Karel Otero

Biogen Idec, Уэстон, Massachusetts, United States

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Publications (26)223.14 Total impact

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    ABSTRACT: Type I interferons (IFN-I) are implicated in the pathogenesis of systemic lupus erythematosus (SLE). In SLE, immune complexes bind to the CD32a (FcγRIIa) receptor on the surface of plasmacytoid dendritic cells (pDCs) and stimulate the secretion of IFN-I from pDCs. BDCA2 is a pDC-specific receptor that, when engaged, inhibits the production of IFN-I in human pDCs. BDCA2 engagement, therefore, represents an attractive therapeutic target for inhibiting pDC-derived IFN-I and may be an effective therapy for the treatment of SLE. In this study, we show that 24F4A, a humanized monoclonal antibody (mAb) against BDCA2, engages BDCA2 and leads to its internalization and the consequent inhibition of TLR-induced IFN-I by pDCs in vitro using blood from both healthy and SLE donors. These effects were confirmed in vivo using a single injection of 24F4A in cynomolgus monkeys. 24F4A also inhibited pDC activation by SLE-associated immune complexes (IC). In addition to the inhibitory effect of 24F4A through engagement of BDCA2, the Fc region of 24F4A was critical for potent inhibition of IC-induced IFN-I production through internalization of CD32a. This study highlights the novel therapeutic potential of an effector-competent anti-BDCA2 mAb that demonstrates a dual mechanism to dampen pDC responses for enhanced clinical efficacy in SLE. © 2015 Biogen Idec. Published under the terms of the CC BY 4.0 license.
    EMBO Molecular Medicine 03/2015; 7(4). DOI:10.15252/emmm.201404719 · 8.25 Impact Factor
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    ABSTRACT: Microglia are phagocytic cells that survey the brain and perform neuroprotective functions in response to tissue damage, but their activating receptors are largely unknown. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immunoreceptor whose loss-of-function mutations in humans cause presenile dementia, while genetic variants are associated with increased risk of neurodegenerative diseases. In myeloid cells, TREM2 has been involved in the regulation of phagocytosis, cell proliferation and inflammatory responses in vitro. However, it is unknown how TREM2 contributes to microglia function in vivo. Here, we identify a critical role for TREM2 in the activation and function of microglia during cuprizone (CPZ)-induced demyelination. TREM2-deficient (TREM2(-/-)) mice had defective clearance of myelin debris and more axonal pathology, resulting in impaired clinical performances compared to wild-type (WT) mice. TREM2(-/-) microglia proliferated less in areas of demyelination and were less activated, displaying a more resting morphology and decreased expression of the activation markers MHC II and inducible nitric oxide synthase as compared to WT. Mechanistically, gene expression and ultrastructural analysis of microglia suggested a defect in myelin degradation and phagosome processing during CPZ intoxication in TREM2(-/-) microglia. These findings place TREM2 as a key regulator of microglia activation in vivo in response to tissue damage.
    Acta Neuropathologica 01/2015; 129(3). DOI:10.1007/s00401-015-1388-1 · 10.76 Impact Factor
  • Journal of Neuroimmunology 10/2014; 275(1-2):106. DOI:10.1016/j.jneuroim.2014.08.284 · 2.79 Impact Factor
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    ABSTRACT: Plasmacytoid dendritic cells (pDCs) are a dendritic cell subset that secrete type I IFNs in response to microbial stimuli. The scaffold protein, CD2-associated protein (CD2AP), is a marker of human pDCs as it is highly expressed in this cell type. Recently, in human pDCs, decreased CD2AP expression appeared to enhance the production of type I IFNs via an inhibitory receptor-induced signaling cascade. In this study, we sought to determine the role of CD2AP in murine pDCs using CD2AP knockout (KO) mice. CD2AP was dispensable for the development of pDCs and for the upregulation of activation markers following stimulation. Loss of CD2AP expression did not affect the production of type I IFNs stimulated by TLR ligation, and only slightly impaired type I IFN production when inhibitory pathways were engaged in vitro. This was also confirmed by showing that CD2AP deficiency did not influence type I IFN production by pDCs in vivo. Because CD2AP plays a role in regulating actin dynamics, we examined the actin cytoskeleton in pDCs and found that activated CD2AP KO pDCs had significantly higher levels of actin polymerization than wild-type pDCs. Using two different inflammation models, we found that CD2AP KO pDCs have a defect in lymph node migration, correlating with the defects in actin dynamics. Our work excludes a role for CD2AP in the regulation of type I IFNs in pDCs, and suggests that the major function of CD2AP is on the actin cytoskeleton, affecting migration to local lymph nodes under conditions of inflammation.
    The Journal of Immunology 11/2013; 191(12). DOI:10.4049/jimmunol.1300454 · 5.36 Impact Factor
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    ABSTRACT: Efferocytosis of apoptotic neutrophils by macrophages following tissue injury is fundamental to the resolution of inflammation and initiation of tissue repair. Using a sterile peritonitis model in mice, we identified IL-4-producing efferocytosing macrophages in the peritoneum that activate invariant NKT cells that produce cytokines including IL-4, IL-13, and IFNγ. Importantly, IL-4 from macrophages contributes to alternative activation of peritoneal exudate macrophages and augments type 2 cytokine production from NKT cells to suppress inflammation. The increased peritonitis in mice deficient in IL-4, NKT cells, or IL-4Rα expression on myeloid cells suggested that each is a key component for resolution of sterile inflammation. The NADPH oxidase is also critical for this model, since in mice with X-linked chronic granulomatous disease (X-CGD) that lack oxidase subunits, activation of iNKT cells by X-CGD peritoneal exudate macrophages was impaired during sterile peritonitis, resulting in enhanced and prolonged inflammation in these mice. Therefore, efferocytosis-induced IL-4 production and activation of IL-4-producing iNKT cells by macrophages are immunomodulatory events in an innate immune circuit required to resolve sterile inflammation and promote tissue repair.
    Blood 02/2013; 121(17). DOI:10.1182/blood-2012-10-461913 · 10.43 Impact Factor
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    ABSTRACT: Acute respiratory infections are responsible for more than 4 million deaths each year. Neutrophils play an essential role in the innate immune response to lung infection. These cells have an armamentarium of pattern recognition molecules and antimicrobial agents that identify and eliminate pathogens. In the setting of infection, neutrophil triggering receptor expressed on myeloid cells 1 (TREM-1) amplifies inflammatory signaling. Here we demonstrate for the first time that TREM-1 also plays an important role in transepithelial migration of neutrophils into the airspace. We developed a TREM-1/3-deficient mouse model of pneumonia and found that absence of TREM-1/3 markedly increased mortality following Pseudomonas aeruginosa challenge. Unexpectedly, TREM-1/3 deficiency resulted in increased local and systemic cytokine production. TREM-1/3-deficient neutrophils demonstrated intact bacterial killing, phagocytosis, and chemotaxis; however, histologic examination of TREM-1/3-deficient lungs revealed decreased neutrophil infiltration of the airways. TREM-1/3-deficient neutrophils effectively migrated across primary endothelial cell monolayers but failed to migrate across primary airway epithelia grown at the air-liquid interface. These data define a new function for TREM-1 in neutrophil migration across airway epithelial cells and suggest that it amplifies inflammation through targeted neutrophil migration into the lung.
    The Journal of clinical investigation 12/2012; 123(1). DOI:10.1172/JCI64181 · 13.77 Impact Factor
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    ABSTRACT: To determine talin1's role in osteoclasts, we mated TLN1(fl/fl) mice with those expressing cathepsin K-Cre (CtsK-TLN1) to delete the gene in mature osteoclasts, or with lysozyme M-Cre (LysM-TLN1) mice to delete TLN1 in all osteoclast lineage cells. Absence of TLN1 impairs M-CSF-stimulated inside-out integrin activation and cytoskeleton organization in mature osteoclasts. Talin1-deficient precursors normally express osteoclast differentiation markers when exposed to M-CSF and RANK ligand, but attach to substrate and migrate poorly, arresting their development into mature resorptive cells. In keeping with inhibited resorption, CtsK-TLN1 mice exhibit an ∼5 fold increase in bone mass. Osteoclast-specific deletion of Rap1 (CtsK-Rap1), which promotes talin/β integrin recognition, yields similar osteopetrotic mice. The fact that the osteopetrosis of CtsK-TLN1 and CtsK-Rap1 mice is substantially more severe than that of those lacking αvβ3 is likely due to added failed activation of β1 integrins. In keeping with osteoclast dysfunction, mice in whom talin is deleted late in the course of osteoclastogenesis are substantially protected from ovariectomy-induced osteoporosis and the periarticular osteolysis attending inflammatory arthritis. Thus, talin1 and Rap1 are critical for resorptive function and their selective inhibition, in mature osteoclasts, retards pathological bone loss.
    Molecular and Cellular Biology 12/2012; 33(4). DOI:10.1128/MCB.00790-12 · 5.04 Impact Factor
  • The Journal of Immunology 06/2012; 188(11):5802-5802. DOI:10.4049/jimmunol.1290014 · 5.36 Impact Factor
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    ABSTRACT: TREM2 is an immunoreceptor expressed on osteoclasts (OC) and microglia that transmits intracellular signals through the adaptor DAP12. Individuals with genetic mutations inactivating TREM2 or DAP12 develop the Nasu-Hakola disease (NHD) with cystic-like lesions of the bone and brain demyelination that lead to fractures and presenile dementia. The mechanisms of this disease are poorly understood. In this study, we report that TREM2-deficient mice have an osteopenic phenotype reminiscent of NHD. In vitro, lack of TREM2 impairs proliferation and β-catenin activation in osteoclast precursors (OcP) in response to M-CSF. This defect results in accelerated differentiation of OcP into mature OC. Corroborating the importance of a balanced proliferation and differentiation of OcP for bone homeostasis, we show that conditional deletion of β-catenin in OcP also results in reduced OcP proliferation and accelerated osteoclastogenesis in vitro as well as osteopenia in vivo. These results reveal that TREM2 regulates the rate of osteoclastogenesis and provide a mechanism for the bone pathology in NHD.
    The Journal of Immunology 03/2012; 188(6):2612-21. DOI:10.4049/jimmunol.1102836 · 5.36 Impact Factor
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    ABSTRACT: Viral infections have been linked to the onset of type I diabetes (T1D), with viruses postulated to induce disease directly by causing β cell injury and subsequent release of autoantigens and indirectly via the host type I interferon (IFN-I) response triggered by the virus. Consistent with this, resistance to T1D is associated with polymorphisms that impair the function of melanoma differentiation associated gene-5 (MDA5), a sensor of viral RNA that elicits IFN-I responses. In animal models, triggering of another viral sensor, TLR3, has been implicated in diabetes. Here, we found that MDA5 and TLR3 are both required to prevent diabetes in mice infected with encephalomyocarditis virus strain D (EMCV-D), which has tropism for the insulin-producing β cells of the pancreas. Infection of Tlr3-/- mice caused diabetes due to impaired IFN-I responses and virus-induced β cell damage rather than T cell-mediated autoimmunity. Mice lacking just 1 copy of Mda5 developed transient hyperglycemia when infected with EMCV-D, whereas homozygous Mda5-/- mice developed severe cardiac pathology. TLR3 and MDA5 controlled EMCV-D infection and diabetes by acting in hematopoietic and stromal cells, respectively, inducing IFN-I responses at kinetically distinct time points. We therefore conclude that optimal functioning of viral sensors and prompt IFN-I responses are required to prevent diabetes when caused by a virus that infects and damages the β cells of the pancreas.
    The Journal of clinical investigation 03/2011; 121(4):1497-507. DOI:10.1172/JCI44005 · 13.77 Impact Factor
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    ABSTRACT: Chemokine CC motif receptor-like 2 (CCRL2) is a heptahelic transmembrane receptor that shows the highest degree of homology with CCR1, an inflammatory chemokine receptor. CCRL2 mRNA was rapidly (30 minutes) and transiently (2-4 hours) regulated during dendritic cell (DC) maturation. Protein expression paralleled RNA regulation. In vivo, CCRL2 was expressed by activated DC and macrophages, but not by eosinophils and T cells. CCRL2(-/-) mice showed normal recruitment of circulating DC into the lung, but a defective trafficking of antigen-loaded lung DC to mediastinal lymph nodes. This defect was associated to a reduction in lymph node cellularity and reduced priming of T helper cell 2 response. CCRL2(-/-) mice were protected in a model of ovalbumin-induced airway inflammation, with reduced leukocyte recruitment in the BAL (eosinophils and mononuclear cells) and reduced production of the T helper cell 2 cytokines, interleukin-4 and -5, and chemokines CCL11 and CCL17. The central role of CCRL2 deficiency in DC was supported by the fact that adoptive transfer of CCRL2(-/-) antigen-loaded DC in wild-type animals recapitulated the phenotype observed in knockout mice. These data show a nonredundant role of CCRL2 in lung DC trafficking and propose a role for this receptor in the control of excessive airway inflammatory responses.
    Blood 10/2010; 116(16):2942-9. DOI:10.1182/blood-2009-12-259903 · 10.43 Impact Factor
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    Marina Cella · Karel Otero · Marco Colonna
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    ABSTRACT: Natural killer-22 (NK-22) cells are a human NK cell subset situated in mucosal-associated lymphoid tissues that specialize in IL-22 secretion in response to IL-23. Here we investigated the cytokine requirements for NK-22 cell expansion. IL-7 maintained the survival of NK-22 cells and IL-22 production in response to IL-23 but was insufficient to induce robust expansion. Proliferation of NK-22 cells was increased markedly by adding either IL-1beta or IL-2 to IL-7 and was even stronger in the presence of IL-1beta plus IL-2. In contrast to IL-7, continuous culture in IL-1beta and IL-2 modified NK-22 cytokine profiles. IL-1beta promoted constitutive IL-22 secretion rather than acute IL-22 production in response to IL-23 and induced IL-17 in some cells. IL-2 reduced secretion of IL-22 and IL-17, increasing production of IFN-gamma and leukemia inhibitory factor. Functional deviation toward IFN-gamma production also was induced by continuous culture in IL-23. These results demonstrate the functional plasticity of NK-22 cells, which may allow flexible responses to different pathogens. Finally, we found that NK-22 cells released the B-cell survival factor, B-cell activating factor belonging to the TNF family (BAFF), suggesting a potential role of NK-22 cells in promoting B-cell-mediated mucosal immunity.
    Proceedings of the National Academy of Sciences 06/2010; 107(24):10961-6. DOI:10.1073/pnas.1005641107 · 9.81 Impact Factor
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    ABSTRACT: Macrophage colony-stimulating factor (M-CSF) influences the proliferation and survival of mononuclear phagocytes through the receptor CSF-1R. The adaptor protein DAP12 is critical for the function of mononuclear phagocytes. DAP12-mutant mice and humans have defects in osteoclasts and microglia, as well as brain and bone abnormalities. Here we show DAP12 deficiency impaired the M-CSF-induced proliferation and survival of macrophages in vitro. DAP12-deficient mice had fewer microglia in defined central nervous system areas, and DAP12-deficient progenitors regenerated myeloid cells inefficiently after bone marrow transplantation. Signaling by M-CSF through CSF-1R induced the stabilization and nuclear translocation of beta-catenin, which activated genes involved in the cell cycle. DAP12 was essential for phosphorylation and nuclear accumulation of beta-catenin. Our results provide a mechanistic explanation for the many defects of DAP12-deficient mononuclear phagocytes.
    Nature Immunology 08/2009; 10(7):734-43. DOI:10.1038/ni.1744 · 24.97 Impact Factor
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    ABSTRACT: Natural killer (NK) cells are classically viewed as lymphocytes that provide innate surveillance against virally infected cells and tumour cells through the release of cytolytic mediators and interferon (IFN)-gamma. In humans, blood CD56(dim) NK cells specialize in the lysis of cell targets. In the lymph nodes, CD56(bright) NK cells secrete IFN-gamma cooperating with dendritic cells and T cells in the generation of adaptive responses. Here we report the characterization of a human NK cell subset located in mucosa-associated lymphoid tissues, such as tonsils and Peyer's patches, which is hard-wired to secrete interleukin (IL)-22, IL-26 and leukaemia inhibitory factor. These NK cells, which we refer to as NK-22 cells, are triggered by acute exposure to IL-23. In vitro, NK-22-secreted cytokines stimulate epithelial cells to secrete IL-10, proliferate and express a variety of mitogenic and anti-apoptotic molecules. NK-22 cells are also found in mouse mucosa-associated lymphoid tissues and appear in the small intestine lamina propria during bacterial infection, suggesting that NK-22 cells provide an innate source of IL-22 that may help constrain inflammation and protect mucosal sites.
    Nature 12/2008; 457(7230):722-5. DOI:10.1038/nature07537 · 42.35 Impact Factor
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    ABSTRACT: Dendritic cells (DC) are professional antigen presenting cells which play a pivotal role in the activation of adaptive immunity. Tissue invasion by pathogens induces the recruitment of blood DC to the site of infection and contributes to their subsequent migration to secondary lymphoid organs. This complex process relies on the expression and regulation of receptors for chemotactic factors on the surface of migrating DC and on the activation of adhesion molecules which allow DC to properly interact with both blood and lymphatic vessels. In the absence of correct tissue localization, DC fail to promote proper immune responses. Therefore, the interaction of DC with endothelial cells represents a fundamental step for DC biology.
    Thrombosis and Haemostasis 02/2006; 95(1):22-8. DOI:10.1160/TH05-10-0974 · 5.76 Impact Factor
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    ABSTRACT: DC are professional APC. To accomplish their biological functions, they need to go through a complex pattern of migration, which includes their localization to both peripheral non-lymphoid tissues and secondary lymphoid organs. In the absence of correct tissue localization, DC fail to promote proper immune responses. DC trafficking includes the interaction with both blood and lymphatic endothelium and the response to chemotactic signals. In the past few years many chemokines have been reported to regulate DC migration in vitro and in vivo; however, more recent findings strongly support the role of a considerable array of non-chemokine chemotactic signals and adhesion molecules in this complex process. A better understanding of the signals involved in the migration of DC subsets in vivo constitutes a valuable basis for the development of new strategies for the control of DC migration and function under pathological conditions.
    12/2005: pages 71-93;
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    ABSTRACT: Although blood monocytes possess significant cytotoxic activity against tumor cells, tumor-infiltrating monocytes are commonly deactivated in cancer patients. Monocytes pre-exposed to tumor cells show significantly decreased expression levels of TNF-α, IL-12p40, and IL-1R-associated kinase (IRAK)-1. Activation of the Ser/Thr kinase IRAK-1 is an important event in several inflammatory processes. By contrast, another IRAK family member, IRAK-M, negatively regulates this pathway, and is up-regulated in cultures of endotoxin-tolerant monocytes and in monocytes from septic patients within the timeframe of tolerance. In this study, we show that IRAK-M expression is enhanced at the mRNA and protein level in human monocytes cultured in the presence of tumor cells. IRAK-M was induced in monocytes upon coculturing with different tumor cells, as well as by fixed tumor cells and medium supplemented with the supernatant from tumor cell cultures. Moreover, blood monocytes from patients with chronic myeloid leukemia and patients with metastasis also overexpressed IRAK-M. Low concentrations of hyaluronan, a cell surface glycosaminoglycan released by tumor cells, also up-regulated IRAK-M. The induction of IRAK-M by hyaluronan and tumor cells was abolished by incubation with anti-CD44 or anti-TLR4 blocking Abs. Furthermore, down-regulation of IRAK-M expression by small interfering RNAs specific for IRAK-M reinstates both TNF-α mRNA expression and protein production in human monocytes re-exposed to a tumor cell line. Altogether, our findings indicate that deactivation of human monocytes in the presence of tumor cells involves IRAK-M up-regulation, and this effect appears to be mediated by hyaluronan through the engagement of CD44 and TLR4.
    The Journal of Immunology 03/2005; 174(5):3032-3040. · 5.36 Impact Factor
  • The Journal of Immunology 02/2005; 174(5):3032-3040. DOI:10.4049/jimmunol.174.5.3032 · 5.36 Impact Factor
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    ABSTRACT: CCL16 is a CC chemokine originally identified as a liver-expressed chemokine. Its expression has been detected in activated monocytes where it is up-regulated by stimulation with IL-10. This is in contrast with IL-10's inhibition of the expression of most chemokines. CCL16 is chemotactic for monocytes, lymphocyte and dendritic cells. We investigated whether CCL16 displays biological activities other than chemotaxis and whether IL-10 affects monocyte response to CCL16. We show that CCL16 induces the expression of CCL2 at the mRNA and protein level, but does not affect that of CCL5, CCL18 and proinflammatory cytokines. This effect was prevented by treatment with pertussis toxin and may thus be mediated by G-protein-coupled receptors. IL-10 markedly increased CCL2 production induced by CCL16, but suppressed that of CXCL8. It also enhanced the chemotactic response to CCL16. Addition of antibodies blocking CCR1, but not CCR8, prevented this enhanced chemotactic response and suggested that CCR1 is primarily involved. We propose that IL-10 modulates the effects of CCL16 on monocytes by increasing their CCR1-dependent response. The coordinated secretion of CCL16 and IL-10 may thus enhance monocyte infiltration.
    International journal of immunopathology and pharmacology 01/2005; 18(2):339-49. · 2.51 Impact Factor
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    ABSTRACT: Summary Pentraxin 3 (PTX3), the first long pentraxin identified, is characterized by a C‐terminal pentraxin like domain, showing sequence similarity to C‐reactive protein and serum amyloid P component, coupled with a N‐terminal unrelated portion. PTX3 is made by diverse cell types, including endothelial cells, macrophages and dendritic cells, in response to proinflammatory signals such as interleukin 1, tumor necrosis factor and lipopolysaccharide. It binds different ligands, including Clq, apoptotic cells and microbial mojcties. PTX3 levels are Keywords: autoimmune disorders; fertility; inflammation; innate immunity; pattern recognition receptors; pentraxins Document Type: Research Article DOI: http://dx.doi.org/10.1111/j.1472-9725.2004.00048.x Affiliations: Istituto di Ricerche Farmacologiche Mario Negri, Milan and Publication date: December 1, 2004 $(document).ready(function() { var shortdescription = $(".originaldescription").text().replace(/\\&/g, '&').replace(/\\, '<').replace(/\\>/g, '>').replace(/\\t/g, ' ').replace(/\\n/g, ''); if (shortdescription.length > 350){ shortdescription = "" + shortdescription.substring(0,250) + "... more"; } $(".descriptionitem").prepend(shortdescription); $(".shortdescription a").click(function() { $(".shortdescription").hide(); $(".originaldescription").slideDown(); return false; }); }); Related content In this: publication By this: publisher In this Subject: Microbiology , Allergy & Immunology By this author: Mantovani, A. ; Garlanda, C. ; Otero, K. ; Peri, G. ; Vecchi, A. ; Bottazzi, B. GA_googleFillSlot("Horizontal_banner_bottom");
    Clinical &amp Experimental Allergy Reviews 12/2004; 4(s2). DOI:10.1111/j.1472-9725.2004.00048.x

Publication Stats

1k Citations
223.14 Total Impact Points

Institutions

  • 2015
    • Biogen Idec
      Уэстон, Massachusetts, United States
  • 2010–2013
    • Washington University in St. Louis
      • • Department of Pediatrics
      • • Department of Pathology and Immunology
      San Luis, Missouri, United States
  • 2005–2010
    • Istituto Clinico Humanitas IRCCS
      • Department of Immunology and Inflammation
      Rozzano, Lombardy, Italy
  • 2001–2005
    • Mario Negri Institute for Pharmacological Research
      Milano, Lombardy, Italy
  • 2004
    • Università degli Studi di Brescia
      • "Istituto Angelo Nocivelli” Centre for Research into Molecular Medicine
      Brescia, Lombardy, Italy