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14 results on '"Poliani P.L."'

4. Hypomorphic Rag1mutations alter the preimmune repertoire at early stages of lymphoid development

Author

Ott de Bruin, L.M., Bosticardo, M., Barbieri, A., Lin, S.G., Rowe, J.H., Poliani, P.L., Ching, K., Eriksson, D., Landegren, N., Kämpe, O., Manis, J.P., and Notarangelo, L.D.

Abstract

Hypomorphic RAG1mutations allowing residual T- and B-cell development have been found in patients presenting with delayed-onset combined immune deficiency with granulomas and/or autoimmunity (CID-G/AI) and abnormalities of the peripheral T- and B-cell repertoire. To examine how hypomorphic Rag1mutations affect the earliest stages of lymphocyte development, we used CRISPR/Cas9 to generate mouse models with mutations equivalent to those found in patients with CID-G/AI. Immunological characterization showed partial development of T and B lymphocytes, with persistence of naïve cells and preserved serum immunoglobulin but impaired antibody responses and presence of autoantibodies, thereby recapitulating the phenotype seen in patients with CID-G/AI. By using high-throughput sequencing, we identified marked skewing of Igh Vand Trb Vgene usage in early progenitors, with a bias for productive Ighand Trbrearrangements after selection occurred and increased apoptosis of B-cell progenitors. Rearrangement at the Igklocus was impaired, and polyreactive immunoglobulin M antibodies were detected. This study provides novel insights into how hypomorphic Rag1mutations alter the primary repertoire of T and B cells, setting the stage for immune dysregulation frequently seen in patients.

Published
2018
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5. Correction of murine rag2 severe combined immunodeficiency by lentiviral gene therapy using a codon-optimized RAG2 therapeutic transgene

Author

Til, N.P. (Niek) van, Boer, H. (Helen) de, Mashamba, N. (Nomusa), Wabik, A. (Agnieszka), Huston, M.W. (Marshall W.), Visser, T.P. (Trudi), Fontana, R.J. (Robert), Poliani, P.L. (Pietro), Cassani, B. (Barbara), Zhang, F. (Fang), Thrasher, A.J. (Adrian), Villa, A. (Anna), Wagemaker, G. (Gerard), Til, N.P. (Niek) van, Boer, H. (Helen) de, Mashamba, N. (Nomusa), Wabik, A. (Agnieszka), Huston, M.W. (Marshall W.), Visser, T.P. (Trudi), Fontana, R.J. (Robert), Poliani, P.L. (Pietro), Cassani, B. (Barbara), Zhang, F. (Fang), Thrasher, A.J. (Adrian), Villa, A. (Anna), and Wagemaker, G. (Gerard)

Abstract

Recombination activating gene 2 (RAG2) deficiency results in severe combined immunodeficiency (SCID) with complete lack of T and B lymphocytes. Initial gammaretroviral gene therapy trials for other types of SCID proved effective, but also revealed the necessity of safe vector design. We report the development of lentiviral vectors with the spleen focus forming virus (SF) promoter driving codon-optimized human RAG2 (RAG2co), which improved phenotype amelioration compared to native RAG2 in Rag2-/- mice. With the RAG2co therapeutic transgene, T-cell receptor (TCR) and immunoglobulin repertoire, T-cell mitogen responses, plasma immunoglobulin levels and T-cell dependent and independent specific antibody responses were restored. However, the thymus double positive T-cell population remained subnormal, possibly due to the SF virus derived element being sensitive to methylation/silencing in the thymus, which was prevented by replacing the SF promoter by the previously reported silencing resistant element (ubiquitous chromatin opening element (UCOE)), and also improved B-cell reconstitution to eventually near normal levels. Weak cellular promoters were effective in T-cell reconstitution, but deficient in B-cell reconstitution. We conclude that immune functions are corrected in Rag2-/- mice by genetic modification of stem cells using the UCOE driven codon-optimized RAG2, providing a valid optional vector for clinical implementation.

Published
2012
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6. Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome

Author

Cassani, B. (Barbara), Poliani, P.L. (Pietro), Marella, V. (Veronica), Schena, F. (Fransesca), Sauer, A.V. (Aisha), Ravanini, M. (Maria), Strina, D. (Dario), Busse, C.E. (Christian), Regenass, S. (Stephan), Wardemann, H. (Hedda), Martini, A. (Alberto), Facchetti, F. (Fabio), Burg, M. (Mirjam) van der, Rolink, A.G. (Antonius), Vezzoni, P. (Paolo), Grassi, F. (Fabio), Traggiai, E. (Elisabetta), Villa, A. (Anna), Cassani, B. (Barbara), Poliani, P.L. (Pietro), Marella, V. (Veronica), Schena, F. (Fransesca), Sauer, A.V. (Aisha), Ravanini, M. (Maria), Strina, D. (Dario), Busse, C.E. (Christian), Regenass, S. (Stephan), Wardemann, H. (Hedda), Martini, A. (Alberto), Facchetti, F. (Fabio), Burg, M. (Mirjam) van der, Rolink, A.G. (Antonius), Vezzoni, P. (Paolo), Grassi, F. (Fabio), Traggiai, E. (Elisabetta), and Villa, A. (Anna)

Abstract

Hypomorphic RAG mutations, leading to limited V(D)J rearrangements, cause Omenn syndrome (OS), a peculiar severe combined immunodeficiency associated with autoimmune-like manifestations. Whether B cells play a role in OS pathogenesis is so far unexplored. Here we report the detection of plasma cells in lymphoid organs of OS patients, in which circulating B cells are undetectable. Hypomorphic Rag2R229Q knock-in mice, which recapitulate OS, revealed, beyond severe B cell developmental arrest, a normal or even enlarged compartment of immunoglobulin-secreting cells (ISC). The size of this ISC compartment correlated with increased expression of Blimp1 and Xbp1, and these ISC were sustained by elevated levels of T cell derived homeostatic and effector cytokines. The detection of high affinity pathogenic autoantibodies toward target organs indicated defaults in B cell selection and tolerance induction. We hypothesize that impaired B cell receptor (BCR) editing and a serum B cell activating factor (BAFF) abundance might contribute toward the development of a pathogenic B cell repertoire in hypomorphic Rag2R229Q knock-in mice. BAFF-R blockade reduced serum levels of nucleic acid-specific autoantibodies and significantly ameliorated inflammatory tissue damage. These findings highlight a role for B cells in OS pathogenesis.

Published
2010
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10. A gene therapy approach to treat demyelinating diseases using non-replicative herpetic vectors engineered to produce cytokines.

Author

Martino, G., Furlan, R., Galbiati, F., Poliani, P.L., Bergami, A., Grimaldi, L.M.E., Adorini, L., and Comi, G.

Subjects
GENE therapy, MULTIPLE sclerosis, CENTRAL nervous system, DEMYELINATION
Abstract

A successful gene therapy approach in organ-specific autoimmune diseases, such as multiple sclerosis (MS), encompasses the inhibition of the autoreactive T cells or the modification of the target organ cells by the introduction of exogenous ‘protective’ genes. In MS, an autoimmune disease of the central nervous system (CNS), the inciting autoantigen is still unknown and therefore the isolation of autoreactive T cells may only be inferential. At present, gene therapy approaches in MS should therefore aim to the modification of the target organ. Possible candidate genes to be transferred within the CNS of MS patients are those coding for anti-inflammatory cytokines (i.e. interleukin-4, interleukin-10, transforming growth factor β) which have been shown to ameliorate demyelinating diseases at least in experimental models. However, a limiting factor for this therapy is the difficulty to reach the CNS. A gene therapy approach using viral vectors able to infect post-mitotic cells, such as those present within the CNS, without inducing toxic reactions, may overcome this limitation. We propose to use non-replicative herpetic vectors, which represent a viable gene-transfer alternative to the classical retroviral and adenoviral vectors. Key advantages are their size, able to accommodate multiple foreign genes, and their ability to infect post-mitotic cells such as those present within the CNS. We first transferred a gene coding for interleukin-4 within the CNS of mice undergoing experimental allergic encephalomyelitis, an animal model for MS, using non-replicative Herpes Simplex Virus type 1-derived vectors. We found that this approach ameliorates the disease course and delays the disease onset. The establishment of this technique to deliver anti-inflammatory cytokines within the CNS using herpetic vectors should clarify the role of individual cytokines in the demyelinating process and allow assessment of whether gene therapy using herpetic vectors is a feasible and safe approach to treat human demyelinating disorders. [ABSTRACT FROM AUTHOR]

Published
1998
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11. Peripheral levels of caspase-1 mRNA correlate with disease activity in patients with multiple sclerosis; a preliminary study

Author

desina, G., Furlan, R., Bergami, A., Poliani, P.L., Martino, G., Filippi, M., Rocca, M.A., Martinelli, V., Comi, G., and Grimaldi, L.M.E.

Abstract

The cysteine protease caspase-1 plays a crucial part in the inflammatory process due to its ability to proteolitically activate proinflammatory cytokine precursors, such as interleukin (IL)-1β and IL-18. Multiple sclerosis is a chronic inflammatory demyelinating disease of the CNS in which the pathogenic process is mainly orchestrated by proinflammatory cytokines. The role of caspase-1 in multiple sclerosis was evaluated by measuring its mRNA levels in peripheral blood mononuclear cells (PBMCs) from seven patients with relapsing-remitting multiple sclerosis every 15 days over a 1 year period. The recorded levels were compared with clinical and MRI evidence of disease activity. Brain MRI was performed monthly in each patient. Caspase-1 mRNA levels were significantly increased in PBMCs from patients with multiple sclerosis compared with healthy controls (p<0.001). In patients with multiple sclerosis, a twofold to threefold increase of caspase-1 mRNA mean level was found in the week preceding an acute attack (p<0.05). The magnitude of caspase-1 mRNA increase correlated with the number of new (p=0.01) but not persisting gadolinium enhancing brain MRI lesions. In conclusion, caspase-1 might be involved in the immune mediated process underlying CNS inflammation and might represent a suitable peripheral immunological marker of disease activity in multiple sclerosis.

Published
1999

13. High doses of cobalt induce optic and auditory neuropathy

Author

Sarah Duse, Simona Catalani, Raffaele De Caro, Pietro Apostoli, Alessandro Padovani, Valentina Vielmi, Anna Zaghini, Pietro Luigi Poliani, Andrea Porzionato, Maria Cristina Rizzetti, Andrea Mariotti, Francesco Semeraro, Veronica Macchi, Apostoli P., Catalani S., Zaghini A., Mariotti A., Poliani P.L., Vielmi V., Semeraro F., Duse S., Porzionato A., Macchi V., Padovani A., Rizzetti M.C., and De Caro R.

Subjects
Male, Retinal Ganglion Cells, doses of cobalt, optic neuropathy, auditory neuropathy, Auditory neuropathy, Physiology, Toxicology, chemistry.chemical_compound, CHROMIUM, optic and auditory neuropathie, Tissue Distribution, Hearing Loss, Central, Ultrasonography, human prosthesis, Cobalt, Heavy Metal Poisoning, Nervous System, General Medicine, Sciatic Nerve, Cochlea, medicine.anatomical_structure, Toxicity, Optic nerve, Female, Rabbits, inorganic chemicals, medicine.medical_specialty, Retina, Pathology and Forensic Medicine, Chlorides, RABBIT, Chromium Compounds, Hair Cells, Auditory, otorhinolaryngologic diseases, medicine, Animals, Pathological, Spiral ganglion, Dose-Response Relationship, Drug, business.industry, Neurotoxicity, Optic Nerve, Retinal, Cell Biology, medicine.disease, Surgery, Microscopy, Electron, Peripheral neuropathy, chemistry, business
Abstract

The adverse biological effects of continuous exposure to cobalt and chromium have been well defined. In the past, this toxicity was largely an industrial issue concerning workers exposed in occupational setting. Nevertheless, recent reports have described a specific toxicity mediated by the high levels of cobalt and chromium released by metallic prostheses, particularly in patients who had received hip implants. Clinical symptoms, including blindness, deafness and peripheral neuropathy, suggest a specific neurotropism. However, little is known about the neuropathological basis of this process, and experimental evidence is still lacking. We have investigated this issue in an experimental setting using New Zealand White rabbits treated with repeated intravenous injections of cobalt and chromium, alone or in combination. No evident clinical or pathological alterations were associated after chromium administration alone, despite its high levels in blood and tissue while cobalt–chromium and cobalt-treated rabbits showed clinical signs indicative of auditory and optic system toxicity. On histopathological examination, the animals showed severe retinal and cochlear ganglion cell depletion along with optic nerve damage and loss of sensory cochlear hair cells. Interestingly, the severity of the alterations was related to dosages and time of exposure. These data confirmed our previous observation of severe auditory and optic nerve toxicity in patients exposed to an abnormal release of cobalt and chromium from damaged hip prostheses. Moreover, we have identified the major element mediating neurotoxicity to be cobalt, although the molecular mechanisms mediating this toxicity still have to be defined.

Published
2013

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