Functional analysis of α-fetoprotein by genetically engineered mice

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α-fetoprotein (AFP) is a serum protein in appreciable amounts in fetal but not in adult serum. However, serum AFP is frequently elevated in patients with hepatocellular carcinomas and yolk sac tumors. Numerous studies have suggested that immunomodulation may be one of the biological functions of AFP. To clarify the biological function of the AFP in vivo, we have established two transgenic mice, which have human and mouse AFP genes under the control of β-actin promoter. In these mice, ubiquitous expressions of AFP were observed. Using these mice, we have been analyzed experimental autoimmune diseases, such as arthritis, autoimmune thyroiditis and experimental allergic encephalomyelitis. We have showed that development of all these experimental autoimmune diseases were significantly suppressed in AFP produced transgenic mice compared with wild mice. The development of experimental allergic encephalomyelitis of the mouse AFP producing mice was more suppressed than the mouse producing human AFP.Monoclonal antibodies (MAbs) against human AFP have been used in a variety of procedures including immuno assay, immunoscintigraphy and immunotherapy. A number of MAbs have been produced, but their epitopes remain to be defined. We have analyzed 36 MAbs against human AFP using recombinant AFP peptides and synthesized overlapping octapeptides. Epitopes of 13 MAbs were mapped in domain I and 17 were on domain II. The epitope of one of the MAb, AFY6, was localized on C^<175>KAENAVE^<182>.We also analyzed the AFP gene regulation. Glucocorticoid inhibit rodent AFP gene activity but stimulate expression of the human AFP. The glucocorticoid induction of human AFP is mediated by a GRE on the AFP gene promoter and corresponding element of the mouse is a binding site of the HNF4, a hepatocyte enriched transcription factor. The interaction of the glucocorticoid receptor and HNF4 may account for this opposite effects.