title: Evidence that 15-deoxyspergualin inhibits natural antibody production but fails to prevent hyperacute rejection in a discordant xenograft model.
abstract: Preventing hyperacute rejection (HAR) is a difficult and unsolved problem in xenotransplantation. This may be due, in part, to a lack of therapies that can suppress production of natural antibodies (NA), which are thought to be critical mediators of HAR. This study examined the effect of 15-deoxyspergualin (DSPG) and splenectomy (Spx) on NA production and return of NA after plasma exchange (PE) in a discordant species combination (strain 2 guinea pig to Lewis rat). A dose of 5 mg/kg/day DSPG + Spx significantly reduced Lewis rat anti-guinea pig NA titer after one week of therapy. Antibody titer was not significantly reduced in rats treated with splenectomy alone. PE alone acutely depleted NA titers; however, complete rebound was seen in 48 hr. When PE was performed in rats treated with DSPG + Spx, an additional significant NA reduction occurred; no rebound 24-48 hr after PE was seen. Except for a 20% reduction in body weight, no serious complications occurred in DSPG + Spx recipients. Despite a profound NA titer reduction, treatment with DSPG, Spx, and PE did not prolong guinea pig cardiac xenograft survival in a clinically significant fashion. Immunopathological study of rejected cardiac xenografts revealed no antibody deposition but persistent complement deposition on vascular endothelium. We conclude that DSPG + Spx effectively inhibits synthesis of rat anti-guinea pig NA, that further NA titer reduction can be achieved with the addition of PE, and that DSPG + Spx prevents post-PE antibody rebound. We also conclude that the limited prolongation in cardiac xenograft survival achieved, despite marked suppression of NA, supports a complement-mediated mechanism of HAR in our animal model.
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis 55455.
authors.forename: J R
authors.initials: JR
authors.lastname: Leventhal
authors.forename: H C
authors.initials: HC
authors.lastname: Flores
authors.forename: S A
authors.initials: SA
authors.lastname: Gruber
authors.forename: J
authors.initials: J
authors.lastname: Figueroa
authors.forename: J L
authors.initials: JL
authors.lastname: Platt
authors.forename: J C
authors.initials: JC
authors.lastname: Manivel
authors.forename: F H
authors.initials: FH
authors.lastname: Bach
authors.forename: A J
authors.initials: AJ
authors.lastname: Matas
authors.forename: R M
authors.initials: RM
authors.lastname: Bolman
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000187:drug effects*; D001792:Blood Platelets / Q000276:immunology; D006084:Graft Rejection / Q000187:drug effects*; D006085:Graft Survival / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology*; D016027:Heart Transplantation; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D051381:Rats; D011917:Rats, Inbred Lew; D013156:Splenectomy; D014183:Transplantation, Heterologous
chemical_list: D006146:Guanidines; D007166:Immunosuppressive Agents; C037258:gusperimus