title: Resistance of established porcine islet xenografts to humoral rejection by hyperimmune sera.
abstract: BACKGROUND
  Although preformed natural antibodies cause hyperacute rejection of primarily vascularized xenografts, tissue grafts such as skin or islets are revascularized by in-growth of host capillaries and therefore might be resistant to circulating antibodies. We examined the effect of hyperimmune serum and primed T cells on the survival of long-term porcine islet xenografts in diabetic nude mice.
  
  
  METHODS
  Porcine islets were transplanted beneath the kidney capsule of streptozotocin-induced diabetic BALB/c athymic mice. Hyperimmune serum and sensitized splenocytes were prepared by repeated immunization of BALB/c mice with porcine lymph node cells. Splenic T cells were enriched by nylon wool column separation. Tissues were examined by immunohistology using murine- and porcine-specific monoclonal antibodies.
  
  
  RESULTS
  Porcine islets survived in nude mice for > 100 days with high levels of circulating porcine C-peptide and maintenance of normoglycemia. Injection of the hyperimmune sera (IgG) into normoglycemic nude mice bearing porcine islets for > 70 days failed to induce rejection despite the continued presence of circulating anti-porcine cytotoxic antibody. Injection of sensitized T cells caused acute rejection of long-term (>140 days) porcine islets, whereas injection of naive T cells had no effect. Histologically, porcine islets removed from mice treated with hyperimmune serum showed no staining for IgG. Long-surviving porcine islet grafts showed strong staining for interleukin (IL)-10 and a lesser amount of IL-4 but no staining for IL-2 or interferon-gamma. Although fresh porcine islets were positive for swine leukocyte antigen class 1 antigen and intercellular adhesion molecule (ICAM)-1 but negative for mouse platelet endothelial cell adhesion molecule and ICAM-2, long-surviving porcine islets showed positive endothelial staining for mouse platelet endothelial cell adhesion molecule and ICAM-2.
  
  
  CONCLUSIONS
  Established islet xenografts are resistant to hyperimmune serum as a result of a lack of target endothelial antigens, whereas they remain susceptible to rejection caused by primed T cells. Local production of Th2 cytokines may explain the inability of long-surviving islet xenografts to activate injected naive T cells.
authors.affiliation: Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: W A
authors.initials: WA
authors.lastname: Gourlay
authors.forename: J J
authors.initials: JJ
authors.lastname: O'Neil
authors.forename: W W
authors.initials: WW
authors.lastname: Hancock
authors.forename: A P
authors.initials: AP
authors.lastname: Monaco
authors.forename: T
authors.initials: T
authors.lastname: Maki
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D002096:C-Peptide / Q000097:blood; D003602:Cytotoxicity, Immunologic; D004229:Dithiothreitol / Q000494:pharmacology; D004351:Drug Resistance; D006084:Graft Rejection / Q000276:immunology; D007106:Immune Sera / Q000494:pharmacology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D013552:Swine; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014183:Transplantation, Heterologous / Q000276:immunology*
chemical_list: D002096:C-Peptide; D007106:Immune Sera; D004229:Dithiothreitol