Use of allochimeric proteins to mitigate graft-versus-host and host-versus-graft immune responses to rat small bowel allografts

Background. We aimed to identify the polymorphic epitopes that mitigate gra ft-versus-host disease (GVHD) and host-versus-graft response (HvGR) toward rat small bowel allografts in rats. Methods. We tailored class I major histocompatibility complex (MHC) allochi meric antigens encoding 10 alpha1-helical (alpha (1hl)58-80-RT1.A(a)) or 4 (alpha (1hl/u)62-69.RT1.A(a)) polymorphic amino acids. In the GVHD model, A CI (RT1(a)) donors were pretreated (day -14) with an intrathymic injection of (alpha (1hl)58-80-RT1.A(a), alpha (1hl/u)62-69-RT1.A(a), or RT1.A(1) pro tein, with or without simultaneous intravenous injection of anti-T-cell rec eptor R73 monoclonal antibodies. Wistar-Furth (WF; RT1(u)) donors were test ed with a similar protocol. In the HvGR model, ACI recipients were treated with a protocol designed to induce transplantation tolerance toward WF hear t allografts: a portal vein injection of alpha (1hl/u)62-69-RT1.A(a) protei n and cyclosporine (4 mg/kg, intramuscular; days 0-6). Results. GvHD was prevented in all (ACI x LEW) F-1 recipients (ET1(a/l)) by pretreating ACI donors with R73 monoclonal antibody and recipient RT1.A(l) or alpha (1hl)58-80-RT1.A(a) protein. Similarly, pretreatment of WF donors with RT1.A(a) protein also prevented GvHD in (ACI x WF) F-1 recipients. Ho wever, in a combined GvHD/HvGR model, ACI recipient perioperative treatment designed to prevent HvGR only modestly prolonged WF small bowel allograft survival (27.7+/-5.3 days compared to 17.4+/-4.6 days in the cyclosporine-a lone group). In contrast, application of the two protocols significantly pr olonged WF allograft survival (55.6+/-34.6 days), with two of seven recipie nts surviving more than 100 days. Conclusion. Simultaneous inhibition of GVHD and HvGR significantly prolongs small bowel allograft survival.