Depending on the mode of immunization, a single administration of CFA may result in the development of a local inflammatory process or chronic poly adjuvant-induced arthritis (AA). Administration of naked DNA encoding TNF-α results in the generation of immunological memory to its gene product. Upon induction of AA, this memory effectively inhibited the development of disease. Self-specific Abs developed in DNA-vaccinated animals were neutralizing in vitro and could adoptively transfer the beneficial effect of the vaccine. Administration of CFA to induce a local delayed-type hypersensitivity response rather than AA did not lead to an elicited production of Abs to the gene product of the above vaccine. Thus, elicitation of protective immunity is dependent on the development of an autoimmune condition. Most importantly, the administration of the TNF-α DNA construct after the onset of disease led to a rapid, long-lasting remission. This suggests a highly effective way by which a DNA vaccine encoding an autologous proinflammatory cytokine can be used to reprogram the immune system to generate protective immunity to its own potentially harmful activities.