title: Key role of the alternate complement pathway in hyperacute rejection of rat hearts transplanted into fetal sheep.
abstract: Hyperacute rejection (HAR) mediated by xenoreactive natural antibodies (XNA), which are thought to develop in early infancy, is a major impediment to transplantation between widely disparate species. The ability to diagnose certain forms of congenital heart defects early in prenatal life suggests the potential for these defects to be corrected by cardiac transplantation, prior to the development of XNA and host immunocompetence. This study investigated whether discordant cardiac xenotransplantation into fetal and neonatal recipients might obviate HAR due to the relative lack of XNA. Six neonatal lambs at 3 days (n=3) or 7 days (n=3) of life, and two fetal lambs at 125 and 142 days of gestation (term = 145 days) received cardiac grafts from adult Wistar-Furth (275-350 g) rats. All eight cardiac xenografts showed clinical evidence of HAR, with rapid swelling, loss of contractility, and ecchymosis and a mean survival time of 12.5 +/- 6.4 min. Sections of explanted grafts showed classical histologic features of HAR, including interstitial hemorrhages, platelet microthrombi, and edema, without leukocyte infiltration. Immunopathology of grafts harvested from fetal recipients showed a lack of significant intragraft deposition of sheep IgM, IgG, or C1q, but widespread endothelial labeling for C3, factor B, and properdin. In contrast, grafts in neonatal recipients showed IgM, IgG, and C1q deposition, as well as C3, factor B, properdin, and terminal complement (C) components. Fibrin deposition and platelet thrombi were seen in both groups of recipients. Injection of cobra venom factor resulted in prolongation of cardiac xenograft survival in neonatal lambs (n=3) to 12 hr. Analysis by immunohistology showed that normal sera from neonatal and adult, but not fetal, sheep contained IgM and IgG XNA reactive with rat cells. In conclusion, rodent grafts transplanted into fetal sheep undergo HAR, likely through direct activation of the alternate pathway of C, whereas neonatal lambs acquire XNA in the very early postnatal period and reject rat hearts through activation of both the classical and alternate pathways of C. Thus, at least in some species combinations, cardiac transplantation during the early postnatal period, or even in utero, may still be subject to development of HAR.
authors.affiliation: Division of Cardiothoracic Surgery, University of California, San Francisco 94143, USA.
authors.forename: H A
authors.initials: HA
authors.lastname: Rajasinghe
authors.forename: V M
authors.initials: VM
authors.lastname: Reddy
authors.forename: W W
authors.initials: WW
authors.lastname: Hancock
authors.forename: M H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: F L
authors.initials: FL
authors.lastname: Hanley
mesh_terms: D000208:Acute Disease; D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000276:immunology; D003167:Complement Activation; D003170:Complement Pathway, Alternative / Q000502:physiology*; D003171:Complement Pathway, Classical; D006084:Graft Rejection / Q000473:pathology; D006085:Graft Survival; D016027:Heart Transplantation; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000032:analysis; D007075:Immunoglobulin M / Q000032:analysis; D051381:Rats; D011920:Rats, Inbred WF; D012756:Sheep / Q000196:embryology; D014183:Transplantation, Heterologous
chemical_list: D000906:Antibodies; D007074:Immunoglobulin G; D007075:Immunoglobulin M