Tumor immunity and autoimmunity induced by immunization with homologous DNA

Area of Science:

• Immunology
• Cancer Research
• Molecular Biology

Background:

• Self antigens on cancer cells, like differentiation antigens, can be recognized by the immune system.
• Tyrosinase family proteins are differentiation antigens found in melanoma, but immune tolerance can limit anti-cancer responses.
• Immune tolerance to the brown locus protein, gp75/tyrosinase-related protein-1, was investigated.

Purpose of the Study:

• To investigate methods for breaking immune tolerance to gp75.
• To determine if immunity against mouse gp75 could provide tumor protection.
• To explore the relationship between anti-gp75 immunity and autoimmune manifestations.

Main Methods:

• A syngeneic mouse model (C57BL/6) was used, which is naturally tolerant to gp75.
• Mice were immunized with DNA encoding human gp75 or syngeneic mouse gp75.
• Tumor protection and autoimmune responses were assessed after immunization and tumor challenge.

Main Results:

• Immunization with human gp75 DNA, but not mouse gp75 DNA, generated autoantibodies against gp75 in tolerant mice.
• Priming with human gp75 DNA successfully broke tolerance to mouse gp75.
• Immunity against mouse gp75 conferred significant tumor protection.
• Autoimmune manifestations, specifically coat depigmentation, were observed.
• Tumor rejection required CD4(+) and NK1.1(+) cells and Fc receptor gamma-chain, whereas depigmentation did not.

Conclusions:

• Homologous DNA immunization can break immune tolerance to self antigens like mouse gp75, potentially via CD4(+) T cell help.
• Tumor immunity and autoimmune manifestations can be uncoupled, as the mechanisms required for tumor protection were not essential for autoimmunity.