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Papers by Andrea Sanchis Gregorio

Rheumatology, 2006

Objectives. Recent laboratory and clinical data suggest that two prototype autoimmune diseases, s... more Objectives. Recent laboratory and clinical data suggest that two prototype autoimmune diseases, systemic lupus erythematosus and rheumatoid arthritis are mainly driven by distinct cytokines, interferon (IFN)-and tumour necrosis factor (TNF)-, respectively. We here investigated the presence and characteristics of natural type I IFN-producing cells (IPCs), as well as IFN-and TNF-expression at sites of inflammation in juvenile idiopathic arthritis (JIA). Methods. Peripheral blood (PB) and synovial fluid (SF) mononuclear cells (MNCs) (n ¼ 25 each) from JIA patients with active disease were studied. IPCs were identified as BCDA-2 þ CD123 þ HLA-DR þ CD45RA þ cells, and dendritic cells (DCs) as CD11c þ CD14 À/low lin À cells by flow cytometry. IPCs and DCs were analysed for Toll-like receptor-7 and-9 mRNA expression by real-time polymerase chain reaction. IFN-was measured by enzyme-linked immunosorbent assay in serum, SF and in supernatants of influenza virus-infected, cultured IPCs. Synovial tissues of n ¼ 6 additional JIA patients were analysed by immunohistochemistry using mAbs against CD123, IFN-, TNF-, CD3, CD19 and CD138. Results. IPCs were enriched in SF MNCs compared with PB MNCs in all JIA patients. Influenza-induced, but no spontaneous IFN-release was detected from SF IPCs, and serum and SF IFN-levels were not elevated. Nonetheless, in synovial tissue IFN-producing cells accumulated at inflammatory lymph-follicular-like structures, while TNF-producing cells were mostly found at the lining and sublining layers. Conclusions. These data suggest that besides TNF-expressing cells, IFN-producing IPCs are involved in initiation, maintenance or regulation of the inflammatory response in JIA.

Arthritis & Rheumatism, 2010

Bone marrow-derived mesenchymal stem cells (BM-MSCs) are multipotent cells characterized by immun... more Bone marrow-derived mesenchymal stem cells (BM-MSCs) are multipotent cells characterized by immunomodulatory properties and are therefore considered a promising tool for the treatment of immune-mediated diseases. This study was undertaken to assess the influence of murine BM-MSCs on the activation of B cells in (NZB ؋ NZW)F 1 mice as an animal model of systemic lupus erythematosus (SLE). Methods. We evaluated the in vitro effects of BM-MSCs on the proliferation and differentiation to plasma cells of splenic mature B cell subsets, namely follicular and marginal zone B cells isolated from (NZB ؋ NZW)F 1 mice. Lupus mice were also treated with BM-MSCs, and serum autoantibodies, proteinuria, histologic changes in the kidney, and survival rates were monitored. Results. BM-MSCs inhibited antigen-dependent proliferation and differentiation to plasma cells of follicular and marginal zone B cells in vitro. This inhibitory effect was dependent on interferon-␥ (IFN␥) and was mediated by cell-to-cell contact, involving the programmed death 1 (PD-1)/PD ligand pathway. In vivo treatment with BM-MSCs did not affect the levels of anti-double-stranded DNA antibodies or proteinuria. However, a reduction in glomerular immune complex deposition, lymphocytic infiltration, and glomerular proliferation was observed. Conclusion. Our findings indicate that BM-MSCs affect B cell receptor-dependent activation of both follicular and marginal zone B cells from lupus mice. This inhibitory effect is IFN␥-dependent and cell contact-dependent. MSCs in vivo do not affect the production of autoantibodies, the level of proteinuria, or the mortality rates. Nonetheless, the significant improvement in histologic findings in the kidney supports the potential role of MSCs in the prevention of glomerular damage. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of serum autoantibodies directed against nucleic acids. It is presumed that, analogous to other experimental models as well as other autoimmune diseases, a defect in T cell tolerance and/or activation might be at the origin of the disease (1,2). Nonetheless, several lines of evidence support a crucial role of B lymphocytes in the pathogenesis of SLE, both in mice and in humans. Autoantibodies directed to DNA, RNA, or other nuclear and cytoplasmic antigens have been detected in serum from humans with SLE as well as from strains of lupus-prone mice, and serum autoantibodies have been correlated with disease activity in humans with SLE, particularly in Supported by grants from the Associazione Italiana per la Ricerca sul Cancro, the Istituto Superiore di Sanità, and the Ministero della Salute (Ricerca Finalizzata Ministeriale 2005 "Caratterizzazione delle proprietà di immunomodulazione delle cellule mesenchimali e possibile applicazione nel trattamento delle malattie autoimmuni").

Rheumatology, 2006

Objectives. Recent laboratory and clinical data suggest that two prototype autoimmune diseases, s... more Objectives. Recent laboratory and clinical data suggest that two prototype autoimmune diseases, systemic lupus erythematosus and rheumatoid arthritis are mainly driven by distinct cytokines, interferon (IFN)-and tumour necrosis factor (TNF)-, respectively. We here investigated the presence and characteristics of natural type I IFN-producing cells (IPCs), as well as IFN-and TNF-expression at sites of inflammation in juvenile idiopathic arthritis (JIA). Methods. Peripheral blood (PB) and synovial fluid (SF) mononuclear cells (MNCs) (n ¼ 25 each) from JIA patients with active disease were studied. IPCs were identified as BCDA-2 þ CD123 þ HLA-DR þ CD45RA þ cells, and dendritic cells (DCs) as CD11c þ CD14 À/low lin À cells by flow cytometry. IPCs and DCs were analysed for Toll-like receptor-7 and-9 mRNA expression by real-time polymerase chain reaction. IFN-was measured by enzyme-linked immunosorbent assay in serum, SF and in supernatants of influenza virus-infected, cultured IPCs. Synovial tissues of n ¼ 6 additional JIA patients were analysed by immunohistochemistry using mAbs against CD123, IFN-, TNF-, CD3, CD19 and CD138. Results. IPCs were enriched in SF MNCs compared with PB MNCs in all JIA patients. Influenza-induced, but no spontaneous IFN-release was detected from SF IPCs, and serum and SF IFN-levels were not elevated. Nonetheless, in synovial tissue IFN-producing cells accumulated at inflammatory lymph-follicular-like structures, while TNF-producing cells were mostly found at the lining and sublining layers. Conclusions. These data suggest that besides TNF-expressing cells, IFN-producing IPCs are involved in initiation, maintenance or regulation of the inflammatory response in JIA.

Arthritis & Rheumatism, 2010

Bone marrow-derived mesenchymal stem cells (BM-MSCs) are multipotent cells characterized by immun... more Bone marrow-derived mesenchymal stem cells (BM-MSCs) are multipotent cells characterized by immunomodulatory properties and are therefore considered a promising tool for the treatment of immune-mediated diseases. This study was undertaken to assess the influence of murine BM-MSCs on the activation of B cells in (NZB ؋ NZW)F 1 mice as an animal model of systemic lupus erythematosus (SLE). Methods. We evaluated the in vitro effects of BM-MSCs on the proliferation and differentiation to plasma cells of splenic mature B cell subsets, namely follicular and marginal zone B cells isolated from (NZB ؋ NZW)F 1 mice. Lupus mice were also treated with BM-MSCs, and serum autoantibodies, proteinuria, histologic changes in the kidney, and survival rates were monitored. Results. BM-MSCs inhibited antigen-dependent proliferation and differentiation to plasma cells of follicular and marginal zone B cells in vitro. This inhibitory effect was dependent on interferon-␥ (IFN␥) and was mediated by cell-to-cell contact, involving the programmed death 1 (PD-1)/PD ligand pathway. In vivo treatment with BM-MSCs did not affect the levels of anti-double-stranded DNA antibodies or proteinuria. However, a reduction in glomerular immune complex deposition, lymphocytic infiltration, and glomerular proliferation was observed. Conclusion. Our findings indicate that BM-MSCs affect B cell receptor-dependent activation of both follicular and marginal zone B cells from lupus mice. This inhibitory effect is IFN␥-dependent and cell contact-dependent. MSCs in vivo do not affect the production of autoantibodies, the level of proteinuria, or the mortality rates. Nonetheless, the significant improvement in histologic findings in the kidney supports the potential role of MSCs in the prevention of glomerular damage. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of serum autoantibodies directed against nucleic acids. It is presumed that, analogous to other experimental models as well as other autoimmune diseases, a defect in T cell tolerance and/or activation might be at the origin of the disease (1,2). Nonetheless, several lines of evidence support a crucial role of B lymphocytes in the pathogenesis of SLE, both in mice and in humans. Autoantibodies directed to DNA, RNA, or other nuclear and cytoplasmic antigens have been detected in serum from humans with SLE as well as from strains of lupus-prone mice, and serum autoantibodies have been correlated with disease activity in humans with SLE, particularly in Supported by grants from the Associazione Italiana per la Ricerca sul Cancro, the Istituto Superiore di Sanità, and the Ministero della Salute (Ricerca Finalizzata Ministeriale 2005 "Caratterizzazione delle proprietà di immunomodulazione delle cellule mesenchimali e possibile applicazione nel trattamento delle malattie autoimmuni").