Blockade of both CD28/B7 and OX40/OX40L co-stimulatory signal pathways prolongs the survival of islet xenografts.
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.
Wang
G M
GM
Department of Immunology, Peking University Health Science Center, Beijing, People's Republic of China.
Yang
Y
Y
Jin
Y Z
YZ
Li
A L
AL
Hao
J
J
Gao
X
X
Xie
S S
SS
D000818:Animals; D000943:Antigens, Differentiation / Q000032:analysis*; D018122:B7-1 Antigen / Q000032:analysis*; D018106:CD28 Antigens / Q000032:analysis*; D006085:Graft Survival / Q000276:immunology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000032:analysis*; D051379:Mice; D008807:Mice, Inbred BALB C; D051381:Rats; D011917:Rats, Inbred Lew; D014183:Transplantation, Heterologous / Q000276:immunology*; D048069:Tumor Necrosis Factors / Q000032:analysis*
D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D008562:Membrane Glycoproteins; C406562:OX40Ig; C504587:Tnfsf4 protein, rat; D048069:Tumor Necrosis Factors