IN-VIVO TREATMENT WITH A MHC CLASS I-RESTRICTED BLOCKING PEPTIDE CAN PREVENT VIRUS-INDUCED AUTOIMMUNE DIABETES

We tested the in vivo potential of a MHC class I-restricted blocking p eptide to sufficiently lower an anti-viral CTL response for preventing virus-induced CTL-mediated autoimmune diabetes (insulin-dependent dia betes mellitus (IDDM)) in vivo without affecting systemic viral cleara nce. By designing and screening several peptides with high binding aff inities to MHC class I H-2D(b) for best efficiency in blocking killing of target cells by lymphocytic choriomeningitis virus (LCMV) and othe r viral CTL, we identified the peptide for this study. In vitro, it se lectively lowered CTL killing restricted to the D-b allele, which corr elated directly with the affinity of the respective epitopes, Expressi on of the blocking peptide in the target cell lowered recognition of a ll D-b-restricted LCMV epitopes, In addition, in vitro expansion of LC MV memory CTL was prevented, resulting in decreased IFN-gamma secretio n. In vivo, a 2-wk treatment with this peptide lowered the LCMV D-b-re stricted CTL response by over threefold without affecting viral cleara nce. However, the CTL reduction by the peptide treatment was sufficien t to prevent LCMV-induced IDDM in rat insulin promoter-LCMV-glycoprote in transgenic mice. Following LCMV infection, these mice develop IDDM, which depends on D-b-restricted anti-self(viral) CTL, Precursor numbe rs of splenic LCMV-CTL in peptide-treated mice were reduced, but their cytokine profile was not altered, indicating that the peptide did not induce regulatory cells. Further, non-LCMV-CTL recognizing the blocki ng peptide secreted IFN-gamma and did not protect from IDDM. This stud y demonstrates that in vivo treatment with a MHC class I blocking pept ide can prevent autoimmune disease by directly affecting expansion of autoreactive CTL.