Using a polypeptide oligomer harboring 16 repeats of the neuritogenic epitope (aa 58-73) of myelin P2 protein separated by spacers, enhancement of the immune response to the P2 protein, an important neuritogenic autoantigen in experimental autoimmune neuritis (EAN), was attempted. In contrast to a previous study with PLP-16-mer antigen-specific response of T cells was attenuated at all doses examined to a variable degree. Treatment of Lewis rats with the P2-16-mer up to 2 months before immunization with P2(53-78) (vaccination) or after immunization but before appearance of disease (prevention) had a strong tolerizing effect against the induction of EAN on immunization with P2(53-78). Moreover, rats injected with 200 microg of the P2-16-mer i.v. on day 11 after disease induction, at which time the initial signs of disease had appeared, were almost completely protected against progression of clinical disease, whereas animals treated with the same amount of monomeric control peptide developed severe disease (treatment). Similar results were obtained by i.v. treatment of adoptive-transfer EAN with the P2-16-mer. The lack of clinical signs of disease after 16-mer therapy could be correlated with a reduced proliferative response of P2(53-78)-specific lymph node cells. The frequency of apoptotic T cells in sciatic nerve or in lymph node cells, however, was not increased by the 16-mer treatment, suggesting that induction of anergy or other forms of peripheral tolerance may be responsible for the effect. Thus, the oligomerized P2 peptide antigen was highly effective in all three treatment modalities examined in this specific autoreactive T cell-mediated immune response.