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Klingenberg R.,Experimental Cardiovascular Research Unit | Ketelhuth D.F.J.,Experimental Cardiovascular Research Unit | Strodthoff D.,Experimental Cardiovascular Research Unit | Gregori S.,San Raffaele Telethon Institute for Gene Therapy HSR TIGET | Hansson G.K.,Experimental Cardiovascular Research Unit
Immunobiology | Year: 2012

Objective: To modulate atherosclerosis by combining subcutaneous immunization with heat shock protein 65 (hsp65) in alum adjuvant and anti-CD45RB monoclonal antibodies (mAb). Methods: 8 week old Apoe -/- mice on normal chow were treated for 12 weeks: group A received hsp65-alum immunization combined with anti-CD45RB mAb, group B hsp65-alum immunization combined with isotype control antibody, and group C mock vaccine combined with isotype control antibody. Results: Unexpectedly, atherosclerotic lesions in the aortic root were significantly reduced in both hsp65-alum immunization groups (A and B) compared with the control group (C). Significantly elevated antibody titers against hsp65 were detected in both groups along with a significant increase in MHC class II expression on B cells. Body weight, total cholesterol and triglyceride levels were not different between groups. Treatment with anti-CD45RB antibody mediated a shift on CD4 + T cells from the CD45RB high to CD45RB low isoform with a relative increase in CD4 +Foxp3 + regulatory T cells (Treg) in an overall reduced T cell pool. Furthermore, anti-CD45RB treatment mediated a transient reduction of peripheral leukocytes and increased IFN-γ and IL-17A plasma levels. Conclusions: Subcutaneous immunization with hsp65-alum protects Apoe -/- mice against progression of early atherosclerosis. Administration of anti-CD45RB antibody provided no incremental benefit to the athero-protective effects of hsp65-alum treatment alone. © 2011 Elsevier GmbH.

Carosella E.D.,French Atomic Energy Commission | Carosella E.D.,University Paris Diderot | Gregori S.,San Raffaele Telethon Institute for Gene Therapy HSR TIGET | Rouas-Freiss N.,French Atomic Energy Commission | And 7 more authors.
Cellular and Molecular Life Sciences | Year: 2011

The non-classical HLA class I molecule HLA-G was initially shown to play a major role in feto-maternal tolerance. Since this discovery, it has been established that HLA-G is a tolerogenic molecule which participates to the control of the immune response. In this review, we summarize the recent advances on (1) the multiple structures of HLA-G, which are closely associated with their role in the inhibition of NK cell cytotoxicity, (2) the factors that regulate the expression of HLA-G and its receptors, (3) the mechanism of action of HLA-G at the immunological synapse and through trogocytosis, and (4) the generation of suppressive cells through HLA-G. Moreover, we also review recent findings on the non-immunological functions of HLA-G in erythropoiesis and angiogenesis. © 2010 Springer Basel AG.

Battaglia M.,San Raffaele Diabetes Research Institute HSR DRI | Battaglia M.,San Raffaele Telethon Institute for Gene Therapy HSR TIGET
Transplant International | Year: 2010

Graft survival has been lately improved by the introduction of efficient immunosuppressive drugs. However, late graft loss caused by chronic rejection and the side effects of long-term immunosuppression remain major obstacles for successful transplantation. Operational tolerance, which is defined by the lack of acute and chronic rejection and indefinite graft survival with normal graft function in the absence of continuous immunosuppression, represents an attractive alternative. Nevertheless, tolerance after allogeneic transplantation is commonly considered the 'mission impossible' for both immunologists and clinicians. One of the mechanisms involved in tolerance is the suppression of graft-specific alloreactive T cells, which largely mediate graft rejection, by regulatory T cells (Tregs) or by soluble factors produced by Treg cells. With this review, I will make an effort to collect and describe the significant studies performed in transplanted patients, and not in animal models or in in vitro systems, with the attempt to: (i) understand how tolerance is achieved, (ii) define whether and how Treg cells influence transplant tolerance, (iii) describe the first clinical trials with Treg cells in humans (i.e. how far have we come) and (iv) predict the future of Treg cell-based therapy in humans (i.e. how far can we go). © 2010 European Society for Organ Transplantation.

Cristofori P.,Glaxosmithkline | Sauer A.V.,San Raffaele Telethon Institute for Gene Therapy HSR TIGET | Trevisan A.,University of Padua
Cell Biology and Toxicology | Year: 2015

Glutathione-dependent bioactivation is a common pathway in nephrotoxicity caused by haloalkanes and haloalkenes. Glutathione conjugation forms the link between halogenated hydrocarbons, based on the formation of an episulfonium ion (vicinal halomethanes) or a cysteine conjugate (haloalkenes). Herein, we review the metabolic pathways underlying the nephrotoxic effects of the three well-known haloalkenes trichloroethylene, tetrachloroethylene, and hexachloro-1:3-butadiene to emphasize the role of cysteine-conjugate β-lyase and the oxidative metabolism in renal toxicity. Activation by cysteine-conjugate β-lyase is the best-characterized mechanism causing toxicity due to haloalkene treatment in experimental models. However, the severity of toxicity differs considerably, with S-(1,2,2-trichlorovinyl)-l-cysteine being more toxic than S-(1,2-dichlorovinyl)-l-cysteine, which is in turn more toxic than S-(1,2,3,4,4-pentachloro-1:3-butadienyl)-l-cysteine. Moreover, two oxidative pathways involving cysteine S-conjugates (mediated by flavin-containing monooxigenase 3) and N-acetyl-l-cysteine conjugates (mediated by cytochrome P-450 3A) form derived sulfoxides, which represent alternative metabolites with toxic effects. In vitro and in vivo studies showed that sulfoxide metabolites are more toxic than cysteine-conjugate derivates. The cytochrome P-450 3A family, on the other hand, is sex specific, and its expression has only been reported in adult male rats and rabbits. In summary, haloalkenes are highly nephrotoxic in vivo and in vitro and their toxicity mechanisms are well documented experimentally. However, little information is available on their toxicity in humans, except for the carcinogenic effects established for high exposure levels of trichloroethylene and tetrachloroethylene. © 2015, Springer Science+Business Media Dordrecht.

Merelli I.,CNR Institute of Biomedical Technologies | Calabria A.,San Raffaele Telethon Institute for Gene Therapy HSR TIGET | Cozzi P.,CNR Institute of Biomedical Technologies | Viti F.,CNR Institute of Biomedical Technologies | And 2 more authors.
BMC Bioinformatics | Year: 2013

Background: The capability of correlating specific genotypes with human diseases is a complex issue in spite of all advantages arisen from high-throughput technologies, such as Genome Wide Association Studies (GWAS). New tools for genetic variants interpretation and for Single Nucleotide Polymorphisms (SNPs) prioritization are actually needed. Given a list of the most relevant SNPs statistically associated to a specific pathology as result of a genotype study, a critical issue is the identification of genes that are effectively related to the disease by re-scoring the importance of the identified genetic variations. Vice versa, given a list of genes, it can be of great importance to predict which SNPs can be involved in the onset of a particular disease, in order to focus the research on their effects.Results: We propose a new bioinformatics approach to support biological data mining in the analysis and interpretation of SNPs associated to pathologies. This system can be employed to design custom genotyping chips for disease-oriented studies and to re-score GWAS results. The proposed method relies (1) on the data integration of public resources using a gene-centric database design, (2) on the evaluation of a set of static biomolecular annotations, defined as features, and (3) on the SNP scoring function, which computes SNP scores using parameters and weights set by users. We employed a machine learning classifier to set default feature weights and an ontological annotation layer to enable the enrichment of the input gene set. We implemented our method as a web tool called SNPranker 2.0 (http://www.itb.cnr.it/snpranker), improving our first published release of this system. A user-friendly interface allows the input of a list of genes, SNPs or a biological process, and to customize the features set with relative weights. As result, SNPranker 2.0 returns a list of SNPs, localized within input and ontologically enriched genes, combined with their prioritization scores.Conclusions: Different databases and resources are already available for SNPs annotation, but they do not prioritize or re-score SNPs relying on a-priori biomolecular knowledge. SNPranker 2.0 attempts to fill this gap through a user-friendly integrated web resource. End users, such as researchers in medical genetics and epidemiology, may find in SNPranker 2.0 a new tool for data mining and interpretation able to support SNPs analysis. Possible scenarios are GWAS data re-scoring, SNPs selection for custom genotyping arrays and SNPs/diseases association studies. © 2013 Merelli et al.; licensee BioMed Central Ltd.

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