title: Blockade of the CD28 and CD40 pathways result in the acceptance of pig and rat islet xenografts but not rat cardiac grafts in mice.
abstract: Previously, we demonstrated that combination CTLA4-Fc and anti-CD40L mAb treatment results in tolerance to concordant, cellular islet xenografts. The aim of this study was to determine its effectiveness in a model of fetal pig pancreas (FPP) xenotransplantation. Survival of FPP fragment grafts were compared to the survival of rat islet or cardiac xenografts following short term CTLA4-Fc and anti-CD40L mAb treatment. Rat islet and FPP fragment grafts survived long-term. However, rat cardiac grafts were rejected by 52-91 days. Both rat islet and FPP grafts showed similar histology with intact islet structures and adjacent 'nests' of lymphocytes. Concordant vascularised rat hearts showed extensive polymorphonuclear infiltrate, concentric vasculitis and a perivascular infiltrate predominantly of CD8+ T cells. This suggests that this therapy is effective for prolonging islet xenografts and demonstrates that the cellular mechanism of rejection for vascularised and non-vascularised xenografts are different.
authors.affiliation: National Pancreas Transplant Unit, University of Sydney, Westmead Hospital, NSW, Australia.
authors.forename: A M
authors.initials: AM
authors.lastname: Lehnert
authors.forename: P L
authors.initials: PL
authors.lastname: Mottram
authors.forename: W
authors.initials: W
authors.lastname: Han
authors.forename: S N
authors.initials: SN
authors.lastname: Walters
authors.forename: A T
authors.initials: AT
authors.lastname: Patel
authors.forename: W J
authors.initials: WJ
authors.lastname: Hawthorne
authors.forename: P J
authors.initials: PJ
authors.lastname: Cowan
authors.forename: A J
authors.initials: AJ
authors.lastname: d'Apice
authors.forename: P J
authors.initials: PJ
authors.lastname: O'Connell
mesh_terms: D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000627:therapeutic use*; D018106:CD28 Antigens / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand / Q000276:immunology*; D060908:CTLA-4 Antigen; D003331:Coronary Vessels / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000601:surgery; D004353:Drug Evaluation, Preclinical; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology; D016027:Heart Transplantation / Q000276:immunology*; D018796:Immunoconjugates; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008297:Male; D051379:Mice / Q000276:immunology*; D008808:Mice, Inbred CBA; D009206:Myocardium / Q000473:pathology; D009504:Neutrophils / Q000276:immunology; D009928:Organ Specificity; D010179:Pancreas / Q000098:blood supply / Q000196:embryology; D051381:Rats / Q000276:immunology*; D011919:Rats, Inbred Strains; D013045:Species Specificity; D013552:Swine / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014183:Transplantation, Heterologous / Q000276:immunology*; D014657:Vasculitis / Q000209:etiology / Q000276:immunology / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; C556708:Ctla4 protein, rat; D018796:Immunoconjugates; D023201:CD40 Ligand; D000069594:Abatacept