Mg. Vonherrath et al., IN-VIVO TREATMENT WITH A MHC CLASS I-RESTRICTED BLOCKING PEPTIDE CAN PREVENT VIRUS-INDUCED AUTOIMMUNE DIABETES, The Journal of immunology (1950), 161(9), 1998, pp. 5087-5096
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.