Pietro Luigi Poliani

University of Brescia

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Co-Authors

Manuela Cominelli

University of Brescia

Rossella Galli

Vita-Salute San Raffaele University

Daniela Corno

Canadian Institutes of Health Research

Letterio S. Politi

Humanitas University

Alessandro Bulfone

Environment Park

Mauro Pala

Institute of Genetic and Biomedical Research

Lucia Sergi Sergi

The San Raffaele Telethon Institute for Gene Therapy

Anna Villa

Institute of Genetic and Biomedical Research

Fabio Facchetti

Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia

Raffaella Melzi

IRCCS Ospedale San Raffaele

Cooperative Institutions

Istituti di Ricovero e Cura a Carattere Scientifico

371

University of Brescia

265

Vita-Salute San Raffaele University

176

Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia

157

University of Milan

134

Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele

129

San Raffaele University of Rome

125

Brescia University

110

IRCCS Ospedale San Raffaele

Harvard University

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Intra-tumoral dendritic cells increase efficacy of peripheral vaccination by modulation of glioma microenvironment

Neuro-Oncology (2010)

Serena Pellegatta Pietro Luigi Poliani Elena Stucchi Daniela Corno Chiara Colombo

Pilot data showed that adding intratumoral (IT) injection of dendritic cells (DCs) prolongs survival of patients affected by glioblastoma multiforme (GBM) treated by subcutaneous (SC) delivery of DCs. Using a murine model resembling GBM, we investigated the immunological mechanisms underlying this effect. C57BL6/N mice received brain injections of GL261 glioma cells. Seven days later, mice were treated by 3 SC injections of DCs with or without 1 IT injection of DCs. DC maturation, induced by pulsing with GL261 lysates, was necessary to develop effective immune responses. IT injection of pulsed (pDC), but not unpulsed DCs (uDC), increased significantly the survival, either per se or in combination with SC-pDC (P < .001 vs controls). Mice treated by IT-pDC plus SC-pDC survived longer than mice treated by SC-pDC only (P = .03). Injected pDC were detectable in tumor parenchyma, but not in cervical lymph nodes. In gliomas injected with IT-pDC, CD8+ cells were significantly more abundant and Foxp3+ cells were significantly less abundant than in other groups. Using real-time polymerase chain reaction, we also found enhanced expression of IFN-γ and TNF-α and decreased expression of transforming growth factor-beta (TGF-β) and Foxp3 in mice treated with SC-pDC and IT-pDC. In vitro, pDC produced more TNF-α than uDC: addition of TNF-α to the medium decreased the proliferation of glioma cells. Overall, the results suggest that IT-pDC potentiates the anti-tumor immune response elicited by SC-pDC by pro-immune modulation of cytokines in the tumor microenvironment, decrease of Treg cells, and direct inhibition of tumor proliferation by TNF-α.

Parenchyma

10.1093/neuonc/nop024

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Citations (43)

Sellar metastasis from clear cell sarcoma: Description of the first case

Clinical Neuropathology (2022)

Francesco Doglietto Linda Daffini Elena Fazzari Manuela Cominelli Francesca Pagani

Metastases to the sellar region and pituitary gland are rare and usually occur in advanced cancers, commonly breast and lung adenocarcinomas. Metastases from sarcomas to the pituitary gland are extremely rare. Here, we report the case of a 52-year-old man who had undergone surgery and radiotherapy for a clear cell sarcoma (CCS) of the knee at age of 42. The patient underwent resection of 2 distinct metastatic lung nodules 9 years later. During follow-up, he developed a persistent headache and diabetes insipidus. MRI revealed a sellar and suprasellar lesion, which was removed with an endoscopic trans-sphenoidal approach. Histopathology was consistent with CSS metastasis. At 2-year follow-up, there was no evidence of local recurrence in the sella, while a single brain metastasis was documented, together with other deposits in the paravertebral and pelvic muscles. CCS is a rare, aggressive neoplasm usually involving the deep soft tissue of the extremities, including trunk or limb girdles, and extensive surgical removal, along with adjuvant chemo- and radiotherapy, significantly prolongs survival. Nevertheless, prognosis remains poor, mainly due to frequent local recurrences and eventually distant metastases, usually within regional lymph nodes, lung, and bone. To the best of our knowledge, this is the first description of a sellar metastasis from CCS.

Histopathology

10.5414/np301448

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Citations (3)

CCRL2 regulates M1/M2 polarization during EAE recovery phase

Journal of Leukocyte Biology (2016)

Cristina Mazzon Lucia Zanotti Li Wang Annalisa Del Prete Elena Fontana

Chemokine (CC motif) receptor-like 2 is a 7-transmembrane protein related to the family of the atypical chemokine receptors, which are proteins devoid of chemotactic activity and involved in the control of inflammation. Experimental autoimmune encephalitis is an autoimmune disorder that replicates the inflammatory aspects of multiple sclerosis. Chemokine (CC motif) receptor-like 2-deficient mice developed exacerbated, nonresolving disease with protracted inflammatory response and increased demyelination. The increased severity of the disease was associated with higher levels of microglia/macrophage activation markers and imbalanced M1/M2 polarization. Thus, chemokine (CC motif) receptor-like 2 is involved in the downregulation of central nervous system-associated experimental autoimmune encephalitis inflammation in the recovery phase of the disease. Therefore chemokine (CC motif) receptor-like 2 should be considered to be a molecule involved in the regulation of the inflammatory response associated with multiple sclerosis.

Autoimmune encephalitis

CCR1

CCR2

10.1189/jlb.3ma0915-444rr

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Citations (38)

Supplementary Figure 6 from Gene Signatures Associated with Mouse Postnatal Hindbrain Neural Stem Cells and Medulloblastoma Cancer Stem Cells Identify Novel Molecular Mediators and Predict Human Medulloblastoma Molecular Classification

Daniela Corno Mauro Pala Manuela Cominelli Barbara Cipelletti Ketty Leto

<p>PDF file - 130K, EBF3 expression can be retrieved in silico in human MBs by exploiting publicly available human data sets</p>

Hindbrain

10.1158/2159-8290.22528860

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Central Nervous System Delivery of Interleukin 4 by a Nonreplicative Herpes Simplex Type 1 Viral Vector Ameliorates Autoimmune Demyelination

Human Gene Therapy (1998)

Roberto Furlan Pietro Luigi Poliani Francesca Galbiati A. Bergami Luigi Maria Grimaldi

Multiple sclerosis (MS) is a T cell-mediated organ-specific inflammatory disease leading to central nervous system (CNS) demyelination. On the basis of results obtained in experimental autoimmune encephalomyelitis (EAE) models, MS treatment by administration of antiinflammatory cytokines such as interleukin 4 (IL-4) is promising but is hampered by the limited access of the cytokines to the CNS and by the pleiotropic effects of systemically administered cytokines. We established a cytokine delivery system within the CNS using nonreplicative herpes simplex type 1 (HSV-1) viral vectors engineered with cytokine genes. These vectors injected into the cisterna magna (i.c.) of mice diffuse in all ventricular and subarachnoid spaces and infect with high efficiency the ependymal and leptomeningeal cell layers surrounding these areas, without obvious toxic effects. Heterologous genes contained in the vectors are efficiently transcribed in infected ependymal cells, leading to the production of high amounts of the coded proteins. For example, 4.5 ng of interferon γ (IFN-γ) per milliliter is secreted into the cerebrospinal fluid (CSF) up to day 28 postinjection (p.i.) and reaches the CNS parenchyma in bioactive form, as demonstrated by upregulation of MHC class I expression on CNS-resident cells. We then exploited the therapeutic potential of the vectors in EAE mice. An HSV-1-derived vector containing the IL-4 gene was injected i.c. in Biozzi AB/H mice at the time of EAE induction. We found the following in treated mice: (1) delayed EAE onset, (2) a significant decrease in clinical score, (3) a significant decrease in perivascular inflammatory infiltrates and in the number of macrophages infiltrating the CNS parenchyma and the submeningeal spaces, and (4) a reduction in demyelinated areas and axonal loss. Peripheral T cells from IL-4-treated mice were not affected either in their antigen-specific proliferative response or in cytokine secretion pattern. Our results indicate that CNS cytokine delivery with HSV-1 vectors is feasible and might represent an approach for the treatment of demyelinating diseases. Advantages of this approach over systemic cytokine administration are the high cytokine level reached in the CNS, the absence of effects on the peripheral immune system, and the long-lasting cytokine production in the CNS after a single vector administration. Gene therapy of organ-specific autoimmune diseases can be approached by delivering heterologous genes encoding immunomodulatory molecules either to the target organ or to the peripheral autoreactive T cells. However, when the autoantigen responsible for the disease is unknown only the former option is available. We established a gene delivery system based on CNS administration of nonreplicative HSV-1-derived vectors engineered with cytokine genes. Gene delivery within the CNS by an HSV-1-derived vector showed itself to be feasible and nontoxic. EAE, an inflammatory demyelinating disease of the CNS mimicking human MS, was ameliorated both at clinical and pathological levels when an HSV-1 vector containing the antiinflammatory cytokine gene IL-4 was injected within the CNS. The efficacy in the inhibition of EAE was relatively long-lasting and did not affect peripheral immune responses.

Cisterna magna

10.1089/hum.1998.9.17-2605

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Citations (85)

Development of Central Nervous System Autoimmunity Is Impaired in the Absence of Wiskott-Aldrich Syndrome Protein

PLoS ONE (2014)

Marita Bosticardo Silvia Musio Elena Fontana Stefano Angiari Elena Draghici

Wiskott-Aldrich Syndrome protein (WASP) is a key regulator of the actin cytoskeleton in hematopoietic cells. Defective expression of WASP leads to multiple abnormalities in different hematopoietic cells. Despite severe impairment of T cell function, WAS patients exhibit a high prevalence of autoimmune disorders. We attempted to induce EAE, an animal model of organ-specific autoimmunity affecting the CNS that mimics human MS, in Was−/− mice. We describe here that Was−/− mice are markedly resistant against EAE, showing lower incidence and milder score, reduced CNS inflammation and demyelination as compared to WT mice. Microglia was only poorly activated in Was−/− mice. Antigen-induced T-cell proliferation, Th-1 and -17 cytokine production and integrin-dependent adhesion were increased in Was−/− mice. However, adoptive transfer of MOG-activated T cells from Was−/− mice in WT mice failed to induce EAE. Was−/− mice were resistant against EAE also when induced by adoptive transfer of MOG-activated T cells from WT mice. Was+/− heterozygous mice developed an intermediate clinical phenotype between WT and Was−/− mice, and they displayed a mixed population of WASP-positive and -negative T cells in the periphery but not in their CNS parenchyma, where the large majority of inflammatory cells expressed WASP. In conclusion, in absence of WASP, T-cell responses against a CNS autoantigen are increased, but the ability of autoreactive T cells to induce CNS autoimmunity is impaired, most probably because of an inefficient T-cell transmigration into the CNS and defective CNS resident microglial function.

Adoptive Cell Transfer

Wiskott–Aldrich syndrome protein

Wiskott–Aldrich syndrome

Peripheral tolerance

10.1371/journal.pone.0086942

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Citations (2)

Dendritic cells pulsed with glioma lysates induce immunity against syngeneic intracranial gliomas and increase survival of tumor-bearing mice

Neurological Research (2006)

Serena Pellegatta Pietro Luigi Poliani Daniela Corno Marina Grisoli Michael D. Cusimano

In recent years, the use of dendritic cells (DC), the most powerful antigen presenting cells, has been proposed for the creation of vaccines against gliomas. This approach has been demonstrated to be safe and non-toxic in phase I or I-II trials (2, 3). Immunotherapy plays a central role in the search for new treatments for glioblastoma multiforme (GBM). In particular, several phase I studies have been performed using DC pulsed by GBM proteins as a vaccine for patients with relapsing GBM. The studies demonstrated that DC vaccination is safe and may produce a significant increase in overall survival. As the first step in the preparation of appropriate conditions for a clinical evaluation in Italy, we have performed pre-clinical experiments on immune-competent mice injected intra-cerebrally with syngeneic GL261GBM cells and treated subcutaneously and intra-tumorally with DC loaded with a GL261 homogenate. These results show that vaccination with DC pulsed with a tumor lysate increases considerably survival in mice bearing intracranial glioblastomas and supports the development of DC-based clinical trials for patients with glioblastomas that do not respond to standard therapies.

10.1179/016164106x116809

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Citations (37)

Cutaneous distribution of plasmacytoid dendritic cells in lupus erythematosus. Selective tropism at the site of epithelial apoptotic damage

Immunobiology (2009)

William Vermi Silvia Lonardi Mauro Morassi Cristina Rossini Regina Tardanico

Plasmacytoid dendritic cell

Pathogenesis

Infiltration (HVAC)

10.1016/j.imbio.2009.06.013

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Citations (135)

Primary Primitive Peripheral Neuroectodermal Tumor of the Prostate

Archives of Pathology & Laboratory Medicine (2003)

Maurizio Colecchia Gian Paolo Dagrada Pietro Luigi Poliani A. Messina Silvana Pilotti

Abstract A case of primitive peripheral neuroectodermal tumor arising in the prostate gland of a 31-year-old man and first diagnosed through a biopsy is reported. Microscopically, the tumor was made up of solid nests and sheets of small round cells, and it was difficult to distinguish the neoplasm from other small round cell tumors, such as small cell carcinoma, rhabdomyosarcoma, or malignant lymphoma. Immunohistochemically, the tumor cells showed immunoreactivity for CD99, vimentin, neuron-specific enolase, and synaptophysin. The neoplasm was excised by a radical surgical procedure preceded by chemotherapy and radiation therapy. The morphologic diagnosis of the prostatectomy specimen was complemented by molecular analysis performed on viable microdissected tissue obtained from formalin-fixed, paraffin-embedded tumor sections. Polymerase chain reaction and sequencing assessment showed the presence of EWS/FLI1 type 2 chimeric transcript, confirming the diagnosis of peripheral primitive neuroectodermal tumor. To our knowledge, this is the first description of a primary peripheral primitive neuroectodermal tumor in the prostate gland.

Primitive neuroectodermal tumor

CD99

Synaptophysin

Neuroectodermal tumor

Neoplasm

10.5858/2003-127-e190-pppnto

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Citations (28)

Homeostatic expansion of autoreactive immunoglobulin-secreting cells in the Rag2 mouse model of Omenn syndrome

The Journal of Experimental Medicine (2010)

Barbara Cassani Pietro Luigi Poliani Veronica Marrella Francesca Schena Aisha V. Sauer

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.

RAG2

Immunoglobulin M

10.1084/jem.20091928

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Citations (65)