INDUCTION OF TRANSPLNATATION TOLERANCE BY CHIMERIC DONOR/RECIPIENT CLASS I RT1.AA MOLECULES1,2

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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.AacDNA molecules by substituting nucleotides in the α1helical region that encode 10 Lewis (LEW; RT1.A1) a.a., namely Asp58, Arg62, Glu63, Gln65, Lys66, Gly69, Asn70, Asn73, Ser77, and Asn80([α1h1]-RT1.Aa). The chimeric[α1h1]-RT1.AacDNAsequence was verified before transfection into Buffalo (BUF; RT1b) hepatoma cells. Interestingly, the helical regions of LEW rats (α1h1) and Wistar Furth (WF; RT1u) rats(α1hu) share four a.a.(Arg62, Glu63, Gln65, and Gly69). Consequently, subcutaneous administration of[α11]-RT1.Aatransfectants (20×106; 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; PPa) rats with[α11]-RT1.Aatransfectants (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;P11]-RT1.Aatransfectants (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 (P11]-RT1.Aa(but not RT1.Aa, RT1.Au, or[α21]-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.