubation when comparing to bcl-2 level before incubation. Our data adds further evidence regarding the potential role of heparin in oncogene inhibition and in apoptosis induction. In particular, the induction of apoptosis in neoplastic lymphocytes by heparin may have a role in the complicated field of interactions between the immune system and the blood vessels by glycosaminoglycans

Immunomodulatory properties of mesenchymal stem cells : a review based on an interdisciplinary meeting held at the Kennedy Institute of Rheumatology Division, London, UK, 31 October 2005

Peer reviewedPublisher PD

A Simple Modelling Tool for Fast Combined Simulation of Interconnections, Inter-Symbol Interference and Equalization in High-Speed Serial Interfaces for Chip-to-Chip Communications

We describe an effcient system-level simulator that, starting from the architecture of a well-specified transmissive medium (a channel modelled as single-ended or coupled differential microstrips plus cables) and including the system-level characteristics of transmitter and receiver (voltage swing, impedance, etc.), computes the eye diagram and the bit-error rate that is obtained in high-speed serial interfaces. Various equalization techniques are included, such as feed-forward equalization at the transmitter, continuous-time linear equalization and decision-feedback equalization at the receiver. The impact of clock and data jitter on the overall system performance can easily be taken into account and fully-adaptive equalization can be simulated without increasing the computational burden or the model\u2019s complexity

Silicon Photomultiplier Research and Development Studies for the Large Size Telescope of the Cherenkov Telescope Array

The Cherenkov Telescope Array (CTA) is the the next generation facility of imaging atmospheric Cherenkov telescopes; two sites will cover both hemispheres. CTA will reach unprecedented sensitivity, energy and angular resolution in very-high-energy gamma-ray astronomy. Each CTA array will include four Large Size Telescopes (LSTs), designed to cover the low-energy range of the CTA sensitivity ($\sim$20 GeV to 200 GeV). In the baseline LST design, the focal-plane camera will be instrumented with 265 photodetector clusters; each will include seven photomultiplier tubes (PMTs), with an entrance window of 1.5 inches in diameter. The PMT design is based on mature and reliable technology. Recently, silicon photomultipliers (SiPMs) are emerging as a competitor. Currently, SiPMs have advantages (e.g. lower operating voltage and tolerance to high illumination levels) and disadvantages (e.g. higher capacitance and cross talk rates), but this technology is still young and rapidly evolving. SiPM technology has a strong potential to become superior to the PMT one in terms of photon detection efficiency and price per square mm of detector area. While the advantage of SiPMs has been proven for high-density, small size cameras, it is yet to be demonstrated for large area cameras such as the one of the LST. We are working to develop a SiPM-based module for the LST camera, in view of a possible camera upgrade. We will describe the solutions we are exploring in order to balance a competitive performance with a minimal impact on the overall LST camera design.Comment: 8 pages, 5 figures. In Proceedings of the 34th International Cosmic Ray Conference (ICRC2015), The Hague, The Netherlands. All CTA contributions at arXiv:1508.0589

Is platelet gel safe enough for neutropenic patients?

Our group recently described a case of life-threatening oral mucositis (OM) following highdose conditioning chemotherapy for peripheral blood stem cell transplantation (PBSCT), which was successfully treated with cord blood platelet gel (CBPG

Combined inhibition of p97 and the proteasome causes lethal disruption of the secretory apparatus in multiple myeloma cells.

Inhibition of the proteasome is a widely used strategy for treating multiple myeloma that takes advantage of the heavy secretory load that multiple myeloma cells (MMCs) have to deal with. Resistance of MMCs to proteasome inhibition has been linked to incomplete disruption of proteasomal endoplasmic-reticulum (ER)-associated degradation (ERAD) and activation of non-proteasomal protein degradation pathways. The ATPase p97 (VCP/Cdc48) has key roles in mediating both ERAD and non-proteasomal protein degradation and can be targeted pharmacologically by small molecule inhibition. In this study, we compared the effects of p97 inhibition with Eeyarestatin 1 and DBeQ on the secretory apparatus of MMCs with the effects induced by the proteasome inhibitor bortezomib, and the effects caused by combined inhibition of p97 and the proteasome. We found that p97 inhibition elicits cellular responses that are different from those induced by proteasome inhibition, and that the responses differ considerably between MMC lines. Moreover, we found that dual inhibition of both p97 and the proteasome terminally disrupts ER configuration and intracellular protein metabolism in MMCs. Dual inhibition of p97 and the proteasome induced high levels of apoptosis in all of the MMC lines that we analysed, including bortezomib-adapted AMO-1 cells, and was also effective in killing primary MMCs. Only minor toxicity was observed in untransformed and non-secretory cells. Our observations highlight non-redundant roles of p97 and the proteasome in maintaining secretory homeostasis in MMCs and provide a preclinical conceptual framework for dual targeting of p97 and the proteasome as a potential new therapeutic strategy in multiple myeloma

Pluripotent Stem Cell-Derived Hepatocytes Inhibit T Cell Proliferation In Vitro through Tryptophan Starvation.

Regenerative medicine aims to replace damaged tissues by stimulating endogenous tissue repair or by transplanting autologous or allogeneic cells. Due to their capacity to produce unlimited numbers of cells of a given cell type, pluripotent stem cells, whether of embryonic origin or induced via the reprogramming of somatic cells, are of considerable therapeutic interest in the regenerative medicine field. However, regardless of the cell type, host immune responses present a barrier to success. The aim of this study was to investigate in vitro the immunological properties of human pluripotent stem cell (PSC)-derived hepatocyte-like cells (HLCs). These cells expressed MHC class I molecules while they lacked MHC class II and co-stimulatory molecules, such as CD80 and CD86. Following stimulation with IFN-γ, HLCs upregulated CD40, PD-L1 and MHC class I molecules. When co-cultured with allogeneic T cells, HLCs did not induce T cell proliferation; furthermore, when T cells were stimulated via αCD3/CD28 beads, HLCs inhibited their proliferation via IDO1 and tryptophan deprivation. These results demonstrate that PSC-derived HLCs possess immunoregulatory functions, at least in vitro

Diagnosi e valutazione della personalit alleanza terapeutica e scambio clinico nella ricerca in psicoterapia

Questo contributo si propone di fornire una breve rassegna delle principali linee di ricerca seguite negli ultimi anni dal gruppo coordinato da Vittorio Lingiardi. Tra queste, ci soffermeremo in particolare su: a) valutazione e diagnosi della personalità con SWAP-200 e PDM (Psychodynamic Diagnostic Manual); b) sviluppo e validazione di strumenti clinician-report per operazionalizare l'uso del PDM; c) valutazione dei meccanismi di difesa e degli stili difensivi mediante DMRS e sua versione Q sort; d) studio del processo e della relazione terapeutica (alleanza terapeutica, rotture e riparazioni dell'alleanza controtransfert); in particolare, in quest'area di ricerca, ci siamo impegnati nello sviluppo e validazione di nuovi strumenti per la valutazione dei processi di rottura e riparazione dell'alleanza (Collaborative Interaction Scale) e della qualità dell'attaccamento tra paziente e terapeuta (Patient-Therapist Attachment Q Sort); d) sviluppo della ricerca clinica e applicativa sui temi dell'identità di genere, dell'orientamento sessuale e dell'omofobia sociale e interiorizzata