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Division of Virology, Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037; and
Institut de Pharmacologie et de Biologie Structurale, Unité Propre de Recherche 9062 Centre National de la Recherche Scientifique, Toulouse, France
We tested the in vivo potential of a MHC class I-restricted
blocking peptide to sufficiently lower an anti-viral CTL response
for preventing virus-induced CTL-mediated autoimmune diabetes
(insulin-dependent diabetes mellitus (IDDM)) in vivo without affecting
systemic viral clearance. By designing and screening several peptides
with high binding affinities to MHC class I H-2Db for best
efficiency in blocking killing of target cells by lymphocytic
choriomeningitis virus (LCMV) and other viral CTL, we identified the
peptide for this study. In vitro, it selectively lowered CTL killing
restricted to the Db allele, which correlated directly with
the affinity of the respective epitopes. Expression of the blocking
peptide in the target cell lowered recognition of all
Db-restricted LCMV epitopes. In addition, in vitro
expansion of LCMV memory CTL was prevented, resulting in decreased
IFN-
secretion. In vivo, a 2-wk treatment with this peptide lowered
the LCMV Db-restricted CTL response by over threefold
without affecting viral clearance. However, the CTL reduction by the
peptide treatment was sufficient to prevent LCMV-induced IDDM in rat
insulin promoter-LCMV-glycoprotein transgenic mice. Following LCMV
infection, these mice develop IDDM, which depends on
Db-restricted anti-self (viral) CTL. Precursor numbers
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 blocking
peptide secreted IFN- and did not protect from IDDM. This study
demonstrates that in vivo treatment with a MHC class I blocking peptide
can prevent autoimmune disease by directly affecting expansion of
autoreactive CTL.
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