Abstract
249 The aim of this work was to study whether soluble donor class I antigens induce tolerance. Recombinant soluble RT1.A1 (Lew) and RT1.Aa (DA) rat class I molecules were expressed in the rat myeloma cell line Y3-Ag. Conformational folding of the recombinant proteins and association with β2-microglobuline were verified by imunoprecipitation experiments. Soluble MHC class I molecules were estimated by a newly established semiquantitative ELISA specific for recombinant MHC class I molecules. As determined by SDS-gelelectrophoresis and western blotting, the recombinant class I heavy chains had a molecular weight of 39 kDa, respectively. To test the efficacy of recombinant MHC to modulate graft survival, 8 weeks old DA (RT1.Aa) rats were treated by intraperitoneal injection of soluble RT1.A1. DA rats were heterotopically transplanted Lewis cardiac allografts and injected a single subtherapeutic dosis of 20 mg/kg Cyclosporin A (CsA), that allows graft rejection by day 14. 40% of these animals indefinitely accepted Lewis allografts as compared to animals that received CsA only, which acutely rejected. The immunosuppression was donor-specific, since DA-recipients treated with soluble syngeneic antigen rejected Lewis heart allografts in normal fashion after 13 days. The number of graft infiltrating cells in tolerated allografts was remarkably reduced compared to acutely rejected allografts. These cells were predominantly CD4+. To test the robustness of graft acceptance, syngeneic, allogeneic and third party (CAP, RT1.Ac) skin grafts were transplanted. Third party allografts were acutely rejected (11 d) but donor type were lost by delayed rejection (19 d). Thus, these data demonstrate for the first time the potency of donor-derived soluble MHC molecules to modulate graft survival. Further, they define soluble MHC molecules as a new therapeutic modality. This work was partially supported by the Novartis Therapeutische Stiftung, Nürnberg and the Volkswagen Foundation, Wolfsburg.
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