BLOCKADE OF PROLIFERATION AND TUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION OCCURRING DURING MIXED LYMPHOCYTE-REACTION BY INTERFERON-GAMMA-SPECIFIC NATURAL ANTIBODIES CONTAINED IN INTRAVENOUS IMMUNOGLOBULINS

The mechanism of action of intravenous immunoglobulins (IVIg) for prev ention of graft rejection and graft-versus-host disease (GVHD) is poor ly understood, Recently, it has been shown that these preparations con tain 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 proliferatio n 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 an d its subsequent impact on T cell proliferation and tumor necrosis fac tor (TNF)-alpha secretion. We tested IVIg preparations for the presenc e of anti-IFN-gamma and anti-TNF-alpha antibodies. High amounts of ant i-IFN-gamma, but not anti-TNF-alpha antibodies, were found. IVIg addit ion at the initiation of culture resulted in IFN-gamma secretion block ade, Likewise, lymphocyte proliferation and TNF-alpha secretion were i nhibited. This inhibition was reversed by the addition of recombinant human IFN-gamma. Furthermore, the inhibitory properties of IVIg were m imicked by an IFN-gamma-specific neutralizing monoclonal antibody. We conclude that the capacity of Mg to inhibit proliferation and TNF-alph a release during MLR is due to IFN-gamma blockade by natural antibodie s. This immunosuppressive mechanism could contribute to the effect of IVIg on prophylaxis of organ graft rejection and GVHD after allogeneic bone marrow transplantation.