AFFINITY FOR CLASS-II MHC DETERMINES THE EXTENT TO WHICH SOLUBLE PEPTIDES TOLERIZE AUTOREACTIVE T-CELLS IN NAIVE AND PRIMED ADULT MICE - IMPLICATIONS FOR AUTOIMMUNITY

The N-terminal peptide (Ac1-9) of myelin basic protein (MBP) is the im munodominant encephalitogenic epitope in H-2(u) mice. Previous studies have defined the role of amino acid residue 4 in binding to I-A(u). A ccordingly, substitutions at this residue have generated peptides span ning a wide range of affinities for the MHC. In the present study, we have tested the tolerogenicity of three of these peptides, Ac1-9, Ac1- 9[4A] and Ac1-9[4Y], by administering these to mice i.p. in the absenc e of adjuvant, Significantly, mice treated with the high affinity anal ogues Ac1-9[4A] and Ac1-9[4Y] prior to immunization became less suscep tible to Ac1-9-induced experimental autoimmune encephalomyelitis (EAE) , whereas those given the low affinity peptide Ac1-9 were only moderat ely protected. T cell priming, as assessed by in vitro proliferative a nd lymphokine assays, demonstrated a direct correlation between the le vel of disease inhibition and T cell unresponsiveness. In treatment st udies, Ac1-9 and Ac1-9[4Y] were also shown to be effective when given on the first day of disease onset. Priming of T cells, when measured b y proliferation in vitro, however, became more resistant to inactivati on when soluble peptides were administered close to the day of assay. Kinetic studies revealed that tolerance could be achieved in primed mi ce but that this takes time to develop, Two conclusions can be drawn f rom this study: (i) administration of peptide in solution is effective in prevention of EAE both before and after autoreactive T cell activa tion, and (ii) high affinity analogues of self-peptides inactivate the ir cognate T cells readily whereas lower affinity peptides, being less efficient in tolerance induction, may allow potentially autoreactive T cells to persist in healthy individuals.