Allochimeric class I MHC molecules prevent chronic rejection and attenuatealloantibody responses

Background. We have shown that treatment with molecularly engineered, alloc himeric [alpha (1) (l/u)(h)]-RT1.A(a) class I MHC antigens bearing donor-ty pe Wistar-Furth (WF, RT1.A(u)) amino acid substitutions for host-type ACI ( RT1.A(a)) sequences in the alpha -helical region induces donor-specific tol erance to cardiac allografts in rat recipients. This study examined the eff ect of allochimeric molecules on the development of chronic rejection. Methods. Allochimeric [(l/u)(alpha1 h)]RT1.A(a) class I MHC antigenic extra cts (1 mg) were administered via the portal vein into ACI recipients of WF hearts on the day of transplantation in conjunction with subtherapeutic ora l cyclosporine (CsA, 10 mg/kg/day, days 0-2). Control groups included recip ients 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 archi tectural disorganization, ventricular fibrosis, intimal hyperplasia, and pr ogressive luminal narrowing. In contrast, WF hearts in rats treated with [a lpha (1 h) (l/u)]-RT1.A(a) molecules revealed only mild perivascular fibros is, minimal intimal thickening, and preserved myocardial architecture. Allo antibody analysis demonstrated no IgM alloantibodies in all groups. An atte nuated, but detectable, anti-WF IgG response was present in recipients rece iving allochimeric molecules, with IgG1 and IgG2a subclasses predominating. Immunohistochemical analysis of allografts demonstrated minimal T cell inf iltration and IgG binding to vascular endothelium. Conclusion. Treatment with allochimeric molecules prevents the development of chronic rejection. Such effect may be in part caused by deviation of hos t alloantibody responses.