Use of Genetically Modified Allograft to Deliver Local Immunomodulatory Molecule with Minimal Systemic Toxicity in a Rat Model of Allogeneic Skin Flap Transplantation

• Published in: Transplantation proceedings 2010-11, Vol.42 (9), p.3815-3819
• Main Authors: Fu, S, Yang, Y, Xiao, B, Li, Y, Yi, C.G, Xia, W, Guo, S.Z
• Format: Article
• Language: English
• Subjects: Acute Disease; Adenoviridae - genetics; Animals; Antigens, Differentiation - biosynthesis; Antigens, Differentiation - genetics; Biological and medical sciences; Combined Modality Therapy; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Genetic Therapy; Genetic Vectors; Graft Rejection - genetics; Graft Rejection - immunology; Graft Rejection - pathology; Graft Rejection - prevention & control; Graft Survival - drug effects; Immunosuppression - methods; Immunosuppressive Agents - pharmacology; Medical sciences; Membrane Glycoproteins - antagonists & inhibitors; Models, Animal; Rats; Rats, Inbred BN; Rats, Inbred Lew; Sirolimus - pharmacology; Skin Transplantation - adverse effects; Surgery; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Surgical Flaps - adverse effects; Time Factors; Tissue, organ and graft immunology; Transplantation, Homologous; Tumor Necrosis Factors - antagonists & inhibitors
• ISSN: 0041-1345; 1873-2623
• DOI: 10.1016/j.transproceed.2010.08.040

Abstract The effects of OX40-OX40 ligand (OX40L) costimulatory pathway blockade to prevent T-cell-mediated acute rejection were investigated in a rat model of allogeneic superficial inferior epigastric artery flap transplantation. An ex vivo gene transfer technique was used to modify allografts to locally deliver an immunomodulatory molecule. The flaps were separated from donors, perfused with an adenoviral vector expressing the OX40 immunoglobulin (AdOX40Ig) for 1 hour, and incubated at 37°C for 2 hours. Before transplantation, the flaps were flushed with phosphate-buffered saline solution to remove unincorporated viral particles. Recipients were randomly divided into 5 groups, and treated with topical OX40Ig gene transfer, a single low dose of rapamycin alone, or a combination of agents. Graft survival was assessed using histopathologic classification of skin rejection. All animals in the untreated group (n = 9) or the group treated with adenovirus expressing green fluorescence protein (n = 9) developed grade 3 clinical rejection by postoperative day 7. No significant difference was observed in graft survival between the locally treated AdOX40Ig groups (mean [SD], 8.1 [0.7] days) and the untreated groups (7.7 [1.2] days) could be observed ( P > .05, t test). Graft survival in the locally treated AdOX40Ig groups was extended to 18.7 (1.2) days when transduction was combined with a low dose of rapamycin, a significant improvement over survival with rapamycin treatment alone (13.2 [0.6] days) ( P < .01). These results demonstrated that local immunomodulation by the allograft itself and low-dose rapamycin treatment promote graft acceptance. This protocol may enable reduction of the dosage of immunosuppressive drugs needed for successful inhibition of acute rejection in the early postoperative period.