Induction of transplantation tolerance by chimeric donor/recipient class I RT1.A(A) molecules

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.A(a) cDNA molecules by substituting nucleotides in the alpha(1) helical region that encode 10 Lewis (LEW; RT1.A(1)) a,a., namely Asp(58), Arg(62), Glu(63), Gln(65), Lys(66), Gly(69), Asn(70), Asn(73), Ser(77), and Asn(80) ([alpha(1h)(1)]-RT1.A(a)). The chimeric [alpha(1h)(1)]-RT1.A(a) cDNA sequence was verified before transfection into Buffalo (BUF; RT1(b)) hepatoma cells, Interestingly, the helical regions of LEW rats (alpha(1h)(1)) and Wistar Furth (WF; RT1(u)) rats (alpha(1h)(u)) share four a.a. (Arg(62), Glu(63), Gln(63), and Gln(65)). Consequently, subcutaneous administration of [alpha(1)(1)] -RT1.A(a) transfectants (20 x 10(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 (RT1(a)) rats with [alpha(1)(1)]-RT1.A(a) 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 [alpha(1)(1)]-RT1.A(a) 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 [alpha(1)(1)]-RT1.A(a) (but not RT1.A(a), RT1.A(u), or [alpha(1)(1)]-RT1.A(a)) antigens in conjunction with brief oral gavage treatment with cyclosporine, Thus, selected donor immunogenic a.a. (Arg(62), Glu(63), Gln(65), and Gly(69)) of class I MHC antigens become tolerogenic when flanked by host sequences.