Peptide-induced T cell regulation of experimental autoimmune encephalomyelitis: a role for IL-10

Experimental autoimmune encephalomyelitis (EAE) is a CD4(+) T cell-mediated , inflammatory disease with similarities to multiple sclerosis in humans. I ntranasal (i.n.) administration of a myelin basic protein (MBP)-derived pep tide can protect susceptible mice from EAE, The mechanisms underlying this phenomenon, however, remain unclear, To analyze the phenotypic and function al changes taking place during the induction of tolerance by peptide inhala tion, we have studied the fate of CD4(+) T cells after i.n. peptide applica tion using transgenic mice expressing a TCR specific for the N-terminal pep tide (Ac1-9) of MBP, Peripheral T cell death was variably observed in TCR t ransgenic mice after a single i.n. administration of antigenic peptide but was transient and incomplete, Transgenic spleen cells and cervical lymph no de cells responded with a cytokine burst to peptide inhalation and hyperpro liferation when re-stimulated in vitro, Transfer experiments demonstrated t hat the duration of peptide administration required to induce tolerance dep ended on the precursor frequency of T cells in recipient animals, The strin gency of i.n. peptide treatment was increased so as to test the efficacy of tolerance induction both in vitro and in vivo in the presence of high prec ursor frequencies of antigen-specific T cells. Multiple i.n. doses of pepti de completely protected TCR transgenic mice from EAE induced with myelin, S uch repeated peptide administration resulted in down-regulation of the capa city of antigen-specific CD4+ T cells to proliferate or to produce IL-2, IF N-gamma and IL-4 but increased the production of IL-10. The role of IL-10 i n suppression of EAE in vivo was demonstrated by neutralization of IL-10, T his completely restored susceptibility to EAE in mice previously protected by i.n. peptide, Considering the immunosuppressive properties of IL-10, T c ells which are resistant to apoptosis might act as regulatory cells and med iate bystander suppression.