title: Allochimeric class I MHC molecules prevent chronic rejection and attenuate alloantibody responses.
abstract: BACKGROUND
  We have shown that treatment with molecularly engineered, allochimeric [alpha1 hl/u]-RT1.Aa class I MHC antigens bearing donor-type Wistar-Furth (WF, RT1.Au) amino acid substitutions for host-type ACI (RTI.Aa) sequences in the alpha1-helical region induces donor-specific tolerance to cardiac allografts in rat recipients. This study examined the effect of allochimeric molecules on the development of chronic rejection.
  
  
  METHODS
  Allochimeric [alpha1 hl/u]-RT1.Aa class I MHC antigenic extracts (1 mg) were administered via the portal vein into ACI recipients of WF hearts on the day of transplantation in conjunction with subtherapeutic oral cyclosporine (CsA, 10 mg/kg/day, days 0-2). Control groups included recipients of syngeneic grafts and ACI recipients of WF heart allografts treated with high-dose CsA (10 mg/kg/day, days 0-6).
  
  
  RESULTS
  WF hearts in ACI rats receiving 7 days of CsA exhibited myocardial fibrosis, perivascular inflammation, and intimal hyperplasia at day 80. At day 120, these grafts displayed severe chronic rejection with global architectural disorganization, ventricular fibrosis, intimal hyperplasia, and progressive luminal narrowing. In contrast, WF hearts in rats treated with [alpha1 hl/u]-RT1.Aa molecules revealed only mild perivascular fibrosis, minimal intimal thickening, and preserved myocardial architecture. Alloantibody analysis demonstrated no IgM alloantibodies in all groups. An attenuated, but detectable, anti-WF IgG response was present in recipients receiving allochimeric molecules, with IgG1 and IgG2a subclasses predominating. Immunohistochemical analysis of allografts demonstrated minimal T cell infiltration and IgG binding to vascular endothelium.
  
  
  CONCLUSIONS
  Treatment with allochimeric molecules prevents the development of chronic rejection. Such effect may be in part caused by deviation of host alloantibody responses.
authors.affiliation: UCLA School of Medicine, Dumont-UCLA Transplant Center, Los Angeles, CA 90095-7054, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Singer
authors.forename: A
authors.initials: A
authors.lastname: Mhoyan
authors.forename: M C
authors.initials: MC
authors.lastname: Fishbein
authors.forename: X D
authors.initials: XD
authors.lastname: Shen
authors.forename: F
authors.initials: F
authors.lastname: Gao
authors.forename: D
authors.initials: D
authors.lastname: Zhao
authors.forename: A J
authors.initials: AJ
authors.lastname: Coito
authors.forename: B L
authors.initials: BL
authors.lastname: Reemtsen
authors.forename: F
authors.initials: F
authors.lastname: Amersi
authors.forename: R W
authors.initials: RW
authors.lastname: Busuttil
authors.forename: J W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
authors.forename: R M
authors.initials: RM
authors.lastname: Ghobrial
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002908:Chronic Disease; D016572:Cyclosporine / Q000494:pharmacology; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology*; D006649:Histocompatibility Antigens / Q000276:immunology*; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000145:classification; D007150:Immunohistochemistry; D007518:Isoantibodies / Q000096:biosynthesis*; D008297:Male; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D051381:Rats; D011912:Rats, Inbred ACI; D011920:Rats, Inbred WF; D011993:Recombinant Fusion Proteins / Q000276:immunology*
chemical_list: D006649:Histocompatibility Antigens; D007074:Immunoglobulin G; D007518:Isoantibodies; D011993:Recombinant Fusion Proteins; C038353:histocompatibility antigens RT, rat; D016572:Cyclosporine