Different in vivo tolerogenicity of MHC class I peptides.
The efficacy of MHC class I-derived peptides to induce tolerance was tested in a cardiac transplantation model. Two 25-mer peptides from the polymorphic region of the DA class I molecule (RT1.Aa) 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 was 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 by grafting of full-thickness skin and in vitro by appropriate proliferation and cytotoxicity assays using donor and third-party rats. Donor-specific tolerance was 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.
Fändrich
F
F
Department of General and Thoracic Surgery, University of Kiel, Germany.
Zhu
X
X
Schröder
J
J
Dresske
B
B
Henne-Bruns
D
D
Oswald
H
H
Zavazava
N
N
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic; D015870:Gene Expression; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D007519:Isoantigens / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000276:immunology* / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D016038:Skin Transplantation / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D015854:Up-Regulation
D016207:Cytokines; D015395:Histocompatibility Antigens Class I; D007519:Isoantigens; D010446:Peptide Fragments; D016753:Interleukin-10; D015847:Interleukin-4