title: Evidence that rapamycin rescue therapy delays rejection of major (MHC) plus minor (non-MHC) histoincompatible heart allografts in rats.
abstract: The capacity of delayed onset of rapamycin (RAPA) therapy to block process of destruction was examined in rats undergoing heart allograft rejection. Untreated Wistar Furth (WFu; RT-1u) recipients reject Buffalo (BUF; RT-1b) heart allograft with a mean survival time (MST) of 6.5 +/- 0.5 days. A 14-day i.v.infusion of 0.8 mg/kg RAPA begun on the day of transplantation prolonged the survival to 74.1 +/- 20.2 days (P < 0.001), 0.2 mg/kg to 32.2 +/- 10.0 days (P < 0.001), and 0.08 mg/kg to 36.4 +/- 11.8 days (P < 0.001). When RAPA therapy (0.8 mg/kg) was begun 3 or 4 days after transplantation, the grafts survived 85.2 +/- 31.1 (P < 0.001), and 70.2 +/- 43.3 (P < 0.005) days, respectively. Therapy initiated on day 5 was much less effective; most transplants were rejected within 10 days; one graft survived 32 and two grafts 60 days (MST = 17.6 +/- 20.0, NS). A 0.2 mg/kg RAPA dose prolonged graft survival with initial use on days 3 (31.6 +/- 12.2 days; P < 0.001) or 4 (31.4 +/- 8.1 days; P < 0.001) but not on day 5. The 0.08 mg/kg RAPA prolonged hearts only when started on day 3 (47.2 +/- 2.7 days; P < 0.001) but not on days 4 or 5. WFu recipients treated with a subtherapeutic dose of cyclosporine (1 mg/kg; 9.1 +/- 1.5 days) displayed prolonged heart allograft function when treated subsequently with RAPA (0.8 or 0.08) beginning from days 4, 5, or 6 postgrafting. These in vivo results are supported by in vitro experiments. The frequency of BUF alloreactive elements among normal WFu LN cells (fTc) was 337 +/- 139/10(6) T cells in limiting dilution assay. Addition of RAPA (1 muMol) at the beginning of culture significantly reduced (P < 0.025) the fTc to 17 +/- 6.6/10(6), or alternatively on days 4 or 6 to 37.3 +/- 20.0/10(6) and 58.6 +/- 21.8/10(6), respectively. Thus, both in vivo and in vitro data demonstrate that delayed RAPA therapy may interrupt alloimmune reactions.
authors.affiliation: Department of Surgery, University of Texas Medical School, Houston 77030.
authors.forename: M E
authors.initials: ME
authors.lastname: Wang
authors.forename: S M
authors.initials: SM
authors.lastname: Stepkowski
authors.forename: M
authors.initials: M
authors.lastname: Ferraresso
authors.forename: B D
authors.initials: BD
authors.lastname: Kahan
mesh_terms: D000818:Animals; D016572:Cyclosporine / Q000627:therapeutic use; D006084:Graft Rejection / Q000188:drug therapy; D016027:Heart Transplantation / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008285:Major Histocompatibility Complex; D008297:Male; D008912:Minor Histocompatibility Loci; D011090:Polyenes / Q000627:therapeutic use*; D051381:Rats; D011915:Rats, Inbred BUF; D011920:Rats, Inbred WF; D016879:Salvage Therapy; D020123:Sirolimus; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D007166:Immunosuppressive Agents; D011090:Polyenes; D016572:Cyclosporine; D020123:Sirolimus