AN IN VIVO MODEL OF HYPERACUTE REJECTION: CHARACTERIZATION AND EVALUATION OF THE EFFECT OF TRANSGENIC HUMAN COMPLEMENT INHIBITORS

Hyperacute rejection (HAR) occurring after transplantation within phylogenetically distant species is a severe reaction triggered by preexisting xenoreactive antibodies and complement activation, leading to the destruction of the donor organ. Expression of human complement inhibitors in transgenic pig organs prolongs the survival of xenograft in experimental models. Moreover, the extent of protection from hyperacute rejection is dependent on the level and site of expression of the transgenic molecules and, probably, on the combination of different molecules. In this regard a small animal model to test the efficacy of expression vectors and different human molecules could be very advantageous. A murine model developed in our laboratory was characterized by measurement of several parameters characteristic of HAR in the livers of control and transgenic mice expressing transgenic human DAF (CD55) or MCP (CD46) at the end of 2 h of perfusion with human plasma and after 1 day. The parameters studied were heamatological values of hepatic functions (GOT and GPT), induction of pro-inflammatory molecules and histopathological evaluation. Cytokines (IL-1 alpha, IL-1 beta, IL-6) induction and exposure of P-selectin on the endothelial cell surface, was only observed in control animals after 2 h of perfusion, as an early event. GOT and GPT values increase drammatically after 2 h perfusion and 1 day after the treatment according to the histopathological observation of liver damage. On the contrary, the livers of hDAF or hMCP transgenic mice, under the same treatment were significantly protected although the extent of this protection is dependent on the level of expression of transgenic human molecules

Multiway modeling and analysis in stem cell systems biology

<p>Abstract</p> <p>Background</p> <p>Systems biology refers to multidisciplinary approaches designed to uncover emergent properties of biological systems. Stem cells are an attractive target for this analysis, due to their broad therapeutic potential. A central theme of systems biology is the use of computational modeling to reconstruct complex systems from a wealth of reductionist, molecular data (e.g., gene/protein expression, signal transduction activity, metabolic activity, etc.). A number of deterministic, probabilistic, and statistical learning models are used to understand sophisticated cellular behaviors such as protein expression during cellular differentiation and the activity of signaling networks. However, many of these models are bimodal i.e., they only consider row-column relationships. In contrast, multiway modeling techniques (also known as tensor models) can analyze multimodal data, which capture much more information about complex behaviors such as cell differentiation. In particular, tensors can be very powerful tools for modeling the dynamic activity of biological networks over time. Here, we review the application of systems biology to stem cells and illustrate application of tensor analysis to model collagen-induced osteogenic differentiation of human mesenchymal stem cells.</p> <p>Results</p> <p>We applied Tucker1, Tucker3, and Parallel Factor Analysis (PARAFAC) models to identify protein/gene expression patterns during extracellular matrix-induced osteogenic differentiation of human mesenchymal stem cells. In one case, we organized our data into a tensor of type protein/gene locus link × gene ontology category × osteogenic stimulant, and found that our cells expressed two distinct, stimulus-dependent sets of functionally related genes as they underwent osteogenic differentiation. In a second case, we organized DNA microarray data in a three-way tensor of gene IDs × osteogenic stimulus × replicates, and found that application of tensile strain to a collagen I substrate accelerated the osteogenic differentiation induced by a static collagen I substrate.</p> <p>Conclusion</p> <p>Our results suggest gene- and protein-level models whereby stem cells undergo transdifferentiation to osteoblasts, and lay the foundation for mechanistic, hypothesis-driven studies. Our analysis methods are applicable to a wide range of stem cell differentiation models.</p

Mesenchymal stem cell as salvage treatment for refractory chronic GVHD

Refractory chronic GVHD (cGVHD) is an important complication after allogeneic hematopoietic SCT and is prognostic of poor outcome. MSCs are involved in tissue repair and modulating immune responses in vitro and in vivo. From April 2005 to October 2008, 19 patients with refractory cGVHD were treated with MSCs derived from the BM of volunteers. The median dose of MSCs was 0.6 × 106 cells per kg body weight. Fourteen of 19 patients (73.7%) responded well to MSCs, achieving a CR (n=4) or a PR (n=10). The immunosuppressive agent could be tapered to less than 50% of the starting dose in 5 of 14 surviving patients, and five patients could discontinue immunosuppressive agents. The median duration between MSC administration and immunosuppressive therapy discontinuation was 324 days (range, 200–550 days). No patients experienced adverse events during or immediately after MSC infusion. The 2-year survival rate was 77.7% in this study. Clinical improvement was accompanied by the increasing ratio of CD5+CD19+/CD5−CD19+ B cells and CD8+CD28−/CD8+CD28+ T cells. In conclusion, transfusion of MSCs expanded in vitro, irrespective of the donor, might be a safe and effective salvage therapy for patients with steroid-resistant, cGVHD

TARJETA POSTAL NAVIDEÑA [Material gráfico]

ITALIACopia digital. Madrid : Ministerio de Educación, Cultura y Deporte, 201

The organizational model of the interregional transplant agency Organizzazione Centro-Sud Trapianti.

In Italy, all donation and transplant activities were officially disciplined in 1999 by the law 91 of April 1, 1999. This law enacted a coordinator-based model of transplantation, instituted the National Center for Transplantation (Centro Nazionale Trapianti-CNT), and endorsed the existing interregional transplant agencies (ITA), such as the Nord Italia Transplant program (NITp), the Associazione InterRegionale Trapianti (AIRT), and the Organizzazione Centro-Sud Trapianti (OCST). Within its borders each ITA has adopted its own organizational model; there is no overt centralized control exerted by the CNT according to the law 91/1999. The aim of the current work is to report on the organizational model adopted by OCST, the ITA gathering the Italian regions of Abruzzo, Basilicata, Calabria, Campania, Latium, Molise, Sardinia, Sicily, and Umbri

Organizzazione Centro-Sud Trapianti: Outcome analysis 1999 to 2002

Background. The Organizzazione Centro-Sud Trapianti (OCST), which was created in 1998, is organized into eight regional areas, each referring to a local Regional Transplant Coordinating Center. Organs are primarily allocated to meet the demands of transplant C, centers in each regional area. Urgencies, pediatric grafts, and paybacks are managed by an Interregional Transplant Coordinating Center. The aim of the current work is to report on the impact of introduction of OCST on organ donation and transplant activity over the period from 1999 to 2002. Materials and methods. A retrospective analysis of donor and transplant data charts over the period from 1999 to 2002 focused on outcome analysis based on donor epidemiological data, cause of death, reasons for discards and grafts performed at OCST local transplant centers. Results. From 1999 to 2002, we observed a remarkable increase in organ donation from 8.8 to 22.5 donors per million people. Donor epidemiology showed an increase in median a(ye and stroke incidence rates and a decrease in trauma cases. The nonharvested donor rate rose steadily over the study period, plateauing at 58%, which was compensated for by a threefold increase in donation. Family oppositions ranged as high as 35.5% on average, despite public efforts to support donation. Transplant activity rose by 76%. Conclusions. The institution of OCST and the efforts from central and regional authorities have yielded a significant increase in organ donation and transplant activity rates over the period from 1999 to 2002. Major areas of concern are the high opposition rate and the decreasing quality of harvested grafts. Long-term analysis is underway to assess the impact of OCST on the quality of transplants performed in the catchment area