title: Induction of tolerance toward rat cardiac allografts by treatment with allochimeric class I MHC antigen and FTY720.
abstract: 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.Au) heart allografts in ACI (RT1.Aa) recipients.
  
  
  METHODS
  Allochimeric alpha(1h)l58-80-RT1.Aa proteins were produced by substituting the allogeneic nucleotide sequence encoding 10 aa residues unique to the alpha1 helical (alpha1h) region of RT1.Al Lewis (Asp58, Arg62, Glu63, Gln65, Lys66, Gly69, Asn70, Asn73, Ser77, and Asn80) for native RT1.Aa residues. The RT1.Au and the RT1.Al haplotypes share four of these aa (Arg62, Glu63, Gln65, and Gly69). A baculovirus/Spodoptera frugiperda insect cell system was used to express the alpha(1h)l58-80-RT1.Aa 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 microg alpha(1h)l58-80-RT1.Aa protein induced permanent acceptance of WF heart allografts in 16 of 26 ACI recipients (>100 days); the alpha(1h)l58-80-RT1.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 (RT1.An) 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 x 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.
authors.affiliation: Department of Surgery, The University of Texas Medical School at Houston, 77030, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Chueh
authors.forename: L
authors.initials: L
authors.lastname: Tian
authors.forename: M
authors.initials: M
authors.lastname: Wang
authors.forename: M E
authors.initials: ME
authors.lastname: Wang
authors.forename: S M
authors.initials: SM
authors.lastname: Stepkowski
authors.forename: B D
authors.initials: BD
authors.lastname: Kahan
mesh_terms: D000818:Animals; D000939:Epitopes; D000068876:Fingolimod Hydrochloride; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000627:therapeutic use*; D007108:Immune Tolerance / Q000187:drug effects; D007116:Immunization, Passive; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000494:pharmacology; D008297:Male; D011409:Propylene Glycols / Q000627:therapeutic use*; D051381:Rats; D011912:Rats, Inbred ACI; D011914:Rats, Inbred BN; D011920:Rats, Inbred WF; D013110:Sphingosine / Q000031:analogs & derivatives; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine