Intravenous Immunoglobulins for Therapeutic Use Contain Anti-idiotypes against Xenophile Antibodies and Prolong Discordant Graft Survival

Abstract

Xenotransplantation between discordant species leads to a graft survival of a few minutes, due to binding of natural antibodies to the xenogeneic endothelial cells, complement activation, and endothelial cell activation. Polyclonal human immunoglobulins for intravenous use (IVIg) from normal donors have been proven effective in a variety of antibody-mediated disorders and contain anti-idiotypic antibodies directed against a number of disease-associated and natural antibodies. We have shown that administration of IVIg delays rejection of a guinea pig heart to a rat. We demonstrate herein that IVIg can inhibit the binding of xenoreactive rat IgG antibodies to guinea pig endothelial cells. This inhibition is likely due to the presence, among IVIg, of anti-idiotypic antibodies as F(ab′) 2fragments of IVIg were as effective as whole IVIg. In addition, natural anti-endothelium rat antibodies were retained on a column of F(ab′) 2fragments of IVIg coupled to Sepharose. The degree of inhibition of binding of IgG natural antibodies correlated with the survival of the xenograft when IVIg was administered prior to transplantation. Thus IVIg prolong xenograft survival through idiotypic–anti-idiotypic interactions with natural xenoreactive antibodies of the IgG isotype.