Blockade of Both CD28/B7 and OX40/OX40L Co-Stimulatory Signal Pathways Prolongs the Survival of Islet Xenografts

• DOI: 10.1016/j.transproceed.2005.10.117
• Publication Date: 2005-12-29T07:13:10Z
• Authors: G.M. Wang; Y. Yang; Y.Z. Jin; A.L. Li; J. Hao; X. Gao; S.S. Xie
• Keywords: 0301 basic medicine; Mice, Inbred BALB C; Membrane Glycoproteins; Graft Survival; Transplantation, Heterologous; Islets of Langerhans Transplantation; Antigens, Differentiation; Rats; 3. Good health; Mice; 03 medical and health sciences; 0302 clinical medicine; CD28 Antigens; Rats, Inbred Lew; Tumor Necrosis Factors; B7-1 Antigen; Animals

CTLA4Ig, a recombinant fusion protein composed of the extracellular domain of human CTLA4 and the constant region of human IgG1, inhibits the interaction of CD28/B7 pathway by binding the B7 molecule. OX40Ig, a recombinant fusion protein composed of the extracellular domain of human OX40 and the constant region of human IgG1, abrogates the interaction of OX40/OX40L pathway by binding the OX40L on APCs. So blockade of CD28/B7 or OX40/OX40L co-stimulatory pathways alone in mice with CTLA4Ig or OX40Ig can result in finitely prolonging the survival of islet grafts (43.2 +/- 4.81 and 67.7 +/- 7.74 days, respectively). In this study, a novel replication-defective adenovirus containing both of the CTLA4Ig and OX40Ig genes, AdCTLA4Ig-IRES-OX40Ig, was constructed by homologous recombination and injected into the streptozocin-rendered diabetic BalB/c mouse recipients (H-2d) through the tail vein, at the same day, the freshly isolated islets from Lewis rats (RT-1) were transplanted under the left kidney capsule of the recipients. The results showed that the mean survival time of the islet xenografts in the AdCTLA4Ig-IRES-OX40Ig-treated diabetic mice was significantly prolonged (100.3 +/- 14.94 days), while those in the untreated or AdEGFP-treated mice were rejected in normal fashion (6.7 +/- 0.94 and 7.0 +/- 1.0 days, respectively). In conclusion, utilizing AdCTLA4Ig-IRES-OX40Ig in vivo which can simultaneously express CTLA4Ig and OX40Ig proteins can improve the survival of Lewis-->BalB/c islet xenografts.