Allochimeric class I MHC molecules prevent chronic rejection and attenuate alloantibody responses

Jennifer S. Singer, Anna Mhoyan, Michael C. Fishbein, Xiu Da Shen, Feng Gao, Danyun Zhao, Ana J. Coito, Brian L. Reemtsen, Farin Amersi, Ronald W. Busuttil, Jerzy W. Kupiec-Weglinski, Rafik M. Ghobrial

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Background. We have shown that treatment with molecularly engineered, allochimeric [α1 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 α1-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 [α1 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 [α1 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. Conclusion. Treatment with allochimeric molecules prevents the development of chronic rejection. Such effect may be in part caused by deviation of host alloantibody responses.

Original languageEnglish (US)
Pages (from-to)1408-1416
Number of pages9
JournalTransplantation
Volume72
Issue number8
DOIs
StatePublished - Oct 27 2001

ASJC Scopus subject areas

  • Transplantation

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