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Fabio Facchetti

Publications and source records attributed to Fabio Facchetti.

At least 37 records · Page 2Linked to original sources
PubMed2005

European consensus on grading bone marrow fibrosis and assessment of cellularity.

Quantification of characteristic bone marrow biopsy features includes basic parameters such as cellularity and fiber content. These are important to assess the dynamics of disease processes with a significant impact on risk stratification, survival patterns and, especially, therapy-related changes. A panel of experienced European pathologists and a foreign expert evaluated, at a multi-headed microscope, a large number of representative slides of trephine biopsies from patients with myelofibrosis in an attempt to reach a consensus on how to grade cellularity and fibrosis. This included a critical evaluation of previously described scoring systems. During the microscopic analysis and subsequent discussion and voting, the importance of age-dependent decrease in cellularity was recognized. Grading of myelofibrosis was simplified by using four easily reproducible categories including differentiation between reticulin and collagen. A consensus was reached that the density of fibers must be assessed in relation to the hematopoietic tissue. This feature is especially important in order to avoid a false impression of a reduced fiber content in fatty and/or edematous bone marrow samples after treatment. The consensus for measuring myelofibrosis by clear and reproducible guidelines achieved by our group should allow for precise grading during the disease process and after therapy.

Bone Marrow↗
PubMed2004

Adhesion of human T cells to antigen-presenting cells through SIRPbeta2-CD47 interaction costimulates T-cell proliferation.

Signal-regulatory proteins (SIRPs) are transmembrane glycoproteins belonging to the immunoglobulin (Ig) superfamily that are expressed in the immune and central nervous systems. SIRPalpha binds CD47 and inhibits the function of macrophages, dendritic cells, and granulocytes, whereas SIRPbeta1 is an orphan receptor that activates the same cell types. A recently identified third member of the SIRP family, SIRPbeta2, is as yet uncharacterized in terms of expression, specificity, and function. Here, we show that SIRPbeta2 is expressed on T cells and activated natural killer (NK) cells and, like SIRPalpha, binds CD47, mediating cell-cell adhesion. Consequently, engagement of SIRPbeta2 on T cells by CD47 on antigen-presenting cells results in enhanced antigen-specific T-cell proliferation.

CD47 Antigen↗
PubMed2004

Defective dendritic cell migration and activation of adaptive immunity in PI3Kgamma-deficient mice.

Gene-targeted mice were used to evaluate the role of the gamma isoform of phosphoinositide 3-kinase (PI3Kgamma) in dendritic cell (DC) migration and induction of specific T-cell-mediated immune responses. DC obtained from PI3Kgamma-/- mice showed a reduced ability to respond to chemokines in vitro and ex vivo and to travel to draining lymph nodes under inflammatory conditions. PI3Kgamma-/- mice had a selective defect in the number of skin Langerhans cells and in lymph node CD8alpha- DC. Furthermore, PI3Kgamma-/- mice showed a defective capacity to mount contact hypersensitivity and delayed-type hypersensitivity reactions. This defect was directly related to the reduced ability of antigen-loaded DC to migrate from the periphery to draining lymph nodes. Thus, PI3Kgamma plays a nonredundant role in DC trafficking and in the activation of specific immunity. Therefore, PI3Kgamma may be considered a new target to control exaggerated immune reactions.

Animals↗
PubMed2004

TRAIL is expressed in the brain cells of Alzheimer's disease patients.

Tumour-necrosis-factor-related apoptosis-inducing ligand (TRAIL) is a novel cytokine characterized by selective killing activity against tumour cells. We recently found that beta-amyloid-induced apoptosis in a human neuronal cell line was mediated via induction of TRAIL. Here, we show that TRAIL is specifically expressed in the brain of Alzheimer's disease (AD) patients and completely absent in the brain of non-demented patients. TRAIL-like immunoreactivity was localized in AD affected regions, such as cerebral cortex, often in the proximity of Congo-red-positive amyloid plaques. These findings suggest that neurons represent an independent and potential source of TRAIL, suggesting that the latter acts redundantly with other noxious stimuli in neurodegenerative diseases characterized by amyloidosis and neuroinflammation.

Alzheimer Disease↗
PubMed2004

Natural killer lymphoma/leukemia: an uncommon pediatric case with indolent course.

Natural killer (NK) cell lymphomas are rare in the USA and Europe but more common in Asia and Central America although very rare among children. We report a case of Epstein-Barr virus-positive NK lymphoma/leukemia, that showed peculiar features represented by a very long clinical course with a significant interval between the first clinical signs and the diagnosis, detection of neoplastic cells in the peripheral blood but not in the bone marrow, and good response to treatment and clinical outcome.

Antineoplastic Agents, Phytogenic↗
PubMed2004

Nodal and extranodal tumor-forming accumulation of plasmacytoid monocytes/interferon-producing cells associated with myeloid disorders.

Nodal tumor-forming accumulations of plasmacytoid monocytes/interferon-producing cells (PMs/IPCs) have been described in patients with myeloproliferative disorders. Here we report a series of 9 additional cases of such association. The patients were predominantly adult (median, 62 years), males (male/female ratio, 7:2), who presented with chronic myelomonocytic leukemia (4 cases), acute myeloid leukemia (1), acute monocytic leukemia (2), unclassifiable chronic myeloproliferative (1), or myeloproliferative/myelodysplastic disease (1). The prognosis was poor (median survival, 24 months) and related to progression of the underlying myeloid neoplasm. We found that in addition to lymph nodes, PMs/IPCs accumulated to bone marrow (8 cases) and skin (4 cases). Immunohistochemical markers typically expressed by PMs/IPCs (CD68, CLA/HECA452, CD123) were found in all cases and shown useful to identify cells with variations from classic morphology. In addition, PMs/IPCs expressed the interferon-alpha (IFN-alpha) inducible protein MxA, the B-cell oncogene TCL1, and granzyme B. The biologic and clinical significance of the association between PMs/IPCs and myeloid disorders remains not clarified. Using fluorescence in situ hybridization analysis in a case known to harbor monosomy 7 in the myeloid leukemia, we demonstrated that PMs/IPCs share the same chromosomal abnormality, thus indicating that they are clonal, neoplastic in nature, and closely related to the associated myeloid tumor. Recently, a novel CD56+ hematologic neoplasm has been reported and retained to stem from PMs/IPCs. The majority of PMs/IPCs in the present series failed to express CD56, thus indicating that variants of PMs/IPCs neoplasms exist, which might represent parts of a spectrum.

Adult↗
PubMed2004

Intravascular lymphoma: clinical presentation, natural history, management and prognostic factors in a series of 38 cases, with special emphasis on the 'cutaneous variant'.

Despite its recognition as a distinct, extremely rare entity, no large studies of intravascular lymphoma (IVL) have been reported. The clinico-pathological characteristics of 38 human immunodeficiency virus-negative patients with IVL diagnosed in Western countries were reviewed to better delineate clinical presentation, clinical variants, natural history and optimal therapy. The IVL is an aggressive and usually disseminated disease (Ann Arbor stage IV in 68% of cases) that predominantly affects elderly patients (median age 70 years, range: 34-90; male:female ratio 0.9), resulting in poor Eastern Cooperative Oncology Group Performance Status (ECOG-PS >1 in 61%), B symptoms (55%), anaemia (63%) and high serum lactate dehydrogenase level (86%). The brain and skin are the most common sites of disease. In contrast to previous reports, hepatosplenic involvement (26%) and bone marrow infiltration (32%) were found to be common features in IVL, while nodal disease was confirmed as rare (11% of cases). Patients with disease limited to the skin ('cutaneous variant'; 26% of cases) were invariably females with a normal platelet count, and exhibited a significantly better outcome than the remaining patients, which deserves further investigation. Overall survival was usually poor; however, the early use of intensive therapies could improve outcome in young patients with unfavourable features. ECOG-PS >1, 'cutaneous variant', stage I and chemotherapy use were independently associated with improved survival.

Adult↗
PubMed2004

Cytotoxic molecule expression and epithelial cell apoptosis in oral and cutaneous lichen planus.

We evaluated the expression of T cell-restricted intracellular antigen (Tia-1), granzyme B, and perforin by lymphocytes and the degree of epithelial apoptosis in oral and cutaneous lichen planus (LP) in 51 untreated cases, including 27 oral LP (OLP) and 24 cutaneous LP (CLP) cases. The number of total dermal-positive lymphocytes in OLP and CLP was similar, indicating similar activity of the inflammatory process. Intraepithelial Tia-1-positive, perforin-positive, and granzyme B-positive lymphoid cells were more numerous in OLP than in CLP (P < .05). The epithelial cell apoptotic index (AI) was increased significantly in OLP (P < .05), particularly in erosive-atrophic variants. A linear correlation between AI and the mean +/- SEM number of intraepithelial and dermal perforin+ cells (6.85 +/- 2.44 and 27.48 +/- 10.19, respectively), per 10 high-power fields for OLP and for CLP (1.17 +/- 0.88 and 10.42 +/- 5.74, respectively), was found (intraepithelial, r = 0.50; dermal, r = 0.51; P < .01). These data suggest a pivotal role for perforin in triggering epithelial cell apoptosis. The differences of infiltrating cytotoxic cells and related AI observed in OLP and CLP are in keeping with the clinical behaviors that distinguish these LP variants.

Adult↗
PubMed2003

A cell-surface molecule selectively expressed on murine natural interferon-producing cells that blocks secretion of interferon-alpha.

Natural interferon (IFN)-producing cells (IPCs) recognize certain viruses and DNA containing deoxycytidylate-phosphatedeoxyguanylate (CpG) motifs through the toll-like receptor (TLR) 9, resulting in secretion of IFN-alpha, interleukin 12 (IL-12), and proinflammatory chemokines. Human IPCs are found mainly in inflamed lymph nodes, where they are presumably recruited from the blood to activate both innate and adaptive responses to microbial infections. Demonstrating IPC recruitment and function in murine infection models has been difficult because multiple antibodies are required to distinguish IPCs from other immune cells and very few IPCs can be recovered from lymph nodes. Here we describe a monoclonal antibody (mAb) that exclusively detects murine IPCs in all lymphoid organs under both normal and inflammatory conditions. Using this antibody, we demonstrate that IPCs are normally present in the T-cell zone of lymph nodes and spleen and that inoculation of peripheral tissues with inflammatory stimuli triggers recruitment of IPC into sentinel lymph nodes, whether the stimuli are able to directly stimulate IPCs through TLR or not. Remarkably, we show that incubation of IPCs with the antibody in vitro or administration of the antibody in vivo dramatically reduce secretion of IFN-alpha in response to CpG DNA without causing IPC depletion. Thus, the antibody identifies an IPC-specific surface molecule that, when engaged, inhibits IFN-alpha secretion.

Animals↗
PubMed2003

Functional defects of dendritic cells in patients with CD40 deficiency.

We have recently identified 2 patients with a rare autosomal recessive form of hyper IgM disease, known as HIGM3, caused by mutations in the CD40 gene. These patients had opportunistic infections observed on X-linked hyper IgM syndrome (HIGM), suggesting that the CD40-CD40 ligand interaction is important for promoting T-cell-mediated immunity. To evaluate whether innate immunity signals may substitute CD154 for inducing the maturation of dendritic cells (DCs), we analyzed monocyte-derived DCs in these patients. Monocyte-derived DCs of HIGM3 subjects on ex vivo stimulation with tumor necrosis factor-alpha (TNF-alpha) or lipopolysaccharide (LPS) combined with interferon-gamma (IFN-gamma) normally express all the markers of mature DCs, such as CD83 and DC-LAMP. However, cell surface levels of HLA-DR in mature DCs are reduced, as is costimulatory activity of these cells for allogeneic naive T cells. In addition, CD40-deficient DCs secrete lower amounts of interleukin-12 (IL-12) but larger quantities of IL-10 than control subjects. Finally, analysis of circulating plasmacytoid DCs demonstrates a normal percentage of this subset in CD40-deficient cells, but IFN-alpha secretion in response to herpes simplex virus 1 (HSV-1) infection is severely reduced in patients. These observations suggest that the severe impairment of DC maturation may contribute to the defect of T-cell-mediated immunity observed in HIGM3 patients.

CD40 Antigens↗
PubMed2003

Phenotype and genotype of interfollicular large B cells, a subpopulation of lymphocytes often with dendritic morphology.

We describe large B cells, many of which have a stellate or dendritic morphology, found in the interfollicular T-cell-rich areas of human peripheral lymphoid tissue. These B cells probably require CD40/CD40 ligand signaling for their generation and have a unique phenotype and a post-germinal center pattern of immunoglobulin gene mutation. The only comparable B cell is the "asteroid" cell of the thymic medulla. Their anatomic location and pattern of gene mutation suggest that these cells may represent the cell of origin of some human large-cell lymphomas. Studies in experimental animals should help to elucidate the role of these cells in the immune response.

Antigens↗
PubMed2003

TREM-1 (triggering receptor expressed on myeloid cells): a new player in acute inflammatory responses.

TREM-1 (triggering receptor expressed on myeloid cells), a recently discovered receptor of the immunoglobulin superfamily, activates neutrophils and monocytes/macrophages by signaling through the adapter protein DAP12. TREM-1 is the best-characterized member of a growing family of DAP12-associated receptors that regulate the function of myeloid cells in innate and adaptive responses. TREM-1 amplifies Toll-like receptor-initiated responses against microbial challenges and potentiates the secretion of proinflammatory chemokines and cytokines in response to bacterial and fungal infections. Blockade of TREM-1 reduces inflammation and increases survival in animal models of bacterial infections that cause systemic hyperinflammatory syndromes. The TREM-1 ligands are not known. Characterization of TREM-1 natural ligands will further illuminate the mechanisms regulating innate responses against pathogens. Whatever the ligands, targeted activation or blockade of TREM-1 and its ligands may help maximize the efficacy of existing treatments for sepsis.

Animals↗
PubMed2003

Post-transplant Kaposi sarcoma originates from the seeding of donor-derived progenitors.

Kaposi sarcoma (KS) is a vascular tumor that can develop in recipients of solid tissue transplants as a result of either primary infection or reactivation of a gammaherpesvirus, the KS- associated herpesvirus, also known as human herpesvirus-8 (HHV-8). We studied whether HHV-8 and the elusive KS progenitor cells could be transmitted from the donor through the grafts. We used a variety of molecular, cytogenetic, immunohistochemical and immunofluorescence methods to show that the HHV-8-infected neoplastic cells in post-transplant KS from five of eight renal transplant patients harbored either genetic or antigenic markers of their matched donors. These data suggest the use of donor-derived HHV-8-specific T cells for the control of post-transplant KS.

Antigens, CD34↗
PubMed2003

Plasmacytoid dendritic cells prime IFN-gamma-secreting melanoma-specific CD8 lymphocytes and are found in primary melanoma lesions.

Plasmacytoid dendritic cells (PDC) are a small population of leukocytes specialized in the production of type I IFN. It has been shown that PDC have a potent T cell stimulatory capacity in allogeneic mixed lymphocyte reaction, However, their role in initiating primary immune responses remains elusive. We report that blood PDC efficiently prime naive CD8(+) lymphocytes specific for the melan-A(26-35) epitope to become IFN-gamma producing cells in vitro. In addition, we found that CD40L-stimulated PDC induce expression on primed melan-A-specific T cells of cutaneous lymphocyte antigen and L-selectin (CD62L), homing receptors that allow the migration of effector cells to the inflamed skin. Finally, we show that PDC can be found in the peri-tumoral area of most primary cutaneous melanomas in vivo and that type I IFN-containing supernatants derived from PDC increase melanoma cell surface expression of CD95 and MHC class I and class II molecules in vitro. Our results suggest a new immunomodulatory role for tissue infiltrating PDC, which may prime tumor-specific T cell responses and affect tumor growth via soluble factors.

Antigens, Differentiation, T-Lymphocyte↗
PubMed2003

Recruitment of immature plasmacytoid dendritic cells (plasmacytoid monocytes) and myeloid dendritic cells in primary cutaneous melanomas.

The present study has analysed the distribution and phenotype of dendritic cells (DCs) in primary cutaneous melanomas and sentinel lymph nodes by immunohistochemistry. In primary melanomas, an increase of DCs was found in the epidermis and the peritumoural area. Intraepidermal DCs were mostly CD1a(+)/Langerin(+) Langerhans cells. Peritumoural DCs included a large population of DC-SIGN(+)/mannose-receptor(+)/CD1a(-) DCs, a small subset of CD1a(+) DCs, and, remarkably, plasmacytoid monocytes/plasmacytoid DCs (PM/PDCs). The PM/PDCs, most likely recruited by SDF-1 secreted by melanoma cells, produced type I interferon (IFN-I), but the expression of the IFN-alpha inducible protein MxA was extremely variable and very limited in the majority of cases. All DC subsets were predominantly immature. The peritumoural area also contained a minor subset of mature CD1a(+) DCs. However, the small amount of local interleukin (IL)-12 p40 mRNA and the naïve phenotype of 20-50% of peritumoural T-lymphocytes are consistent with poor T-cell stimulation or erroneous recruitment. In sentinel lymph nodes, notable expansion of mature CD1a(+)/Langerin(+) DCs was observed. The paucity of intratumoural DCs and the predominant immature phenotype of peritumoural dermal DCs indicate defective maturation of primary cutaneous melanoma-associated DCs, resulting in lack of T-cell priming. These results may explain why melanoma cells grow despite the presence of infiltrating immune cells.

Aged↗
PubMed2003

NF-kappaB expression in oral and cutaneous lichen planus.

Lichen planus (LP) is a chronic inflammatory disorder involving cutaneous and mucosal surfaces, characterized by a T-cell-mediated immune response against epithelial cells, with persistent accumulation of T lymphocytes and epithelial cell damage. The mechanisms involved in this chronic inflammatory disease are largely unknown. A pivotal role in the pathogenesis of long-lasting inflammatory processes is played by the activation of nuclear factor kappa B (NF-kappaB), a primary transcription factor which upon translocation to the nucleus, binds to promoter regions of different genes encoding immune and pro-inflammatory mediators. Using immunohistochemistry, the present study analysed the expression of NF-kappaB in 25 cases of cutaneous LP (CLP) and 28 cases of oral LP (OLP) and correlated this with the recruitment of cytotoxic T-cells (expressing Tia-1 or perforin) in the inflammatory infiltrate. Nuclear NF-kappaB was expressed on basal and suprabasal keratinocytes in all cases of LP, while normal epithelium was consistently negative; OLP contained significantly higher numbers of NF-kappaB-positive keratinocytes than CLP (means: 89.32 versus 22.6; p<0.05). Furthermore, nuclear NF-kappaB expression by epithelial cells correlated with the amount of cytotoxic cell infiltration (p<0.02). These data suggest that increased NF-kappaB activity may represent the basis of maintenance of the inflammatory response. The differences observed between NF-kappaB expression on epithelial cells in OLP and CLP and their correlation with the degree of cytotoxic inflammatory infiltrate might explain the different clinical courses of the two variants of the disease, since OLP is typically more recalcitrant than CLP. As proposed for other chronic inflammatory disorders associated with increased NF-kappaB activity, the involvement of NF-kappaB in the pathogenesis of LP could be considered for selective therapeutic inhibitory targeting.

Adult↗
PubMed2003

Nodal staging in localized melanoma. The experience of the Brescia Melanoma Unit.

BACKGROUND AND OBJECTIVES: We report our experience with patients affected by cutaneous melanoma undergoing sentinel node (SN) biopsy. METHODS: From November 1997 to October 2000 we performed 128 selective lymphadenectomies (SN biopsy) on 127 patients with cutaneous melanoma with Breslow thickness>1 mm or regression or ulceration. Age, sex, tumour location ad histology were recorded. RESULTS: Two hundred and thirty eight SNs were identified by lymphoscintigraphy in 167 lymphatic stations, 236 of them were identified intraoperatively using a gamma probe and patent blue V injection. Twenty-one patients had SNs with melanoma metastases (15.8%), 12 patients in the groin, eight patients in the axilla and one patient in the neck. After therapeutic lymphadenectomy eight more lymph nodes with metastases of melanoma were found in the specimens of three patients. After a follow-up ranging from 10 to 56 months the results are that 111 patients are free of disease. Ten patients died. Three patients have visceral metastases and are alive. One patient has developed two more melanomas. One patient was lost to follow-up. CONCLUSIONS: Our data confirm the clinical reliability of the SN technique in melanoma; for optimisation of the therapeutic strategy, this technique might be considered the standard method of nodal staging in the evaluation of melanoma patients.

Adolescent↗