title: The immunopathology of cardiac xenograft rejection in the guinea pig-to-rat model.
abstract: The mechanisms underlying rejection by rats of vascularized guinea pig xenografts have been controversial. The aim of this study was to define, using sequential immunopathologic analysis, the contributions of xenoreactive antibody, complement, and effector cells to the rejection of guinea pig cardiac xenografts by Lewis rats. In untreated recipients, hyperacute rejection of guinea pig cardiac xenografts occurred in 20 +/- 10.2 min and was characterized by focal endothelial deposition of IgM and by diffuse deposition of C3. IgG was not localized to endothelial surfaces, but was present in the same locations as albumin, suggesting that the accumulation of IgG might reflect nonspecific leakage of plasma proteins from blood vessels. No polymorphonuclear or monocytic infiltrate was observed. Depletion from rats of xenoreactive antibody to undetectable levels prolonged the survival of guinea pig cardiac xenografts, but did not prevent hyperacute rejection; the rejected xenografts contained deposits of C3 along the microvasculature but no deposits of IgM or IgG. No cellular infiltrate was observed. Depletion of complement with cobra venom factor prolonged the survival of xenografts up to 96 hr. Xenograft tissues from complement-depleted animals had diffuse deposits of IgM along the microvasculature, but no detectable deposits of C3 or IgG were noted. Graft tissues obtained at various times after transplantation into complement-depleted animals revealed cellular infiltrates consisting of granulocytes, monocytes, and lymphocytes, but few cells bearing an NK cell phenotype. Our findings are consistent with the concept that complement activation is essential for the hyperacute rejection of discordant xenografts, and that in this particular model complement activation can proceed without the involvement of antibody. However, our findings also suggest that xenoreactive antibody contributes to hyperacute rejection and, along with effector cells, contributes to the later rejection of a xenograft when hyperacute rejection has been averted. Finally, we show that when hyperacute rejection is avoided, a form of vascular rejection occurs in which certain of the pathologic features--i.e., interstitial hemorrhage, interstitial edema, and thrombosis--are very similar to those observed in hyperacute rejection. Whether this form of rejection is a delayed form of the process that leads to hyperacute rejection or a novel pathologic process of graft rejection has yet to be determined.
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis 55455.
authors.forename: J R
authors.initials: JR
authors.lastname: Leventhal
authors.forename: A J
authors.initials: AJ
authors.lastname: Matas
authors.forename: L H
authors.initials: LH
authors.lastname: Sun
authors.forename: S
authors.initials: S
authors.lastname: Reif
authors.forename: R M
authors.initials: RM
authors.lastname: Bolman
authors.forename: A P
authors.initials: AP
authors.lastname: Dalmasso
authors.forename: J L
authors.initials: JL
authors.lastname: Platt
mesh_terms: D000818:Animals; D000906:Antibodies / Q000032:analysis; D003165:Complement System Proteins / Q000032:analysis; D005455:Fluorescent Antibody Technique; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology*; D006146:Guanidines / Q000627:therapeutic use; D006168:Guinea Pigs; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology*; D007075:Immunoglobulin M / Q000097:blood; D007165:Immunosuppression Therapy / Q000379:methods; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D010951:Plasma Exchange; D051381:Rats; D011917:Rats, Inbred Lew; D013156:Splenectomy; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014183:Transplantation, Heterologous / Q000276:immunology / Q000473:pathology*
chemical_list: D000906:Antibodies; D006146:Guanidines; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; D003165:Complement System Proteins; C037258:gusperimus