Different in vivo tolerogenicity of MHC class I peptides

The efficacy of MHC class I-derived peptides to induce tolerance tvas tested in a cardiac transplantation model, Two 25-mer peptides hom the polymorphic region of the DA class I molecule (RT1.A(a)) were synthesized by F-moc chemistry and injected intrathymically or intraperitoneally into LEW (RT1.(1)) responder animals. Intrathymic treatment of the recipient animals with peptide 1 (residues 56-80) accompanied by intraperitoneal treatment with peptide 4 (residues 96-120) led to indefinite survival of allogeneic DA cardiac allografts (n = 7; >100 days). The tolerogenicity of both peptides differed according to the site of inoculation, as donor-specific tolerance Tvas only observed after administration of peptide 1 into the thymus and injection of peptide 2 into the abdominal cavity of LEW recipients, but not vice versa. Donor-specific tolerance was confirmed in vivo hy grafting of full-thickness skin and in vitro by appropriate proliferation and cytotoxicity assays using donor and third-party rats. Donor-specific tolerance Tvas associated with up-regulation of interleukin-4, transforming growth factor beta, and interleukin-10 gene expression within cardiac allografts, thus suggesting intrathymic clonal deletion and external suppression with expansion of T-helper 2-type lymphocytes as the underlying mechanisms of tolerance induction.