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 α1 helical region that encode 10 Lewis (LEW; RT1.A(l)) a.a., namely Asp58, Arg62, Glu63, Gln65, Lys66, Gly69, Asn70, Asn73, Ser77, and Asn80 ([α(1h)(l))]-RT1.Aa). The chimeric [α(1h)(l)]-RT1.Aa cDNA sequence was verified before transfection into Buffalo (BUF; RT1b) hepatoma cells. Interestingly, the helical regions of LEW rats (α(1h)(l)) and Wistar Furth (WF; RTI(u)) rats (α(1h)(u)) share four a.a. (Arg62, Glu63, Gln65, and Gly69). Consequently, subcutaneous administration of [α(1h)(l)]-RT1.Aa transfectants (20x106; 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 [α1(l)]-RTla 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 [α1(l)]-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 [α1(l)]-RT1.Aa (but not RT1.Aa, RT1.A(u), or [α2(l)]-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.
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