title: Induction of transplantation tolerance by chimeric donor/recipient class I RT1.Aa molecules.
abstract: Donor-specific transplantation tolerance was induced by administration of chimeric antigens in which four donor immunogenic amino acids (a.a.) were substituted onto the host class I MHC protein. We constructed chimeric rat RT1.Aa cDNA molecules by substituting nucleotides in the alpha1 helical region that encode 10 Lewis (LEW; RT1.A1) a.a., namely Asp58, Arg62, Glu63, Gln65, Lys66, Gly69, Asn70, Asn73, Ser77, and Asn80 ([alpha(1h)1]-RT1.Aa). The chimeric [alpha(1h)1]-RT1.Aa cDNA sequence was verified before transfection into Buffalo (BUF; RT1b) hepatoma cells. Interestingly, the helical regions of LEW rats (alpha(1h)1) and Wistar Furth (WF; RT1u) rats (alpha(1h)u) share four a.a. (Arg62, Glu63, Gln65, and Gly69). Consequently, subcutaneous administration of [alpha(1)1]-RT1.Aa transfectants (20x10(6); day -7) immunized BUF rats to reject in rapid fashion either LEW heart allografts (mean survival time [MST] = 4.2+/-0.4 days vs. 5.6+/-0.5 days in controls; P<0.001) or WF heart allografts (MST=4.4+/-0.6 days vs. 6.0+/-0.0 days in controls; P<0.002). Subcutaneous immunization of ACI (RT1a) rats with [a(1)1]-RT1.Aa transfectants (bearing 10 LEW donor a.a.) accelerated the rejection of LEW hearts (MST=5.0+/-0.8 days vs. 8.2+/-0.4 days in controls; P<0.001). In contrast, the same [a(1)1]-RT1.Aa transfectants (bearing only four WF donor a.a.) injected subcutaneously into ACI rats modestly prolonged the survival of WF hearts to 14.0+/-10.3 days from 5.4+/-0.5 days in controls (P<0.001). Furthermore, ACI recipients were rendered tolerant to WF heart allografts by a single injection via the portal vein of soluble [a(1)1]-RT1.Aa (but not RT1.Aa, RT1.Au, or [a(2)1]-RT1.Aa) antigens in conjunction with brief oral gavage treatment with cyclosporine. Thus, selected donor immunogenic a.a. (Arg62, Glu63, Gln65, and Gly69) of class I MHC antigens become tolerogenic when flanked by host sequences.
authors.affiliation: Department of Surgery, University of Texas Medical School at Houston, 77030, USA.
authors.forename: R R
authors.initials: RR
authors.lastname: Ghobrial
authors.forename: T
authors.initials: T
authors.lastname: Hamashima
authors.forename: M E
authors.initials: ME
authors.lastname: Wang
authors.forename: M
authors.initials: M
authors.lastname: Wang
authors.forename: S M
authors.initials: SM
authors.lastname: Stepkowski
authors.forename: B D
authors.initials: BD
authors.lastname: Kahan
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D006649:Histocompatibility Antigens / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D007108:Immune Tolerance; D007519:Isoantigens / Q000235:genetics / Q000276:immunology; D008297:Male; D008969:Molecular Sequence Data; D017354:Point Mutation; D017433:Protein Structure, Secondary; D051381:Rats; D011919:Rats, Inbred Strains; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology*; D014162:Transfection; D018183:Transplantation Chimera / Q000276:immunology*
chemical_list: D006649:Histocompatibility Antigens; D007519:Isoantigens; D011993:Recombinant Fusion Proteins; C038353:histocompatibility antigens RT, rat