Background.

The combination of FTY 720, a novel immunosuppressant, and allochimeric class I MHC proteins bearing donor-type amino acid (aa) epitope substitutions for host-type sequences induces tolerance of Wistar Furth (WF; RT1. A u) heart allografts in ACI (RT1. A u) recipients.

Methods.

Allochimeric α 1 h 1 58-80-RT1. A a proteins were produced by substituting the allogeneic nucleotide sequence encoding 10 aa residues unique to the α 1 helical (α 1h) region of RT1. A 1 Lewis (Asp 58, Arg 62, Glu 63, Gln 65, Lys 66, Gly 69, Asn 70, Asn 73, Ser 77, and Asn 80) for native RT1. A a residues. The RT1. A u and the RT1. A 1 haplotypes share four of these aa (Arg 62, Glu 63, Gln 65, and Gly 69). A baculovirus/Spodoptera frugiperda insect cell system was used to express theα 1h 1 58-80-RT1. A a proteins.

Results.

The addition of a 3-day oral gavage of 0.05 mg/kg/day FTY720 to a single portal vein injection of 10 μgα 1h 1 58-80-RT1. A a protein induced permanent acceptance of WF heart allografts in 16 of 26 ACI recipients (> 100 days); theα 1h 1 58-80-RT1. A a protein alone only modestly prolonged WF heart survival (13.8±0.8 days). The same tolerogenic protocol did not prolong the survival of third-party Brown Norway (RT1. A n) heart allografts (14.3±2.5 days) compared with FTY720 alone (14.0±2.3 days; NS). Tolerant ACI recipients bearing primary WF heart allografts for more than 100 days accepted second WF hearts, but promptly rejected third-party Brown Norway heart grafts (9.3±1.5 days). The tolerant state was transferred to irradiated ACI rats (400 rad) with either purified T cells (4-10× 10 7) or serum (1-2 ml) from tolerant hosts, and was not broken by daily intraperitoneal injections of interleukin-2 (1000 U/day; 7 days).

Conclusions.

The combination of allochimeric protein with FTY720 induces transplantation tolerance, a state that may be associated with the appearance of donor-specific regulatory factors.