Induction of Tolerance toward Rat Cardiac Allografts by Treatment with Allochimeric Class I Mhc Antigen and Fty720
Resource
TRANSPLANTATION v.64 n.10 pp.1407-1414
Journal
TRANSPLANTATION
Journal Volume
v.64
Journal Issue
n.10
Pages
1407-1414
Date Issued
1997
Date
1997
Author(s)
CHUEH, SHIH-CHIEH
LING, TIAN
WANG, MIN
WANG, MOU-ER
STEPKOWSKI STANISLAW M
KAHAN BARRY D
Abstract
Background. The combination of FTY720, 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") hart allografts in ACI (RTI.A") recipients. Mehtods. Allochimeric α-1 h1 58-80-RTI.A" proteins were produced by substituting the allogeneic nucleotide sequence encoding 10 aa residues unique to the α1 helical (α1h) region of RTI/A1 Lewis (AsP58, Arg62, Glu 63, Gln65, Lys66, Gly69, Asn70, Asn73, Ser77, and Asn80) for native RTI.Aa residues. The RTI.Au and the RTI.A1 haplotypes share four of these aa ( Arg62, Glu63, Gln65, and Gly69). A baculovirus / Spodoptera frugiperda insect cell system was used to expres theα1h 1 58-80-RTI.Aa proteins. addition of a 3-day oral gavage of 0.05 mg/kg/day FTY720 to a single portal vein injection of 10μgα1 h 1 58-80-RTI.Aa protein induced permanent accentance of WF heart allografts in 16 of 26 ACI recipients (> 100 days); theα1h 1 58-80-RTI. Aa 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 (RTI.An) heart allografts (14.3±2.5 days) compared with FTY720 alone (14.0±2.3 days; NS ). Tolerant ACI recipients hearing 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 (4-10x10 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.