BACKGROUND: Polyclonal antithymocyte globulins (ATGs) are used clinically to prevent and treat acute allograft rejection and are believed to modulate the immune response primarily by depleting T cells. However, nondepleting mechanisms may also be important mediators of graft survival. In the present study, 14 lots of thymoglobulin (rabbit ATG) were analyzed and compared for nondepletive immunomodulatory activities in vitro. METHODS: Coincubation of human peripheral blood mononuclear cells with thymoglobulin induces CD4+CD25(high)Foxp3+ regulatory T cells, which were evaluated for consistent ability to suppress T-cell activation in mixed lymphocyte reactions. The consistency of CD2, CD3, CD11a, and CD45 antigen specificities in thymoglobulin was determined using flow cytometry to measure inhibition of fluorescent monoclonal antibody binding to Jurkat T cells. A transwell chemotaxis assay was established and used to evaluate ATG-mediated inhibition of stromal cell-derived factor (SDF)-1alpha-driven Jurkat T-cell migration. RESULTS: Physiologic levels of thymoglobulin produced nondepletive immunomodulatory activities, which were consistent from batch to batch. All lots of thymoglobulin induced functionally immunosuppressive regulatory T cells and inhibited monoclonal antibody binding to key T-cell surface antigens. In addition, these studies provide the first demonstration that thymoglobulin effectively inhibits CXCR4/SDF-1alpha-driven T-cell chemotaxis. CONCLUSIONS: This novel, systematic in vitro analysis of 14 different manufactured lots of thymoglobulin demonstrates the overall consistency of this product and provides further insights into nondepletive mechanisms by which thymoglobulin may generate durable immunoregulation and allograft survival.
BACKGROUND: Polyclonal antithymocyte globulins (ATGs) are used clinically to prevent and treat acute allograft rejection and are believed to modulate the immune response primarily by depleting T cells. However, nondepleting mechanisms may also be important mediators of graft survival. In the present study, 14 lots of thymoglobulin (rabbit ATG) were analyzed and compared for nondepletive immunomodulatory activities in vitro. METHODS: Coincubation of human peripheral blood mononuclear cells with thymoglobulin induces CD4+CD25(high)Foxp3+ regulatory T cells, which were evaluated for consistent ability to suppress T-cell activation in mixed lymphocyte reactions. The consistency of CD2, CD3, CD11a, and CD45 antigen specificities in thymoglobulin was determined using flow cytometry to measure inhibition of fluorescent monoclonal antibody binding to Jurkat T cells. A transwell chemotaxis assay was established and used to evaluate ATG-mediated inhibition of stromal cell-derived factor (SDF)-1alpha-driven Jurkat T-cell migration. RESULTS: Physiologic levels of thymoglobulin produced nondepletive immunomodulatory activities, which were consistent from batch to batch. All lots of thymoglobulin induced functionally immunosuppressive regulatory T cells and inhibited monoclonal antibody binding to key T-cell surface antigens. In addition, these studies provide the first demonstration that thymoglobulin effectively inhibits CXCR4/SDF-1alpha-driven T-cell chemotaxis. CONCLUSIONS: This novel, systematic in vitro analysis of 14 different manufactured lots of thymoglobulin demonstrates the overall consistency of this product and provides further insights into nondepletive mechanisms by which thymoglobulin may generate durable immunoregulation and allograft survival.
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Authors: Mark Bosch; Manveer Dhadda; Mette Hoegh-Petersen; Yiping Liu; Laura M Hagel; Peter Podgorny; Alejandra Ugarte-Torres; Faisal M Khan; Joanne Luider; Iwona Auer-Grzesiak; Adnan Mansoor; James A Russell; Andrew Daly; Douglas A Stewart; David Maloney; Michael Boeckh; Jan Storek Journal: Cytotherapy Date: 2012-09-18 Impact factor: 5.414