Evidence that 15-deoxyspergualin inhibits natural antibody production but fails to prevent hyperacute rejection in a discordant xenograft model.
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.
Leventhal
J R
JR
Department of Surgery, University of Minnesota, Minneapolis 55455.
Flores
H C
HC
Gruber
S A
SA
Figueroa
J
J
Platt
J L
JL
Manivel
J C
JC
Bach
F H
FH
Matas
A J
AJ
Bolman
R M
RM
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
D006146:Guanidines; D007166:Immunosuppressive Agents; C037258:gusperimus