Blockade of Proliferation and Tumor Necrosis Factor-?? Production Occurring During Mixed Lymphocyte Reaction by Interferon-??-Specific Natural Antibodies Contained in Intravenous Immunoglobulins1

The mechanism of action of intravenous immunoglobulins (IVIg) for prevention of graft rejection and graft-versus-host disease (GVHD) is poorly understood. Recently, it has been shown that these preparations contain natural antibodies directed toward interferon (IFN)-gamma. During mixed lymphocyte reaction (MLR), which constitutes an in vitro model of allograft rejection and GVHD, T cell recognition of HLA differences induces IFN-gamma release. This cytokine promotes T cell proliferation and acts as a macrophage-activating factor to provoke tumor necrosis factor-alpha secretion. The aim of the present work is to investigate the influence of IVIg on IFN-gamma production occurring during MLR and its subsequent impact on T cell proliferation and tumor necrosis factor (TNF)-alpha secretion. We tested IVIg preparations for the presence of anti-IFN-gamma and anti-TNF-alpha antibodies. High amounts of anti-IFN-gamma, but not anti-TNF-alpha antibodies, were found. IVIg addition at the initiation of culture resulted in IFN-gamma secretion blockade. Likewise, lymphocyte proliferation and TNF-alpha secretion were inhibited. This inhibition was reversed by the addition of recombinant human IFN-gamma. Furthermore, the inhibitory properties of IVIg were mimicked by an IFN-gamma-specific neutralizing monoclonal antibody. We conclude that the capacity of IVIg to inhibit proliferation and TNF-alpha release during MLR is due to IFN-gamma blockade by natural antibodies. This immunosuppressive mechanism could contribute to the effect of IVIg on prophylaxis of organ graft rejection and GVHD after allogeneic bone marrow transplantation.