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Jonathan W Said - One of the best experts on this subject based on the ideXlab platform.
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the humanized anti CD40 antibody sgn 40 inhibits tumor growth in lagκ 1a a CD40 mouse model of human multiple myeloma
Blood, 2006Co-Authors: Richard A Campbell, Melinda S Gordon, Eric Sanchez, Haiming Chen, Lauren Turker, Olivia Trac, Mingjie Li, Shen Pang, Benjamin Bonavida, Jonathan W SaidAbstract:CD40 is a TNF receptor found on the cell surface of mature B cells (B lymphocytes) and most B-cell malignancies including multiple myeloma (MM). SGN-40 is a high-affinity, humanized monoclonal antibody that targets the CD40 Antigen. Recently, it has been shown that SGN-40 decreases the proliferation of malignant B cells by partial agonistic signaling and effector functions in vitro. In this study, we examined the anti-MM effects of SGN-40 in vivo using a CD40+ SCID-hu murine model of human myeloma, LAGκ-1A. Each immunodeficient (SCID) mouse was implanted with a 2.0 – 4.0 mm3 LAGκ-1A tumor fragment into the left hind limb muscle. The tumor was allowed to grow for 14 days at which time human IgG levels were detectable in the mouse serum. Mice were then randomly assigned to one of four SGN-40 treatment groups (6 mice per treatment group). SGN-40 was administered via intraperitoneal injection twice per week at doses of 0.1, 0.3, 1, and 3 mg/kg. Control mice were given a control IgG antibody (3 mg/kg) using the same schedule. Mice receiving the higher doses of SGN-40 showed marked inhibition of tumor growth (0.3 mg/kg, P
Jacques Banchereau - One of the best experts on this subject based on the ideXlab platform.
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B-Cell-Derived IL-10: Production and Function
Methods, 1997Co-Authors: N Burdin, Françoise Rousset, Jacques BanchereauAbstract:In vitro and in vivo studies identify IL-10 as a key cytokine that inhibits cell-mediated immunity and inflammation while promoting humoral responses. The present review summarizes our studies regarding the ability of B cells to secrete IL-10. When established lines are considered, the production of human IL-10 is restricted to mature B-cell lines and correlates with Epstein-Barr Virus (EBV) expression. Accordingly, EBV infection induces purified tonsil B lym phocytes to produce high levels of human IL-10, whereas viral IL-10 (encoded by EBV) remains undetectable. Exogenous IL-10 enhances EBV-induced B-cell growth, while a neutralizing anti-IL-10 antibody inhibits it, suggesting that IL-10 acts as an autocrine growth factor for EBV-infected B lymphocytes. Normal B lymphocytes secrete lower levels of human IL-10 following activation through B-cell receptor or CD40 Antigen. While addition of exogenous IL-4 diminishes CD40-induced secretion of IL-10, addition of Staphyloccocus aureus Cowan I (SAC) particles increases it. Neutralization of endogenous IL-10 does not alter growth of CD40-activated B cells but inhibits their IgG, IgA, and IgM secretion, especially when costimulated with SAC particles. Finally, the simul taneous blocking of both endogenous IL-10 and IL-6 inhibits two-thirds of the production of the three isotypes when B cells were triggered through CD40 in the presence of SAC particles, suggesting that IL-10 synergizes with IL-6 to sustain differentiation of CD40-activated B lymphocytes. Overexpression of B-cell-derived IL-10 is likely to contribute in vivo to different pathologies such as B-lymphoproliferative disorders and autoimmune diseases.
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The functional CD40 Antigen of fibroblasts may contribute to the proliferation of rheumatoid synovium.
Clinical and Experimental Immunology, 1996Co-Authors: Marie-clotilde Rissoan, C Van Kooten, Pierre Miossec, Pascale Chomarat, L Galibert, Isabelle Durand, F. Thivolet-bejui, Jacques BanchereauAbstract:This paper demonstrates that CD40 is expressed on rheumatoid synovial pannus and primary fibroblast cell lines established from rheumatoid and osteoarthritic synovium as well as normal skin. Among various tested cytokines, interferon-gamma (IFN-γ) and to a lower extent, tumour necrosis factor-alpha (TNF-α) were found to upregulate CD40 expression on fibroblasts. Synovial and skin fibroblasts cultured over CD40 Ligand transfected L cells (L-CD40 L) demonstrate a CD40 specific increase of DNA synthesis as measured by tritiated thymidine incorporation. Cell-cycle analysis and enumeration of viable cells further show that CD40 induced fibroblast proliferation. Costimulation with L-CD40 L and IFN-γ resulted in maximal proliferation. Engagement of fibroblasts CD40 increased the IL-1-induced production of granulocyte macrophage-colony stimulating factor and macrophage inflammatory protein-1α MIP-1α. CD40 L activated fibroblasts showed decreased levels of CD40, but only marginal alterations of other cell-surface Antigens. Taken together, the present results indicate that fibroblasts express functional CD40 and suggest a possible role of CD40 L expressing cells, such as activated T cells and mast cells, in the development of synovium hyperplasia.
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Fas ligation induces apoptosis of CD40-activated human B lymphocytes.
Journal of Experimental Medicine, 1995Co-Authors: Pierre Garrone, C Van Kooten, L Galibert, Eric Garcia, E M Neidhardt, Jacques BanchereauAbstract:Since CD40/CD40 ligand (CD40Lig) interactions are essential in vivo for the generation of germinal center B cells that express Fas (Apo-1/CD95), we explored whether CD40 engagement may modulate Fas expression and function on human B lymphocytes. Resting tonsil B cells, isolated by density gradient centrifugation, express either absent or low levels of Fas. They could be induced to promptly express Fas after ligation of their CD40, however, using either a recombinant human CD40Lig or a cross-linked anti-CD40 mAb. In contrast, engagement of the B cell Antigen receptor by immobilized anti-kappa and -lambda antibodies did not turn on Fas expression. Addition of anti-Fas mAb CH11 inhibited the later phases of CD40-induced B cell growth as a result of apoptotic cell death. Furthermore, Fas ligation inhibited proliferation and Ig secretion of CD40-activated B cells in response to recombinant cytokines such as interleukin (IL)-2, IL-4, and IL-10, as well as a cytokine-rich supernatant of phytohemagglutinin-activated T cells, indicating that none of those B cell tropic factors were able to prevent the Fas-induced death. Taken together, the present results show that engagement of CD40 Antigen on B cells induces Fas expression and sensitizes them to Fas-mediated apoptosis. The delayed functional response to Fas ligation after CD40 activation may represent a way to limit the size of a specific B cell clone that is generated during T-B cell interactions.
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Memory B cells from human tonsils colonize mucosal epithelium and directly present Antigen to T cells by rapid up-regulation of B7-1 and B7-2.
Immunity, 1995Co-Authors: Yong-jun Liu, Clarissa Barthélémy, Odette De Bouteiller, Christophe Arpin, Durand Isabelle, Jacques BanchereauAbstract:Abstract Human memory B cells that carry mutated IgV region genes were isolated from tonsils by negative selection of IgD + naive B cells and CD38 + germinal center B cells and plasma cells. They were mainly found within the intraepithelial areas, but not in the B cell follicles of human tonsils. Memory B cells but not naive B cells have the capacity to present Antigen directly to T cells, owing to the constitutive expression of the accessory molecules B7-1 /CD80 and B7-2/CD86. Signals through Antigen receptors and CD40 Antigen result in these two molecules being further up-regulated more rapidly and strongly on memory B cells than on naive B cells. The unique anatomical localization of memory B cells beneath the surface of mucosa, together with their strong APC capacity, may explain the well-known prompt and robust secondary antibody responses.
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Functional expression of CD40 Antigen on human epidermal Langerhans cells
J.Immunol., 1995Co-Authors: J. Peguet-navarro, C Dalbiez-Gauthier, C Van Kooten, Frédérique Marie Rattis, Jacques Banchereau, D A SchmittAbstract:It is now well established that interactions of CD40 on the B cells, along with its ligand (CD40-L) on the T cells, regulate B cell proliferation and differentiation. However, the functional significance of CD40 expression on cells known for most efficient Ag-presenting function, i.e., dendritic cells, is not so clear. In this study, we demonstrate that CD40 is expressed on human dendritic Langerhans cells (LC) freshly isolated from epidermis. Using CD40-L transfected cells, CD40 triggering was found to enhance LC viability when cultured and to result in phenotypic alterations. Thus, a 2-day CD40 activation induced up-regulation of CD54 and CD86 at the LC surface, while it did not significantly affect the levels of HLA-DR, CD1a, CD58, and CD80 expression. These phenotypic changes correlate with enhanced LC allostimulatory property, as shown by the use of paraformaldehyde-fixed LC. Furthermore, mAbs against CD40, as well as CD40-L, strongly inhibit the primary T cell response to allogeneic LC. Collectively, these data support a role for CD40/CD40-L pair in the development of normal T cell functions
Richard A Campbell - One of the best experts on this subject based on the ideXlab platform.
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the humanized anti CD40 antibody sgn 40 inhibits tumor growth in lagκ 1a a CD40 mouse model of human multiple myeloma
Blood, 2006Co-Authors: Richard A Campbell, Melinda S Gordon, Eric Sanchez, Haiming Chen, Lauren Turker, Olivia Trac, Mingjie Li, Shen Pang, Benjamin Bonavida, Jonathan W SaidAbstract:CD40 is a TNF receptor found on the cell surface of mature B cells (B lymphocytes) and most B-cell malignancies including multiple myeloma (MM). SGN-40 is a high-affinity, humanized monoclonal antibody that targets the CD40 Antigen. Recently, it has been shown that SGN-40 decreases the proliferation of malignant B cells by partial agonistic signaling and effector functions in vitro. In this study, we examined the anti-MM effects of SGN-40 in vivo using a CD40+ SCID-hu murine model of human myeloma, LAGκ-1A. Each immunodeficient (SCID) mouse was implanted with a 2.0 – 4.0 mm3 LAGκ-1A tumor fragment into the left hind limb muscle. The tumor was allowed to grow for 14 days at which time human IgG levels were detectable in the mouse serum. Mice were then randomly assigned to one of four SGN-40 treatment groups (6 mice per treatment group). SGN-40 was administered via intraperitoneal injection twice per week at doses of 0.1, 0.3, 1, and 3 mg/kg. Control mice were given a control IgG antibody (3 mg/kg) using the same schedule. Mice receiving the higher doses of SGN-40 showed marked inhibition of tumor growth (0.3 mg/kg, P
Olivia Trac - One of the best experts on this subject based on the ideXlab platform.
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the humanized anti CD40 antibody sgn 40 inhibits tumor growth in lagκ 1a a CD40 mouse model of human multiple myeloma
Blood, 2006Co-Authors: Richard A Campbell, Melinda S Gordon, Eric Sanchez, Haiming Chen, Lauren Turker, Olivia Trac, Mingjie Li, Shen Pang, Benjamin Bonavida, Jonathan W SaidAbstract:CD40 is a TNF receptor found on the cell surface of mature B cells (B lymphocytes) and most B-cell malignancies including multiple myeloma (MM). SGN-40 is a high-affinity, humanized monoclonal antibody that targets the CD40 Antigen. Recently, it has been shown that SGN-40 decreases the proliferation of malignant B cells by partial agonistic signaling and effector functions in vitro. In this study, we examined the anti-MM effects of SGN-40 in vivo using a CD40+ SCID-hu murine model of human myeloma, LAGκ-1A. Each immunodeficient (SCID) mouse was implanted with a 2.0 – 4.0 mm3 LAGκ-1A tumor fragment into the left hind limb muscle. The tumor was allowed to grow for 14 days at which time human IgG levels were detectable in the mouse serum. Mice were then randomly assigned to one of four SGN-40 treatment groups (6 mice per treatment group). SGN-40 was administered via intraperitoneal injection twice per week at doses of 0.1, 0.3, 1, and 3 mg/kg. Control mice were given a control IgG antibody (3 mg/kg) using the same schedule. Mice receiving the higher doses of SGN-40 showed marked inhibition of tumor growth (0.3 mg/kg, P
Benjamin Bonavida - One of the best experts on this subject based on the ideXlab platform.
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the humanized anti CD40 antibody sgn 40 inhibits tumor growth in lagκ 1a a CD40 mouse model of human multiple myeloma
Blood, 2006Co-Authors: Richard A Campbell, Melinda S Gordon, Eric Sanchez, Haiming Chen, Lauren Turker, Olivia Trac, Mingjie Li, Shen Pang, Benjamin Bonavida, Jonathan W SaidAbstract:CD40 is a TNF receptor found on the cell surface of mature B cells (B lymphocytes) and most B-cell malignancies including multiple myeloma (MM). SGN-40 is a high-affinity, humanized monoclonal antibody that targets the CD40 Antigen. Recently, it has been shown that SGN-40 decreases the proliferation of malignant B cells by partial agonistic signaling and effector functions in vitro. In this study, we examined the anti-MM effects of SGN-40 in vivo using a CD40+ SCID-hu murine model of human myeloma, LAGκ-1A. Each immunodeficient (SCID) mouse was implanted with a 2.0 – 4.0 mm3 LAGκ-1A tumor fragment into the left hind limb muscle. The tumor was allowed to grow for 14 days at which time human IgG levels were detectable in the mouse serum. Mice were then randomly assigned to one of four SGN-40 treatment groups (6 mice per treatment group). SGN-40 was administered via intraperitoneal injection twice per week at doses of 0.1, 0.3, 1, and 3 mg/kg. Control mice were given a control IgG antibody (3 mg/kg) using the same schedule. Mice receiving the higher doses of SGN-40 showed marked inhibition of tumor growth (0.3 mg/kg, P