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The breaking of immune tolerance against angiogenesis-associated molecules should be a useful approach for cancer therapy by active immunity. We used chicken integrin β[sub 3] as a model antigen to explore the feasibility of immunogene therapy of the tumors with a vaccine based on a single xenogeneic homologous gene, targeting the molecules associated with angiogenesis. To test this concept we constructed a plasmid DNA encoding the ligand-binding domain of chicken integrin β[sub 3] (P-BD-C) and control vectors. We found that immunogene therapy of tumors with a vaccine based on the ligand-binding domain of chicken integrin β[sub 3] (P-BD-C) was effective in both protective and therapeutic anti-tumor immunity in several tumor models in mice. Autoantibodies against integrin β[sub 3] in sera of mice immunized with the ligand-binding domain of chicken integrin β[sub 3] could be found by Western blot analysis and ELISA assay. The purified immunoglobulins were effective in the inhibition of endothelial cell proliferation in vitro, and in anti-tumor activity as well as in the inhibition of angiogenesis by adoptive transfer in vivo. The anti-tumor activity and the production of integrin β[sub 3]-specific autoantibodies (manifested by significantly elevated Ig G1 and Ig G2b) could be abrogated by the depletion of CD4[sup +] T lymphocytes. These observations may provide a vaccine strategy for cancer therapy through the induction of the autoimmunity against the molecules associated with tumor growth in a cross-reaction with a single xenogeneic homologous gene and may be of importance in the further exploration of the applications of other xenogeneic homologous genes identified in human and other animal genome sequence projects in cancer therapy. [ABSTRACT FROM AUTHOR]